Fungicide sensitivity of Alternaria spp. causing Alternaria leaf spot on sugarbeet in Michigan

USDA-ARS?s Scientific Manuscript database

Alternaria leaf spot (ALS), caused by Alternaria spp., can occur wherever sugarbeet is grown. Infection by Alternaria spp. and disease management has historically been considered a minor issue in sugarbeet production in the US. Recently, increased incidence and severity of ALS has been observed in M...

Influence of polyunsaturated fatty acid supplementation and membrane fluidity on ozone and nitrogen dioxide sensitivity of rat alveolar macrophages

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rietjens, I.M.; van Tilburg, C.A.; Coenen, T.M.

1987-01-01

The phospholipid polyunsaturated fatty acid (PUFA) content and the membrane fluidity of rat alveolar macrophages were modified dose-dependently and in different ways. This was done to study the importance of both membrane characteristics for the cellular sensitivity toward ozone and nitrogen dioxide. Cells preincubated with arachidonic acid (20:4) complexed to bovine serum albumin (BSA) demonstrated an increased in vitro sensitivity versus ozone and nitrogen dioxide. The phenomenon was only observed at the highest 20:4 concentrations tested, whereas the membrane fluidity of the 20:4-treated cells already showed a maximum increase at lower preincubation concentrations. Hence it could be concluded that themore » increased ozone and nitrogen dioxide sensitivity of PUFA-enriched cells is not caused by their increased membrane fluidity, resulting in an increased accessibility of sensitive cellular fatty acid moieties or amino acid residues. This conclusion receives further support from other observations. These results strongly support the involvement of lipid oxidation in the mechanism(s) of toxic action of both ozone and nitrogen dioxide in an intact cell system.« less

PI3K/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice

PubMed Central

Nishida, Hidenori; Sohara, Eisei; Nomura, Naohiro; Chiga, Motoko; Alessi, Dario R; Rai, Tatemitsu; Sasaki, Sei; Uchida, Shinichi

2013-01-01

Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter phosphorylation cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC phosphorylation is regulated by the PI3K/Akt signaling cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome. PMID:22949526

Reduction of PTP1B induces differential expression of PI3-kinase (p85alpha) isoforms.

PubMed

Rondinone, Cristina M; Clampit, Jill; Gum, Rebecca J; Zinker, Bradley A; Jirousek, Michael R; Trevillyan, James M

2004-10-15

Protein tyrosine phosphatase 1B (PTP1B) inhibition increases insulin sensitivity and normalizes blood glucose levels in animals. The molecular events associated with PTP1B inhibition that increase insulin sensitivity remain controversial. Insulin resistant, diabetic ob/ob mice, dosed with PTP1B antisense for 3 weeks exhibited a decrease in PTP1B protein levels and a change in the expression level of p85alpha isoforms in liver, characterized by a reduction in p85alpha and an upregulation of the p50alpha and p55alpha isoforms. Transfection of mouse hepatocytes with PTP1B antisense caused a downregulation PTP1B and p85alpha protein levels. Furthermore, transfection of mouse hepatocytes with PTP1B siRNA downregulated p85alpha protein expression and enhanced insulin-induced PKB phosphorylation. Treatment of mouse hepatocytes with p85alpha antisense oligonucleotide caused a reduction of p85alpha and an increase in p50alpha and p55alpha isoforms and enhanced insulin-stimulated PKB activation. These results demonstrate that PTP1B inhibition causes a direct differential regulation of p85alpha isoforms of PI3-kinase in liver and that reduction of p85alpha may be one mechanism by which PTP1B inhibition improves insulin sensitivity and glucose metabolism in insulin-resistant states. Copyright 2004 Elsevier Inc.

Sensitizing and Eliciting Capacity of Egg White Proteins in BALB/c Mice As Affected by Processing.

PubMed

Pablos-Tanarro, Alba; Lozano-Ojalvo, Daniel; Martínez-Blanco, Mónica; López-Fandiño, Rosina; Molina, Elena

2017-06-07

This study assesses to what extent technological processes that lead to different degrees of denaturation of egg white proteins affect their allergenicity. We focused on heat (80 °C, 10 min) and high-pressure (400 MPa and 37 °C, 10 min) treatments and used a BALB/c mouse model of food allergy. Oral sensitization to egg white using cholera toxin as adjuvant induced the production of IgE and IgG1 isotypes and led to severe clinical signs following challenge with the allergen. Extensive protein denaturation caused by heat treatment increased its ability to induce Th1 responses and reduced both its sensitizing and eliciting capacity. Heated egg white stimulated the production of IgE over IgG1 antibodies directed, at least in part, toward new epitopes exposed as a result of heat treatment. Conversely, partial denaturation caused by high-pressure treatment increased the ability of egg white to stimulate Th2 responses and its allergenic potential.

Differential susceptibility of C57BL/6NCr and B6.Cg-Ptprca mice to commensal bacteria after whole body irradiation in translational bone marrow transplant studies

PubMed Central

Duran-Struuck, Raimon; Hartigan, Adam; Clouthier, Shawn G; Dyson, Melissa C; Lowler, Kathi; Gatza, Erin; Tawara, Isao; Toubai, Tomomi; Weisiger, Elisabeth; Hugunin, Kelly; Reddy, Pavan; Wilkinson, John E

2008-01-01

Background The mouse is an important and widely utilized animal model for bone marrow transplant (BMT) translational studies. Here, we document the course of an unexpected increase in mortality of congenic mice that underwent BMT. Methods Thirty five BMTs were analyzed for survival differences utilizing the Log Rank test. Affected animals were evaluated by physical examination, necropsy, histopathology, serology for antibodies to infectious disease, and bacterial cultures. Results Severe bacteremia was identified as the main cause of death. Gastrointestinal (GI) damage was observed in histopathology. The bacteremia was most likely caused by the translocation of bacteria from the GI tract and immunosuppression caused by the myeloablative irradiation. Variability in groups of animals affected was caused by increased levels of gamma and X-ray radiation and the differing sensitivity of the two nearly genetically identical mouse strains used in the studies. Conclusion Our retrospective analysis of thirty five murine BMTs performed in three different laboratories, identified C57BL/6NCr (Ly5.1) as being more radiation sensitive than B6.Cg-Ptprca/NCr (Ly5.2). This is the first report documenting a measurable difference in radiation sensitivity and its effects between an inbred strain of mice and its congenic counterpart eventually succumbing to sepsis after BMT. PMID:18307812

Fexofenadine and Pseudoephedrine

MedlinePlus

Caffeine-containing beverages (coffee, tea, sodas, and energy drinks) may increase the restlessness and insomnia caused by pseudoephedrine in sensitive individuals, so you may wish to drink less of these beverages. Talk ...

SCHISTOSOMIASIS: AGE OF SNAILS AND SUSCEPTIBILITY TO X-IRRADIATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szumlewicz, A.P.

1964-04-17

Studies on sensitivity of Australorbis glabratus to x rays have defined the chronological and physiological age at which the snail is most sensitive to radiation damage. Results showed that the dose producing 50-percent mortality at 30 days after irradiation increased with age but that at 90 days it was practically constant from 2 to 210 days of age. In view of the avaiIable data on recovery from radiation damage caused by doses from 6000 to 9000 roentgens it is suggested that doses above those causing 50% lethality at 60 days but below those causing 50% lethality for 30 days shouldmore » be considered in setting up radiation barriers to cortrol snails in water-distribution systems. (auth)« less

Disturbance of microcirculation due to unhealthy lifestyle: Cause of type 2 diabetes.

PubMed

Matsumoto, Yukihiro; Ohno, Hideki; Noguchi, Izumi; Kikuchi, Yuji; Kurihara, Takeshi

2006-01-01

Recently, type 2 diabetes seems to be increasing annually in all developed countries. The outcome of type 2 diabetes is often tragic due to succession of complications including renal disorders requiring hemodialysis, blindness, and limb amputation. The expenses for the care of diabetic patients are also a large burden on the society. These circumstances strongly indicate the necessity of prevention. For satisfactory prevention, the clarification of the etiology related to lifestyle is important, but it remains insufficient to date. In this paper, we present a hypothesis of the etiology of type 2 diabetes from the viewpoint of microcirculation. As mentioned later, an unhealthy lifestyle first causes disturbance of the microcirculation, and a portion of the blood is considered to bypass the capillaries via arteriovenous shunts. This prevents the delivery of glucose and insulin to cells of peripheral tissues, causing hyperglycemia unrelated to the cell insulin sensitivity or the endocrine state, i.e., apparent reduction of insulin sensitivity. Disturbance of the microcirculation also causes oxidative stress in peripheral tissues by inducing ischemia and hypoxia. This oxidative stress is considered to further exacerbate reduction of insulin sensitivity. This hypothesis is supported by the well-known fact that insulin sensitivity recovers with improvement in lifestyle including moderate exercise.

Skew Projection of Echo-Detected EPR Spectra for Increased Sensitivity and Resolution

PubMed Central

Bowman, Michael K.; Krzyaniak, Matthew D.; Cruce, Alex A.; Weber, Ralph T.

2013-01-01

The measurement of EPR spectra during pulsed EPR experiments is commonly accomplished by recording the integral of the electron spin echo as the applied magnetic field is stepped through the spectrum. This approach to echo-detected EPR spectral measurement (ED-EPR) limits sensitivity and spectral resolution and can cause gross distortions in the resulting spectra because some of the information present in the electron spin echo is discarded in such measurements. However, Fourier Transformation of echo shapes measured at a series of magnetic field values followed by skew projection onto either a magnetic field or resonance frequency axis can increase both spectral resolution and sensitivity without the need to trade one against the other. Examples of skew-projected spectra with single crystals, glasses and powders show resolution improvements as large as a factor of seven with sensitivity increases of as much as a factor of five. PMID:23644351

Skew projection of echo-detected EPR spectra for increased sensitivity and resolution

NASA Astrophysics Data System (ADS)

Bowman, Michael K.; Krzyaniak, Matthew D.; Cruce, Alex A.; Weber, Ralph T.

2013-06-01

The measurement of EPR spectra during pulsed EPR experiments is commonly accomplished by recording the integral of the electron spin echo as the applied magnetic field is stepped through the spectrum. This approach to echo-detected EPR spectral measurement (ED-EPR) limits sensitivity and spectral resolution and can cause gross distortions in the resulting spectra because some of the information present in the electron spin echo is discarded in such measurements. However, Fourier transformation of echo shapes measured at a series of magnetic field values followed by skew projection onto either a magnetic field or resonance frequency axis can increase both spectral resolution and sensitivity without the need to trade one against the other. Examples of skew-projected spectra with single crystals, glasses and powders show resolution improvements as large as a factor of seven with sensitivity increases of as much as a factor of five.

Effects of Temperature and Supply Voltage on SEU- and SET-Induced Errors in Bulk 40-nm Sequential Circuits

NASA Astrophysics Data System (ADS)

Chen, R. M.; Diggins, Z. J.; Mahatme, N. N.; Wang, L.; Zhang, E. X.; Chen, Y. P.; Zhang, H.; Liu, Y. N.; Narasimham, B.; Witulski, A. F.; Bhuva, B. L.; Fleetwood, D. M.

2017-08-01

The single-event sensitivity of bulk 40-nm sequential circuits is investigated as a function of temperature and supply voltage. An overall increase in SEU cross section versus temperature is observed at relatively high supply voltages. However, at low supply voltages, there is a threshold temperature beyond which the SEU cross section decreases with further increases in temperature. Single-event transient induced errors in flip-flops also increase versus temperature at relatively high supply voltages and are more sensitive to temperature variation than those caused by single-event upsets.

The Pathophysiology and Clinical Aspects of Hypercalcemic Disorders

PubMed Central

Lee, David B. N.; Zawada, Edward T.; Kleeman, Charles R.

1978-01-01

For the purposes of this review, the vast and increasingly complex subject of hypercalcemic disorders can be broken down into the following categories: (1) Physiochemical state of calcium in circulation. (2) Pathophysiological basis of hypercalcemia. (3) Causes of hypercalcemia encountered in clinical practice: causes indicated by experience at the University of California, Los Angeles; neoplasia; hyperparathyroidism; nonparathyroid endocrinopathies; pharmacological agents; possible increased sensitivity to vitamin D; miscellaneous causes. (4) Clinical manifestations and diagnostic considerations of hypercalcemic disorders. (5) The management of hypercalcemic disorders: general measures; measures for lowering serum calcium concentration; measures for correcting primary causes—the management of asymptomatic hyperparathyroidism. PMID:362722

Effects of experimental exposure to triethylamine on vision and the eye

PubMed Central

Jarvinen, P.; Engstrom, K.; Riihimaki, V.; Ruusuvaara, P.; Setala, K.

1999-01-01

OBJECTIVES: To determine the effect of triethylamine (TEA) on the cornea and to evaluate the cause of blurred vision. To find the lowest observed effect concentration of exposure to TEA. METHODS: Four people were exposed to TEA for 4 hours at concentrations of 40.6, 6.5, and 3.0 mg/m3. Before and after every exposure, symptoms and ocular microscopy findings were recorded. Binocular visual acuity and contrast sensitivity at 2.5% contrast were also measured. Also, before and after the 40.6 mg/m3 exposure, corneal thickness was measured and ocular dimensions were recorded by ultrasonography, endothelial cells of the cornea were analysed, and serum and lacrimal specimens were collected for the analysis of TEA. RESULTS: After exposure to 40.6 mg/m3 TEA there was a marked oedema in the corneal epithelium and subepithelial microcysts. However, corneal thickness increased only minimally because of the epithelial oedema. The lacrimal concentrations of TEA were, on average (range) 41 (18-83) times higher than the serum TEA concentrations. The vision was blurred in all subjects and visual acuity and contrast sensitivity had decreased in three of the four subjects. After exposure to TEA at 6.5 mg/m3 two subjects experienced symptoms, and contrast sensitivity had decreased in three of the four subjects. There were no symptoms or decreases in contrast sensitivity after exposure to a TEA concentration of 3.0 mg/m3. CONCLUSIONS: TEA caused a marked oedema and microcysts in corneal epithelium but only minor increases in corneal thickness. The effects may be mediated by the lacrimal fluid owing to its high TEA concentration. Four hour exposure to a TEA concentration of 3.0 mg/m3 seemed to cause no effects, whereas exposure to 6.5 mg/m3 for the same period caused blurred vision and a decrease in contrast sensitivity.   PMID:10341738

The Role of PP2A Methylation in Susceptibility and Resistance to TBI and AD-Induced Neurodegeneration

DTIC Science & Technology

2015-06-01

impairments caused by acute Aexposure. The principal motivation behind this approach is the observation that hyperphosphorylated tau is a common...that we also found that blast causes tau protein changes reducing memory in normal mice, when we exposed our Tg mice to tau, we demonstrated...expression increased sensitivity to electrophysiological and behavioral impairments caused by acute oligomeric Aβ exposure, and that LCMT-1 over

Can virtual autopsy with postmortem CT improve clinical diagnosis of cause of death? A retrospective observational cohort study in a Dutch tertiary referral centre.

PubMed

Sonnemans, Lianne J P; Kubat, Bela; Prokop, Mathias; Klein, Willemijn M

2018-03-16

To investigate whether virtual autopsy with postmortem CT (PMCT) improves clinical diagnosis of the immediate cause of death. Retrospective observational cohort study. inhospital and out-of-hospital deaths over the age of 1 year in whom virtual autopsy with PMCT and conventional autopsy were performed. forensic cases, postmortal organ donors and cases with incomplete scanning procedures. Cadavers were examined by virtual autopsy with PMCT prior to conventional autopsy. The clinically determined cause of death was recorded before virtual autopsy and was then adjusted with the findings of virtual autopsy. Using conventional autopsy as reference standard, we investigated the increase in sensitivity for immediate cause of death, type of pathology and anatomical system involved before and after virtual autopsy. Tertiary referral centre. 86 cadavers that underwent conventional and virtual autopsy between July 2012 and June 2016. PMCT consisted of brain, cervical spine and chest-abdomen-pelvis imaging. Conventional autopsy consisted of thoracoabdominal examination with/without brain autopsy. Increase in sensitivity for the immediate cause of death, type of pathology (infection, haemorrhage, perfusion disorder, other or not assigned) and anatomical system (pulmonary, cardiovascular, gastrointestinal, other or not assigned) involved, before and after virtual autopsy. Using PMCT, the sensitivity for immediate cause of death increased with 12% (95% CI 2% to 22%) from 53% (41% to 64%) to 64% (53% to 75%), with 18% (9% to 27%) from 65% (54% to 76%) to 83% (73% to 91%) for type of pathology and with 19% (9% to 30%) from 65% (54% to 76%) to 85% (75% to 92%) for anatomical system. While unenhanced PMCT is an insufficient substitute for conventional autopsy, it can improve diagnosis of cause of death over clinical diagnosis alone and should therefore be considered whenever autopsy is not performed. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Toxicity of aerosol propellants in the respiratory and circulatory systems. VII. Influence of pulmonary emphysema and anesthesia in the rat.

PubMed

Watanabe, T; Aviado, D M

1975-01-01

Experimental induction of pulmonary emphysema caused an increase in sensitivity of the rat to toxicity from inhalation of propellants. The emphysematous rat showed an exaggerated reduction in pulmonary compliance in response to inhalation of trichlorofluoromethane (FC 11). In emphysematous and non emphysematous rats without anesthesia the inhalation of FC 11 caused tachycardia, arrhythmias and other abnormalities in the electrocardiogram. The tachycardiac response was eliminated by induction of barbiturate anesthesia, which increased the sensitivity of the heart to occurrence of abnormalities in the electrocardiogram in response to inhalation of FC 11 as well as of dichlorodifluoromethane (FC 12) and difluoroethane (FC 152a). The acceleration in heart rate in response to inhalation of FC 11, hypoxia or hypercapnea was prevented by prior treatment with a beta-blocking drug.

Basic Processes in Reading: The Effect of Interletter Spacing

ERIC Educational Resources Information Center

Risko, Evan F.; Lanthier, Sophie N.; Besner, Derek

2011-01-01

Reading is acutely sensitive to the amount of space between letters within a string. In the present investigation, we explore the impairment caused by increasing interletter spacing when reading single words and nonwords aloud. Specifically, 2 hypotheses are tested: (a) whether increasing interletter spacing induces serial processing while reading…

Aconitine Challenge Test Reveals a Single Exposure to Air Pollution Causes Increased Cardiac Arrhythmia Risk in Hypertensive Rats - Abstract

EPA Science Inventory

Epidemiological studies demonstrate a significant association between arrhythmias and air pollution exposure. Sensitivity to aconitine-induced arrhythmia has been used repeatedly to examine the factors that increase the risk of such cardiac electrical dysfunction. In this study, ...

Activities and Effects of Ergot Alkaloids on Livestock Physiology and Production

PubMed Central

Klotz, James L.

2015-01-01

Consumption of feedstuffs contaminated with ergot alkaloids has a broad impact on many different physiological mechanisms that alters the homeostasis of livestock. This change in homeostasis causes an increased sensitivity in livestock to perturbations in the ambient environment, resulting in an increased sensitivity to such stressors. This ultimately results in large financial losses in the form of production losses to livestock producers around the world. This review will focus on the underlying physiological mechanisms that are affected by ergot alkaloids that lead to decreases in livestock production. PMID:26226000

Cause and Effects of Fluorocarbon Degradation in Electronics and Opto-Electronic Systems

NASA Technical Reports Server (NTRS)

Predmore, Roamer E.; Canham, John S.

2002-01-01

Trace degradation of fluorocarbon or halocarbon materials must be addressed in their application in sensitive systems. As the dimensions and/or tolerances of components in a system decrease, the sensitivity of the system to trace fluorocarbon or halocarbon degradation products increases. Trace quantities of highly reactive degradation products from fluorocarbons have caused a number of failures of flight hardware. It is of utmost importance that the risk of system failure, resulting from trace amounts of reactive fluorocarbon degradation products be addressed in designs containing fluorocarbon or halocarbon materials. Thermal, electrical, and mechanical energy input into the system can multiply the risk of failure.

Increased BOLD Activation to Predator Stressor in Subiculum and Midbrain of Amphetamine-Sensitized Maternal Rats

PubMed Central

Febo, Marcelo; Pira, Ashley S.

2011-01-01

Amphetamine, which is known to cause sensitization, potentiates the hormonal and neurobiological signatures of stress and may also increase sensitivity to stress-inducing stimuli in limbic areas. Trimethylthiazoline (5 μL TMT) is a chemical constituent of fox feces that evokes innate fear and activates the neuronal and hormonal signatures of stress in rats. We used blood oxygen level dependent (BOLD) MRI to test whether amphetamine sensitization (1 mg/kg, i.p. X 3 days) in female rats has a lasting effect on the neural response to a stress-evoking stimulus, the scent of a predator, during the postpartum period. The subiculum and dopamine-enriched midbrain VTA/SN of amphetamine-sensitized, but not control mothers showed a greater BOLD signal response to predator odor than a control putrid scent. The greater responsiveness of these two brain regions following stimulant sensitization might impact neural processing in response to stressors in the maternal brain. PMID:21134359

Increased BOLD activation to predator stressor in subiculum and midbrain of amphetamine-sensitized maternal rats.

PubMed

Febo, Marcelo; Pira, Ashley S

2011-03-25

Amphetamine, which is known to cause sensitization, potentiates the hormonal and neurobiological signatures of stress and may also increase sensitivity to stress-inducing stimuli in limbic areas. Trimethylthiazoline (5μL TMT) is a chemical constituent of fox feces that evokes innate fear and activates the neuronal and hormonal signatures of stress in rats. We used blood oxygen level dependent (BOLD) MRI to test whether amphetamine sensitization (1mg/kg, i.p. ×3days) in female rats has a lasting effect on the neural response to a stress-evoking stimulus, the scent of a predator, during the postpartum period. The subiculum and dopamine-enriched midbrain VTA/SN of amphetamine-sensitized but not control mothers showed a greater BOLD signal response to predator odor than a control putrid scent. The greater responsiveness of these two brain regions following stimulant sensitization might impact neural processing in response to stressors in the maternal brain. Copyright © 2010 Elsevier B.V. All rights reserved.

Enhanced sensitization and elicitation responses caused by mixtures of common fragrance allergens.

PubMed

Bonefeld, Charlotte Menné; Nielsen, Morten Milek; Rubin, Ingrid Maria Cecilia; Vennegaard, Marie Torp; Dabelsteen, Sally; Gimenéz-Arnau, Elena; Lepoittevin, Jean-Pierre; Geisler, Carsten; Johansen, Jeanne Duus

2011-12-01

Perfumes are complex mixtures composed of many fragrance ingredients, many of which are known to be only weak allergens when tested individually. It is therefore surprising that fragrance contact allergy is one of the most common forms of contact allergy. To investigate whether mixing different fragrance allergens leads to increased sensitization potency, and to examine the difference in the challenge response to one chemical in mice sensitized either with the mixture of allergens or with only the relevant allergen. CBA mice were sensitized with three different concentrations of three fragrance allergens alone or as a mixture. The sensitization and elicitation responses were measured by ear thickness plus infiltration of B and T cells and T cell proliferation in the draining lymph nodes. We found a dose-dependent sensitization response for each of the allergens. An increased response was seen when the allergens were mixed. A stronger challenge response to cinnamal was seen in mice sensitized with the allergen mixture than in mice sensitized with cinnamal alone. Our findings suggest that mixtures of allergens increase the primary response that potentiates the generation of memory T cells in response to the specific allergen. Thus, allergen mixtures enhance both induction and elicitation of contact allergy. © 2011 John Wiley & Sons A/S.

Why Your Mother Was Right: How Potassium Intake Reduces Blood Pressure.

PubMed

Ellison, David H; Terker, Andrew S

2015-01-01

Low potassium intake, common in western diets, increases blood pressure and enhances salt-sensitivity. Most humans in "Westernized" countries also consume excess salt. In studies using mice, we found that a high-salt, low-potassium diet activates the thiazide-sensitive Na-Cl cotransporter in the kidney. This effect led to sodium retention and increased blood pressure, and was dependent on plasma potassium. We postulated that this effect was mediated by changes in intracellular chloride caused by changes in membrane voltage. We developed a model in cultured cells permitting us to confirm this hypothesis. We then confirmed, using urinary exosomes, that dietary changes in normal humans, affect the thiazide-sensitive Na-Cl cotransporter in the same way. These data show that dietary potassium deficiency increases blood pressure largely by stimulating salt reabsorption along the distal nephron. They suggest that global efforts should focus on increasing potassium intake, which will attenuate the effects of high-salt diets.

Hospitalization of older adults due to ambulatory care sensitive conditions

PubMed Central

Marques, Aline Pinto; Montilla, Dalia Elena Romero; de Almeida, Wanessa da Silva; de Andrade, Carla Lourenço Tavares

2014-01-01

OBJECTIVE To analyze the temporal evolution of the hospitalization of older adults due to ambulatory care sensitive conditions according to their structure, magnitude and causes. METHODS Cross-sectional study based on data from the Hospital Information System of the Brazilian Unified Health System and from the Primary Care Information System, referring to people aged 60 to 74 years living in the state of Rio de Janeiro, Souhteastern Brazil. The proportion and rate of hospitalizations due to ambulatory care sensitive conditions were calculated, both the global rate and, according to diagnoses, the most prevalent ones. The coverage of the Family Health Strategy and the number of medical consultations attended by older adults in primary care were estimated. To analyze the indicators’ impact on hospitalizations, a linear correlation test was used. RESULTS We found an intense reduction in hospitalizations due to ambulatory care sensitive conditions for all causes and age groups. Heart failure, cerebrovascular diseases and chronic obstructive pulmonary diseases concentrated 50.0% of the hospitalizations. Adults older than 69 years had a higher risk of hospitalization due to one of these causes. We observed a higher risk of hospitalization among men. A negative correlation was found between the hospitalizations and the indicators of access to primary care. CONCLUSIONS Primary healthcare in the state of Rio de Janeiro has been significantly impacting the hospital morbidity of the older population. Studies of hospitalizations due to ambulatory care sensitive conditions can aid the identification of the main causes that are sensitive to the intervention of the health services, in order to indicate which actions are more effective to reduce hospitalizations and to increase the population’s quality of life. PMID:25372173

Involvement of Dopamine Receptors in Binge Methamphetamine-Induced Activation of Endoplasmic Reticulum and Mitochondrial Stress Pathways

PubMed Central

Beauvais, Genevieve; Atwell, Kenisha; Jayanthi, Subramaniam; Ladenheim, Bruce; Cadet, Jean Lud

2011-01-01

Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D1 receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D1 and D2 receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D1 or D2 receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58IPK, in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D2-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors. PMID:22174933

The Tradescantia micronucleus assay is a highly sensitive tool for the detection of low levels of radioactivity in environmental samples.

PubMed

Mišík, Miroslav; Krupitza, Georg; Mišíková, Katarina; Mičieta, Karol; Nersesyan, Armen; Kundi, Michael; Knasmueller, Siegfried

2016-12-01

Environmental contamination with radioactive materials of geogenic and anthropogenic origin is a global problem. A variety of mutagenicity test procedures has been developed which enable the detection of DNA damage caused by ionizing radiation which plays a key role in the adverse effects caused by radioisotopes. In the present study, we investigated the usefulness of the Tradescantia micronucleus test (the most widely used plant based genotoxicity bioassay) for the detection of genetic damage caused by environmental samples and a human artifact (ceramic plate) which contained radioactive elements. We compared the results obtained with different exposure protocols and found that direct exposure of the inflorescences is more sensitive and that the number of micronuclei can be further increased under "wet" conditions. The lowest dose rate which caused a significant effect was 1.2 μGy/h (10 h). Comparisons with the results obtained with other systems (i.e. with mitotic cells of higher plants, molluscs, insects, fish and human lymphocytes) show that the Tradescantia MN assay is one to three orders of magnitude more sensitive as other models, which are currently available. Taken together, our findings indicate that this method is due to its high sensitivity a unique tool, which can be used for environmental biomonitoring in radiation polluted areas. Copyright © 2016 Elsevier Ltd. All rights reserved.

Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice.

PubMed

Nishida, Hidenori; Sohara, Eisei; Nomura, Naohiro; Chiga, Motoko; Alessi, Dario R; Rai, Tatemitsu; Sasaki, Sei; Uchida, Shinichi

2012-10-01

Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) phosphorylation cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.

Symptomatic Overt Hypothyroidism Post Induction

DTIC Science & Technology

2017-10-21

to increased sensitivity of anesthetic agents due to decreased ca rdiac contractility, cardiac output, blood volume, 02 consumption and increased SVR...risk of increasing myocardial oxygen demand, and causing ischemia. However, delay in therapy may place the patient at risk of developing myxedema...endocrinologists recommend starting at least low dose T4 ENDO: BMR is only 55 -60% of normal -7 inability to increase core temperature Chronically

A mechanism of extreme growth and reliable signaling in sexually selected ornaments and weapons.

PubMed

Emlen, Douglas J; Warren, Ian A; Johns, Annika; Dworkin, Ian; Lavine, Laura Corley

2012-08-17

Many male animals wield ornaments or weapons of exaggerated proportions. We propose that increased cellular sensitivity to signaling through the insulin/insulin-like growth factor (IGF) pathway may be responsible for the extreme growth of these structures. We document how rhinoceros beetle horns, a sexually selected weapon, are more sensitive to nutrition and more responsive to perturbation of the insulin/IGF pathway than other body structures. We then illustrate how enhanced sensitivity to insulin/IGF signaling in a growing ornament or weapon would cause heightened condition sensitivity and increased variability in expression among individuals--critical properties of reliable signals of male quality. The possibility that reliable signaling arises as a by-product of the growth mechanism may explain why trait exaggeration has evolved so many different times in the context of sexual selection.

The mechanical microenvironment in cancer: How physics affects tumours.

PubMed

Nagelkerke, Anika; Bussink, Johan; Rowan, Alan E; Span, Paul N

2015-12-01

The tumour microenvironment contributes greatly to the response of tumour cells. It consists of chemical gradients, for example of oxygen and nutrients. However, a physical environment is also present. Apart from chemical input, cells also receive physical signals. Tumours display unique mechanical properties: they are a lot stiffer than normal tissue. This may be either a cause or a consequence of cancer, but literature suggests it has a major impact on tumour cells as will be described in this review. The mechanical microenvironment may cause malignant transformation, possibly through activation of oncogenic pathways and inhibition of tumour suppressor genes. In addition, the mechanical microenvironment may promote tumour progression by influencing processes such as epithelial-to-mesenchymal transition, enhancing cell survival through autophagy, but also affects sensitivity of tumour cells to therapeutics. Furthermore, multiple intracellular signalling pathways prove sensitive to the mechanical properties of the microenvironment. It appears the increased stiffness is unlikely to be caused by increased stiffness of the tumour cells themselves. However, there are indications that tumours display a higher cell density, making them more rigid. In addition, increased matrix deposition in the tumour, as well as increased interstitial fluid pressure may account for the increased stiffness of tumours. Overall, tumour mechanics are significantly different from normal tissue. Therefore, this feature should be further explored for use in cancer prevention, detection and treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nighttime dissolution in a temperate coastal ocean ecosystem increases under acidification

PubMed Central

Kwiatkowski, Lester; Gaylord, Brian; Hill, Tessa; Hosfelt, Jessica; Kroeker, Kristy J.; Nebuchina, Yana; Ninokawa, Aaron; Russell, Ann D.; Rivest, Emily B.; Sesboüé, Marine; Caldeira, Ken

2016-01-01

Anthropogenic emissions of carbon dioxide (CO2) are causing ocean acidification, lowering seawater aragonite (CaCO3) saturation state (Ωarag), with potentially substantial impacts on marine ecosystems over the 21st Century. Calcifying organisms have exhibited reduced calcification under lower saturation state conditions in aquaria. However, the in situ sensitivity of calcifying ecosystems to future ocean acidification remains unknown. Here we assess the community level sensitivity of calcification to local CO2-induced acidification caused by natural respiration in an unperturbed, biodiverse, temperate intertidal ecosystem. We find that on hourly timescales nighttime community calcification is strongly influenced by Ωarag, with greater net calcium carbonate dissolution under more acidic conditions. Daytime calcification however, is not detectably affected by Ωarag. If the short-term sensitivity of community calcification to Ωarag is representative of the long-term sensitivity to ocean acidification, nighttime dissolution in these intertidal ecosystems could more than double by 2050, with significant ecological and economic consequences. PMID:26987406

Nighttime dissolution in a temperate coastal ocean ecosystem increases under acidification.

PubMed

Kwiatkowski, Lester; Gaylord, Brian; Hill, Tessa; Hosfelt, Jessica; Kroeker, Kristy J; Nebuchina, Yana; Ninokawa, Aaron; Russell, Ann D; Rivest, Emily B; Sesboüé, Marine; Caldeira, Ken

2016-03-18

Anthropogenic emissions of carbon dioxide (CO2) are causing ocean acidification, lowering seawater aragonite (CaCO3) saturation state (Ω arag), with potentially substantial impacts on marine ecosystems over the 21(st) Century. Calcifying organisms have exhibited reduced calcification under lower saturation state conditions in aquaria. However, the in situ sensitivity of calcifying ecosystems to future ocean acidification remains unknown. Here we assess the community level sensitivity of calcification to local CO2-induced acidification caused by natural respiration in an unperturbed, biodiverse, temperate intertidal ecosystem. We find that on hourly timescales nighttime community calcification is strongly influenced by Ω arag, with greater net calcium carbonate dissolution under more acidic conditions. Daytime calcification however, is not detectably affected by Ω arag. If the short-term sensitivity of community calcification to Ω arag is representative of the long-term sensitivity to ocean acidification, nighttime dissolution in these intertidal ecosystems could more than double by 2050, with significant ecological and economic consequences.

The Basal Thermal Sensitivity of the TRPV1 Ion Channel Is Determined by PKCβII

PubMed Central

Li, Lin; Hasan, Raquibul

2014-01-01

Peripheral nociceptors are excited by the activation of membrane receptors and ion channels. The heat-sensitive TRPV1 ion channel responds to various noxious chemical and thermal stimuli, causing pain and itch. Here, we show that TRPV1 is coexpressed with PKCβII in a subset of mouse sensory neurons and that, in these neurons, TRPV1 binds directly to PKCβII, leading to the activation and translocation of PKCβII. Activated PKCβII, in turn, significantly increases the responsiveness of TRPV1 by phosphorylating Thr705. The heat sensitivity of TRPV1 is almost eliminated by either knocking down PKCβII or mutating Thr705; however, neither of these manipulations affects the potentiation of TRPV1 caused by the activation of PKCε. PKCβII thus acts as an auxiliary subunit of TRPV1 by forming a population-dependent TRPV1 ion channel complex controlling the sensitivity of TRPV1 and setting the threshold for pain and itch. PMID:24920628

Constitutive equation of friction based on the subloading-surface concept

PubMed Central

Ueno, Masami; Kuwayama, Takuya; Suzuki, Noriyuki; Yonemura, Shigeru; Yoshikawa, Nobuo

2016-01-01

The subloading-friction model is capable of describing static friction, the smooth transition from static to kinetic friction and the recovery to static friction after sliding stops or sliding velocity decreases. This causes a negative rate sensitivity (i.e. a decrease in friction resistance with increasing sliding velocity). A generalized subloading-friction model is formulated in this article by incorporating the concept of overstress for viscoplastic sliding velocity into the subloading-friction model to describe not only negative rate sensitivity but also positive rate sensitivity (i.e. an increase in friction resistance with increasing sliding velocity) at a general sliding velocity ranging from quasi-static to impact sliding. The validity of the model is verified by numerical experiments and comparisons with test data obtained from friction tests using a lubricated steel specimen. PMID:27493570

Determinants of relaxation rate in rabbit skinned skeletal muscle fibres

PubMed Central

Luo, Ye; Davis, Jonathan P; Smillie, Lawrence B; Rall, Jack A

2002-01-01

The influence of Ca2+-activated force, the rate of dissociation of Ca2+ from troponin C (TnC) and decreased crossbridge detachment rate on the time course of relaxation induced by flash photolysis of diazo-2 in rabbit skinned psoas fibres was investigated at 15 °C. The rate of relaxation increased as the diazo-2 chelating capacity (i.e. free [diazo-2]/free [Ca2+]) increased. At a constant diazo-2 chelating capacity, the rate of relaxation was independent of the pre-photolysis Ca2+-activated force in the range 0.3-0.8 of maximum isometric force. A TnC mutant that exhibited increased Ca2+ sensitivity caused by a decreased Ca2+ dissociation rate in solution (M82Q TnC) also increased the Ca2+ sensitivity of steady-state force and decreased the rate of relaxation in fibres by approximately twofold. In contrast, a TnC mutant with decreased Ca2+ sensitivity caused by an increased Ca2+ dissociation rate in solution (NHdel TnC) decreased the Ca2+ sensitivity of steady-state force but did not accelerate relaxation. Decreasing the rate of crossbridge kinetics by reducing intracellular inorganic phosphate concentration ([Pi]) slowed relaxation by approximately twofold and led to two phases of relaxation, a slow linear phase followed by a fast exponential phase. In fibres, M82Q TnC further slowed relaxation in low [Pi] conditions by approximately twofold, whereas NHdel TnC had no significant effect on relaxation. These results are consistent with the interpretation that the Ca2+-dissociation rate and crossbridge detachment rate are similar in fast-twitch skeletal muscle, such that decreasing either rate slows relaxation, but accelerating Ca2+ dissociation has little effect on relaxation. PMID:12482894

A review of major factors influencing plant responses to recreation impacts

NASA Astrophysics Data System (ADS)

Kuss, Fred R.

1986-09-01

This article reviews some of the more important factors found to influence the susceptibility of plants to trampling impacts associated with recreational use of natural areas. A three-way interaction mediates plant responses to impacts: plant x environment x stress level(s). Plant responses vary in part according to the genetic constitution of the plant, life and growth form, the adaptive flexibility of the plant, and anatomical differences inherent to growth habit and morphology. Other factors that influence plant sensitivities to impacts are the habitat environments in which plants grow, since a number of conditions such as moisture excesses or deficiencies, nitrogen or oxygen starvation, late frosts, etc., cause physiological injury and may increase plant sensitivity to impacts. Among the environmental factors that may increase or lessen plant sensitivities to impacts are soil moisture levels, canopy density, elevation, aspect, microclimate, soil drainage, texture, fertility and productivity. Seasonal influences also bear consideration since environmental changes and phonological and physiological events are mediated by time of year. Stresses are caused by both direct and indirect forms of impact and vary according to season of use, frequency and amount of use, and the type of activity. These interactions are further complicated by evidence that inter- and intraspecific competition, antagonism, and commensalism may influence differences in the sensitivity of plant communities to impacts.

Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides.

PubMed

Lázár, Viktória; Martins, Ana; Spohn, Réka; Daruka, Lejla; Grézal, Gábor; Fekete, Gergely; Számel, Mónika; Jangir, Pramod K; Kintses, Bálint; Csörgő, Bálint; Nyerges, Ákos; Györkei, Ádám; Kincses, András; Dér, András; Walter, Fruzsina R; Deli, Mária A; Urbán, Edit; Hegedűs, Zsófia; Olajos, Gábor; Méhi, Orsolya; Bálint, Balázs; Nagy, István; Martinek, Tamás A; Papp, Balázs; Pál, Csaba

2018-06-01

Antimicrobial peptides are promising alternative antimicrobial agents. However, little is known about whether resistance to small-molecule antibiotics leads to cross-resistance (decreased sensitivity) or collateral sensitivity (increased sensitivity) to antimicrobial peptides. We systematically addressed this question by studying the susceptibilities of a comprehensive set of 60 antibiotic-resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic-resistant bacteria show a high frequency of collateral sensitivity to antimicrobial peptides, whereas cross-resistance is relatively rare. We identify clinically relevant multidrug-resistance mutations that increase bacterial sensitivity to antimicrobial peptides. Collateral sensitivity in multidrug-resistant bacteria arises partly through regulatory changes shaping the lipopolysaccharide composition of the bacterial outer membrane. These advances allow the identification of antimicrobial peptide-antibiotic combinations that enhance antibiotic activity against multidrug-resistant bacteria and slow down de novo evolution of resistance. In particular, when co-administered as an adjuvant, the antimicrobial peptide glycine-leucine-amide caused up to 30-fold decrease in the antibiotic resistance level of resistant bacteria. Our work provides guidelines for the development of efficient peptide-based therapies of antibiotic-resistant infections.

Gas Plasma Pre-treatment Increases Antibiotic Sensitivity and Persister Eradication in Methicillin-Resistant Staphylococcus aureus

PubMed Central

Guo, Li; Xu, Ruobing; Zhao, Yiming; Liu, Dingxin; Liu, Zhijie; Wang, Xiaohua; Chen, Hailan; Kong, Michael G.

2018-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious nosocomial infections, and recurrent MRSA infections primarily result from the survival of persister cells after antibiotic treatment. Gas plasma, a novel source of ROS (reactive oxygen species) and RNS (reactive nitrogen species) generation, not only inactivates pathogenic microbes but also restore the sensitivity of MRSA to antibiotics. This study further found that sublethal treatment of MRSA with both plasma and plasma-activated saline increased the antibiotic sensitivity and promoted the eradication of persister cells by tetracycline, gentamycin, clindamycin, chloramphenicol, ciprofloxacin, rifampicin, and vancomycin. The short-lived ROS and RNS generated by plasma played a primary role in the process and induced the increase of many species of ROS and RNS in MRSA cells. Thus, our data indicated that the plasma treatment could promote the effects of many different classes of antibiotics and act as an antibiotic sensitizer for the treatment of antibiotic-resistant bacteria involved in infectious diseases. PMID:29628915

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nauntofte, B.; Poulsen, J.H.

Stimulation-induced changes in Cl content and O2 consumption of collagenase-isolated rat parotid acini were measured. In <10 s, carbachol caused a net Cl efflux, corresponding to approx.50% of the Cl content, and increased the O2 uptake by 100%. The increase was inhibitable by ouabain and was dependent on the presence of extracellular CaS . Furosemide reduced the unstimulated TWCl uptake and prevented the reuptake of Cl after carbachol-induced release. This suggests that a cotransport system is operating in both the unstimulated and stimulated states. Furthermore, furosemide inhibited the stimulated ouabain-sensitive OS uptake. Raising intracellular CaS by the calcium ionophore A23187more » evoked the same pattern of Cl loss and O2 uptake as carboachol. Our results ae compatible with the following hypothesis. Carbachol raises intracellular CaS , causing an increased Cl permeability of the luminal membrane, resulting in a net Cl efflux. A subsequently enhanced influx of Cl and Na via a furosemide-sensitive cotransport system increases intracellular Na . This stimulates the Na -K -ATPase and thereby the OS consumption.« less

Hypertrophic cardiomyopathy-linked mutation in troponin T causes myofibrillar disarray and pro-arrhythmic action potential changes in human iPSC cardiomyocytes.

PubMed

Wang, Lili; Kim, Kyungsoo; Parikh, Shan; Cadar, Adrian Gabriel; Bersell, Kevin R; He, Huan; Pinto, Jose R; Kryshtal, Dmytro O; Knollmann, Bjorn C

2018-01-01

Mutations in cardiac troponin T (TnT) are linked to increased risk of ventricular arrhythmia and sudden death despite causing little to no cardiac hypertrophy. Studies in mice suggest that the hypertrophic cardiomyopathy (HCM)-associated TnT-I79N mutation increases myofilament Ca sensitivity and is arrhythmogenic, but whether findings from mice translate to human cardiomyocyte electrophysiology is not known. To study the effects of the TnT-I79N mutation in human cardiomyocytes. Using CRISPR/Cas9, the TnT-I79N mutation was introduced into human induced pluripotent stem cells (hiPSCs). We then used the matrigel mattress method to generate single rod-shaped cardiomyocytes (CMs) and studied contractility, Ca handling and electrophysiology. Compared to isogenic control hiPSC-CMs, TnT-I79N hiPSC-CMs exhibited sarcomere disorganization, increased systolic function and impaired relaxation. The Ca-dependence of contractility was leftward shifted in mutation containing cardiomyocytes, demonstrating increased myofilament Ca sensitivity. In voltage-clamped hiPSC-CMs, TnT-I79N reduced intracellular Ca transients by enhancing cytosolic Ca buffering. These changes in Ca handling resulted in beat-to-beat instability and triangulation of the cardiac action potential, which are predictors of arrhythmia risk. The myofilament Ca sensitizer EMD57033 produced similar action potential triangulation in control hiPSC-CMs. The TnT-I79N hiPSC-CM model not only reproduces key cellular features of TnT-linked HCM such as myofilament disarray, hypercontractility and diastolic dysfunction, but also suggests that this TnT mutation causes pro-arrhythmic changes of the human ventricular action potential. Copyright © 2017 Elsevier Ltd. All rights reserved.

Population viability analysis of Lower Missouri River shovelnose sturgeon with initial application to the pallid sturgeon

USGS Publications Warehouse

Bajer, P.G.; Wildhaber, M.L.

2007-01-01

Demographic models for the shovelnose (Scaphirhynchus platorynchus) and pallid (S. albus) sturgeons in the Lower Missouri River were developed to conduct sensitivity analyses for both populations. Potential effects of increased fishing mortality on the shovelnose sturgeon were also evaluated. Populations of shovelnose and pallid sturgeon were most sensitive to age-0 mortality rates as well as mortality rates of juveniles and young adults. Overall, fecundity was a less sensitive parameter. However, increased fecundity effectively balanced higher mortality among sensitive age classes in both populations. Management that increases population-level fecundity and improves survival of age-0, juveniles, and young adults should most effectively benefit both populations. Evaluation of reproductive values indicated that populations of pallid sturgeon dominated by ages ≥35 could rapidly lose their potential for growth, particularly if recruitment remains low. Under the initial parameter values portraying current conditions the population of shovelnose sturgeon was predicted to decline by 1.65% annually, causing the commercial yield to also decline. Modeling indicated that the commercial yield could increase substantially if exploitation of females in ages ≤12 was highly restricted.

Am80 induces neuronal differentiation via increased tropomyosin-related kinase B expression in a human neuroblastoma SH-SY5Y cell line.

PubMed

Shiohira, Hideo; Kitaoka, Akira; Enjoji, Munechika; Uno, Tsukasa; Nakashima, Manabu

2012-01-01

Am80, a synthetic retinoid, has been used in differentiation therapy for acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) as one of natural retinoid has been also used to treat APL. ATRA treatment causes neuronal differentiation by inducing tropomyosin-related kinase B (TrkB) expression and increasing the sensitivity to brain-derived neurotrophic factor (BDNF), a TrkB ligand. In the present study, we investigated the effects of Am80 on neuronal differentiation, BDNF sensitivity and TrkB expression in human neuroblastoma SH-SY5Y cells. Treatment with Am80 induced morphological differentiation of neurite outgrowth and increased the expression of GAP43 mRNA, a neuronal differentiation marker. Additionally, TrkB protein was also increased, and exogenous BDNF stimulation after treatment with Am80 induced greater neurite outgrowth than without BDNF treatment. These results suggest that Am80 induced neuronal differentiation by increasing TrkB expression and BDNF sensitivity.

Bronchoconstriction induced by increasing airway temperature in ovalbumin-sensitized rats: role of tachykinins.

PubMed

Hsu, Chun-Chun; Lin, Ruei-Lung; Lin, You Shuei; Lee, Lu-Yuan

2013-09-01

This study was carried out to determine the effect of allergic inflammation on the airway response to increasing airway temperature. Our results showed the following: 1) In Brown-Norway rats actively sensitized by ovalbumin (Ova), isocapnic hyperventilation with humidified warm air (HWA) for 2 min raised tracheal temperature (Ttr) from 33.4 ± 0.6°C to 40.6 ± 0.1°C, which induced an immediate and sustained (>10 min) increase in total pulmonary resistance (Rl) from 0.128 ± 0.004 to 0.212 ± 0.013 cmH2O·ml(-1)·s (n = 6, P < 0.01). In sharp contrast, the HWA challenge caused the same increase in Ttr but did not generate any increase in Rl in control rats. 2) The increase in Rl in sensitized rats was reproducible when the same HWA challenge was repeated 60-90 min later. 3) This bronchoconstrictive effect was temperature dependent: a slightly smaller increase in peak Ttr (39.6 ± 0.2°C) generated a significant but smaller increase in Rl in sensitized rats. 4) The HWA-induced bronchoconstriction was not generated by the humidity delivered by the HWA challenge alone, because the same water content delivered by saline aerosol at room temperature had no effect. 5) The HWA-evoked increase in Rl in sensitized rats was not blocked by atropine but was completely prevented by pretreatment either with a combination of neurokinin (NK)-1 and NK-2 antagonists or with formoterol, a β2 agonist, before the HWA challenge. This study showed that increasing airway temperature evoked a pronounced and reversible increase in airway resistance in sensitized rats and that tachykinins released from the vagal bronchopulmonary C-fiber endings were primarily responsible.

Increased expression of CRF and CRF-receptors in dorsal striatum, hippocampus, and prefrontal cortex after the development of nicotine sensitization in rats.

PubMed

Carboni, Lucia; Romoli, Benedetto; Bate, Simon T; Romualdi, Patrizia; Zoli, Michele

2018-05-29

Nicotine addiction supports tobacco smoking, a main preventable cause of disease and death in Western countries. It develops through long-term neuroadaptations in the brain reward circuit by modulating intracellular pathways and regulating gene expression. This study assesses the regional expression of the transcripts of the CRF transmission in a nicotine sensitization model, since it is hypothesised that the molecular neuroadaptations that mediate the development of sensitization contribute to the development of addiction. Rats received intraperitoneal nicotine administrations (0.4 mg/kg) once daily for either 1 day or over 5 days. Locomotor activity was assessed to evaluate the development of sensitization. The mRNA expression of CRF and CRF1 and CRF2 receptors was measured by qPCR in the ventral mesencephalon, ventral striatum, dorsal striatum (DS), prefrontal cortex (PFCx), and hippocampus (Hip). Acute nicotine administration increased locomotor activity in rats. In the sub-chronic group, locomotor activity progressively increased and reached a clear sensitization. Significant effects of sensitization on CRF mRNA levels were detected in the DS (increasing effect). Significantly higher CRF1 and CRF2 receptor levels after sensitization were detected in the Hip. Additionally, CRF2 receptor levels were augmented by sensitization in the PFCx, and treatment and time-induced increases were detected in the DS. Nicotine treatment effects were observed on CRF1R levels in the DS. This study suggests that the CRF transmission, in addition to its role in increasing withdrawal-related anxiety, may be involved in the development of nicotine-habituated behaviours through reduced control of impulses and the aberrant memory plasticity characterising addiction. Copyright © 2018 Elsevier B.V. All rights reserved.

IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide

PubMed Central

Ramcharan, Roger; Aleksic, Tamara; Kamdoum, Wilfride Petnga; Gao, Shan; Pfister, Sophia X.; Tanner, Jordan; Bridges, Esther; Asher, Ruth; Watson, Amanda J.; Margison, Geoffrey P.; Woodcock, Mick; Repapi, Emmanouela; Li, Ji-Liang; Middleton, Mark R.; Macaulay, Valentine M.

2015-01-01

Prior studies implicate type 1 IGF receptor (IGF-1R) in mediating chemo-resistance. Here, we investigated whether IGF-1R influences response to temozolomide (TMZ), which generates DNA adducts that are removed by O6-methylguanine-DNA methyltransferase (MGMT), or persist causing replication-associated double-strand breaks (DSBs). Initial assessment in 10 melanoma cell lines revealed that TMZ resistance correlated with MGMT expression (r = 0.79, p = 0.009), and in MGMT-proficient cell lines, with phospho-IGF-1R (r = 0.81, p = 0.038), suggesting that TMZ resistance associates with IGF-1R activation. Next, effects of IGF-1R inhibitors (IGF-1Ri) AZ3801 and linsitinib (OSI-906) were tested on TMZ-sensitivity, cell cycle progression and DSB induction. IGF-1Ri sensitized BRAF wild-type and mutant melanoma cells to TMZ in vitro, an effect that was independent of MGMT. Cells harboring wild-type p53 were more sensitive to IGF-1Ri, and showed schedule-dependent chemo-sensitization that was most effective when IGF-1Ri followed TMZ. This sequence sensitized to clinically-achievable TMZ concentrations and enhanced TMZ-induced apoptosis. Simultaneous or prior IGF-1Ri caused less effective chemo-sensitization, associated with increased G1 population and reduced accumulation of TMZ-induced DSBs. Clinically relevant sequential (TMZ → IGF-1Ri) treatment was tested in mice bearing A375M (V600E BRAF, wild-type p53) melanoma xenografts, achieving peak plasma/tumor IGF-1Ri levels comparable to clinical Cmax, and inducing extensive intratumoral apoptosis. TMZ or IGF-1Ri caused minor inhibition of tumor growth (gradient reduction 13%, 25% respectively), while combination treatment caused supra-additive growth delay (72%) that was significantly different from control (p < 0.01), TMZ (p < 0.01) and IGF-1Ri (p < 0.05) groups. These data highlight the importance of scheduling when combining IGF-1Ri and other targeted agents with drugs that induce replication-associated DNA damage. PMID:26497996

Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of ε-subunit containing GABA ARs.

PubMed

Hengen, Keith B; Nelson, Nathan R; Stang, Kyle M; Johnson, Stephen M; Smith, Stephanie M; Watters, Jyoti J; Mitchell, Gordon S; Behan, Mary

2015-01-01

The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events. For example, the respiratory control network in pregnant rats becomes relatively insensitive to barbiturates due to increased expression of ε-subunit-containing GABAARs in the ventral respiratory column. We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels. Thus, we tested whether increased inhibitory tone was sufficient to induce ε-subunit upregulation on respiratory and cortical neurons in adult rats. Chronic intermittent increases in inhibitory tone in male and female rats was induced via daily 5-min exposures to 3% isoflurane. After 7d of treatment, phrenic burst frequency was less sensitive to barbiturate in isoflurane-treated male and female rats in vivo. Neurons in the ventral respiratory group and cortex were less sensitive to pentobarbital in vitro following 7d and 30d of intermittent isoflurane-exposure in both male and female rats. The pentobarbital insensitivity in 7d isoflurane-treated rats was reversible after another 7d. We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs.

Genetic diversity among pandemic 2009 influenza viruses isolated from a transmission chain

PubMed Central

2013-01-01

Background Influenza viruses such as swine-origin influenza A(H1N1) virus (A(H1N1)pdm09) generate genetic diversity due to the high error rate of their RNA polymerase, often resulting in mixed genotype populations (intra-host variants) within a single infection. This variation helps influenza to rapidly respond to selection pressures, such as those imposed by the immunological host response and antiviral therapy. We have applied deep sequencing to characterize influenza intra-host variation in a transmission chain consisting of three cases due to oseltamivir-sensitive viruses, and one derived oseltamivir-resistant case. Methods Following detection of the A(H1N1)pdm09 infections, we deep-sequenced the complete NA gene from two of the oseltamivir-sensitive virus-infected cases, and all eight gene segments of the viruses causing the remaining two cases. Results No evidence for the resistance-causing mutation (resulting in NA H275Y substitution) was observed in the oseltamivir-sensitive cases. Furthermore, deep sequencing revealed a subpopulation of oseltamivir-sensitive viruses in the case carrying resistant viruses. We detected higher levels of intra-host variation in the case carrying oseltamivir-resistant viruses than in those infected with oseltamivir-sensitive viruses. Conclusions Oseltamivir-resistance was only detected after prophylaxis with oseltamivir, suggesting that the mutation was selected for as a result of antiviral intervention. The persisting oseltamivir-sensitive virus population in the case carrying resistant viruses suggests either that a small proportion survive the treatment, or that the oseltamivir-sensitive virus rapidly re-establishes itself in the virus population after the bottleneck. Moreover, the increased intra-host variation in the oseltamivir-resistant case is consistent with the hypothesis that the population diversity of a RNA virus can increase rapidly following a population bottleneck. PMID:23587185

Thermal and chemical treatment of polymer optical fiber Bragg grating sensors for enhanced mechanical sensitivity

NASA Astrophysics Data System (ADS)

Pospori, A.; Marques, C. A. F.; Sáez-Rodríguez, D.; Nielsen, K.; Bang, O.; Webb, D. J.

2017-07-01

An investigation of the thermal annealing effects on the strain, stress, and force sensitivities of polymer optical fiber Bragg grating sensors is performed. We demonstrate for the first time that the fiber annealing can enhance both stress and force sensitivities of Bragg grating sensors, with the possible cause being the molecular relaxation of the polymer when fiber is raised above the β -transition temperature. A simple, cost-effective, but well controlled method for fiber annealing is also presented in this work. In addition, the effects of chemical etching on the strain, stress, and force sensitivities have been investigated. Results show that fiber etching too can increase the force sensitivity, and it can also affect the strain and stress sensitivities of the Bragg grating sensors.

Acute Stress Decreases but Chronic Stress Increases Myocardial Sensitivity to Ischemic Injury in Rodents

PubMed Central

Eisenmann, Eric D.; Rorabaugh, Boyd R.; Zoladz, Phillip R.

2016-01-01

Cardiovascular disease (CVD) is the largest cause of mortality worldwide, and stress is a significant contributor to the development of CVD. The relationship between acute and chronic stress and CVD is well evidenced. Acute stress can lead to arrhythmias and ischemic injury. However, recent evidence in rodent models suggests that acute stress can decrease sensitivity to myocardial ischemia–reperfusion injury (IRI). Conversely, chronic stress is arrhythmogenic and increases sensitivity to myocardial IRI. Few studies have examined the impact of validated animal models of stress-related psychological disorders on the ischemic heart. This review examines the work that has been completed using rat models to study the effects of stress on myocardial sensitivity to ischemic injury. Utilization of animal models of stress-related psychological disorders is critical in the prevention and treatment of cardiovascular disorders in patients experiencing stress-related psychiatric conditions. PMID:27199778

The Arabidopsis cax3 mutants display altered salt tolerance, pH sensitivity and reduced plasma membrane H+-ATPase activity.

PubMed

Zhao, Jian; Barkla, Bronwyn J; Marshall, Joy; Pittman, Jon K; Hirschi, Kendal D

2008-02-01

Perturbing CAX1, an Arabidopsis vacuolar H+/Ca2+ antiporter, and the related vacuolar transporter CAX3, has been previously shown to cause severe growth defects; however, the specific function of CAX3 has remained elusive. Here, we describe plant phenotypes that are shared among cax1 and cax3 including an increased sensitivity to both abscisic acid (ABA) and sugar during germination, and an increased tolerance to ethylene during early seedling development. We have also identified phenotypes unique to cax3, namely salt, lithium and low pH sensitivity. We used biochemical measurements to ascribe these cax3 sensitivities to a reduction in vacuolar H+/Ca2+ transport during salt stress and decreased plasma membrane H+-ATPase activity. These findings catalog an array of CAX phenotypes and assign a specific role for CAX3 in response to salt tolerance.

Acute Stress Decreases but Chronic Stress Increases Myocardial Sensitivity to Ischemic Injury in Rodents.

PubMed

Eisenmann, Eric D; Rorabaugh, Boyd R; Zoladz, Phillip R

2016-01-01

Cardiovascular disease (CVD) is the largest cause of mortality worldwide, and stress is a significant contributor to the development of CVD. The relationship between acute and chronic stress and CVD is well evidenced. Acute stress can lead to arrhythmias and ischemic injury. However, recent evidence in rodent models suggests that acute stress can decrease sensitivity to myocardial ischemia-reperfusion injury (IRI). Conversely, chronic stress is arrhythmogenic and increases sensitivity to myocardial IRI. Few studies have examined the impact of validated animal models of stress-related psychological disorders on the ischemic heart. This review examines the work that has been completed using rat models to study the effects of stress on myocardial sensitivity to ischemic injury. Utilization of animal models of stress-related psychological disorders is critical in the prevention and treatment of cardiovascular disorders in patients experiencing stress-related psychiatric conditions.

Evidence for isoleucine as a positive effector of the ilvBN operon in Salmonella typhimurium.

PubMed

Davidson, J P; Wilson, D J

1991-08-15

Concerted efforts were directed towards understanding the control of acetohydroxy acid synthase (AHAS) in the gyrB mutant hisU1820 of Salmonella typhimurium. A media shift from valine to valine plus isoleucine causes a dramatic 4 to 5 fold burst of AHAS valine sensitive activity which appears to be dependent on translation. DJ19, an isolated valine sensitive derivative of the gyrB mutant, maintains a dramatic increase in AHAS valine sensitive activity upon the addition of isoleucine to valine supplemented cultures, suggesting that the isoleucine effect is specific for valine sensitive AHAS. Evidence supports isoleucine as a positive effector on valine sensitive AHAS expression and that the gyrB mutation accentuates the isoleucine effect.

Enhanced insulin sensitivity and acute regulation of metabolic genes and signaling pathways after a single electrical or manual acupuncture session in female insulin-resistant rats.

PubMed

Benrick, Anna; Maliqueo, Manuel; Johansson, Julia; Sun, Miao; Wu, Xiaoke; Mannerås-Holm, Louise; Stener-Victorin, Elisabet

2014-12-01

To compare the effect of a single session of acupuncture with either low-frequency electrical or manual stimulation on insulin sensitivity and molecular pathways in the insulin-resistant dihydrotestosterone-induced rat polycystic ovary syndrome (PCOS) model. Both stimulations cause activation of afferent nerve fibers. In addition, electrical stimulation causes muscle contractions, enabling us to differentiate changes induced by activation of sensory afferents from contraction-induced changes. Control and PCOS rats were divided into no-stimulation, manual-, and electrical stimulation groups and insulin sensitivity was measured by euglycemic hyperinsulinemic clamp. Manually stimulated needles were rotated 180° ten times every 5 min, or low-frequency electrical stimulation was applied to evoke muscle twitches for 45 min. Gene and protein expression were analyzed by real-time PCR and Western blot. The glucose infusion rate (GIR) was lower in PCOS rats than in controls. Electrical stimulation was superior to manual stimulation during treatment but both methods increased GIR to the same extent in the post-stimulation period. Electrical stimulation decreased mRNA expression of Adipor2, Adrb1, Fndc5, Erk2, and Tfam in soleus muscle and increased ovarian Adrb2 and Pdf. Manual stimulation decreased ovarian mRNA expression of Erk2 and Sdnd. Electrical stimulation increased phosphorylated ERK levels in soleus muscle. One acupuncture session with electrical stimulation improves insulin sensitivity and modulates skeletal muscle gene and protein expression more than manual stimulation. Although electrical stimulation is superior to manual in enhancing insulin sensitivity during stimulation, they are equally effective after stimulation indicating that it is activation of sensory afferents rather than muscle contraction per se leading to the observed changes.

Refractive Outcomes, Contrast Sensitivity, HOAs, and Patient Satisfaction in Moderate Myopia: Wavefront-Optimized Versus Tissue-Saving PRK.

PubMed

Nassiri, Nader; Sheibani, Kourosh; Azimi, Abbas; Khosravi, Farinaz Mahmoodi; Heravian, Javad; Yekta, Abasali; Moghaddam, Hadi Ostadi; Nassiri, Saman; Yasseri, Mehdi; Nassiri, Nariman

2015-10-01

To compare refractive outcomes, contrast sensitivity, higher-order aberrations (HOAs), and patient satisfaction after photorefractive keratectomy for correction of moderate myopia with two methods: tissue saving versus wavefront optimized. In this prospective, comparative study, 152 eyes (80 patients) with moderate myopia with and without astigmatism were randomly divided into two groups: the tissue-saving group (Technolas 217z Zyoptix laser; Bausch & Lomb, Rochester, NY) (76 eyes of 39 patients) or the wavefront-optimized group (WaveLight Allegretto Wave Eye-Q laser; Alcon Laboratories, Inc., Fort Worth, TX) (76 eyes of 41 patients). Preoperative and 3-month postoperative refractive outcomes, contrast sensitivity, HOAs, and patient satisfaction were compared between the two groups. The mean spherical equivalent was -4.50 ± 1.02 diopters. No statistically significant differences were detected between the groups in terms of uncorrected and corrected distance visual acuity and spherical equivalent preoperatively and 3 months postoperatively. No statistically significant differences were seen in the amount of preoperative to postoperative contrast sensitivity changes between the two groups in photopic and mesopic conditions. HOAs and Q factor increased in both groups postoperatively (P = .001), with the tissue-saving method causing more increases in HOAs (P = .007) and Q factor (P = .039). Patient satisfaction was comparable between both groups. Both platforms were effective in correcting moderate myopia with or without astigmatism. No difference in refractive outcome, contrast sensitivity changes, and patient satisfaction between the groups was observed. Postoperatively, the tissue-saving method caused a higher increase in HOAs and Q factor compared to the wavefront-optimized method, which could be due to larger optical zone sizes in the tissue-saving group. Copyright 2015, SLACK Incorporated.

Identification of butanol tolerant genes in Lactobacillus mucosae

USDA-ARS?s Scientific Manuscript database

Butanol, though in low concentrations, is produced biologically through fermentation of lignocellulosic biomass-derived substrates by Gram-positive Clostridium species. However, naturally available butanol fermenting microbes are sensitive to stress caused by increased production of butanol and the...

Characterisation of 2,4-Dinitroanisole: An Ingredient for Use in Low Sensitivity Melt Cast Formulations

DTIC Science & Technology

2006-08-01

PETN/TNT 50/50 PMMA Polymethyl methacrylate RDX Cyclotrimethylenetrinitramine RS-RDX Reduced Sensitivity RDX SEM Scanning electron... toxicological data was available on DNAN. It had been proposed that due to the increased solubility of DNAN over TNT in aqueous solution at biologically...While the toxicological study [18], concluded that the vapour pressure of DNAN was not sufficient to cause concerns over inhalation of DNAN during

Quercetin-3-methyl ether inhibits lapatinib-sensitive and -resistant breast cancer cell growth by inducing G2/M arrest and apoptosis

PubMed Central

Li, Jixia; Zhu, Feng; Lubet, Ronald A.; De Luca, Antonella; Grubbs, Clinton; Ericson, Marna E.; D’Alessio, Amelia; Normano, Nicola; Dong, Zigang; Bode, Ann M.

2012-01-01

Lapatinib, an oral, small-molecule, reversible inhibitor of both EGFR and HER2, is highly active in HER2 positive breast cancer as a single agent and in combination with other therapeutics. However, resistance against lapatinib is an unresolved problem in clinical oncology. Recently, interest in the use of natural compounds to prevent or treat cancers has gained increasing interest because of presumed low toxicity. Quercetin-3-methyl ether, a naturally occurring compound present in various plants, has potent anticancer activity. Here, we found that quercetin-3-methyl ether caused in a significant growth inhibition of lapatinib-sensitive and -resistant breast cancer cells. Western blot data showed that quercetin-3-methyl ether had no effect on Akt or ERKs signaling in resistant cells. However, quercetin-3-methyl ether caused a pronounced G2/M block mainly through the Chk1-Cdc25c-cyclin B1/Cdk1 pathway in lapatinib-sensitive and -resistant cells. In contrast, lapatinib produced an accumulation of cells in the G1 phase mediated through cyclin D1, but only in lapatinib-sensitive cells. Moreover, quercetin-3-methyl ether induced significant apoptosis, accompanied with increased levels of cleaved caspase 3, caspase 7 and poly (ADP-ribose) polymerase (PARP) in both cell lines. Overall, these results suggested that quercetin-3-methyl ether might be a novel and promising therapeutic agent in lapatinib-sensitive or -resistant breast cancer patients. PMID:22086611

Calcium-independent phospholipase A2 participates in KCl-induced calcium sensitization of vascular smooth muscle.

PubMed

Ratz, Paul H; Miner, Amy S; Barbour, Suzanne E

2009-07-01

In vascular smooth muscle, KCl not only elevates intracellular free Ca(2+) ([Ca(2+)](i)), myosin light chain kinase activity and tension (T), but also can inhibit myosin light chain phosphatase activity by activation of rhoA kinase (ROCK), resulting in Ca(2+) sensitization (increased T/[Ca(2+)](i) ratio). Precisely how KCl causes ROCK-dependent Ca(2+) sensitization remains to be determined. Using Fura-2-loaded isometric rings of rabbit artery, we found that the Ca(2+)-independent phospholipase A(2) (iPLA(2)) inhibitor, bromoenol lactone (BEL), reduced the KCl-induced tonic but not early phasic phase of T and potentiated [Ca(2+)](i), reducing Ca(2+) sensitization. The PKC inhibitor, GF-109203X (> or =3 microM) and the pseudo-substrate inhibitor of PKCzeta produced a response similar to BEL. BEL reduced basal and KCl-stimulated myosin phosphatase phosphorylation. Whereas BEL and H-1152 produced strong inhibition of KCl-induced tonic T (approximately 50%), H-1152 did not induce additional inhibition of tissues already inhibited by BEL, suggesting that iPLA(2) links KCl stimulation with ROCK activation. The cPLA(2) inhibitor, pyrrolidine-1, inhibited KCl-induced tonic increases in [Ca(2+)](i) but not T, whereas the inhibitor of 20-HETE production, HET0016, acted like the ROCK inhibitor H-1152 by causing Ca(2+) desensitization. These data support a model in which iPLA(2) activity regulates Ca(2+) sensitivity.

Thapsigargin defines the roles of cellular calcium in secretagogue-stimulated enzyme secretion from pancreatic acini.

PubMed

Metz, D C; Patto, R J; Mrozinski, J E; Jensen, R T; Turner, R J; Gardner, J D

1992-10-15

In the present study we used thapsigargin (TG), an inhibitor of microsomal calcium ATPase, to evaluate the roles of free cytoplasmic calcium and intracellular stored calcium in secretagogue-stimulated enzyme secretion from rat pancreatic acini. Using microspectrofluorimetry of fura-2-loaded pancreatic acini, we found that TG caused a sustained increase in free cytoplasmic calcium by mobilizing calcium from inositol 1,4,5-trisphosphate-sensitive intracellular stores and by increasing influx of extracellular calcium. TG also caused a small increase in basal amylase secretion, inhibited the stimulation of amylase secretion caused by secretagogues that increase inositol 1,4,5-trisphosphate, and potentiated the stimulation of amylase secretion caused by 12-O-tetradecanoylphorbol-13-acetate or secretagogues that increase cyclic adenosine 3',5'-monophosphate. Bombesin, which like TG increased free cytoplasmic calcium, also potentiated the stimulation of amylase secretion caused by secretagogues that increase cyclic adenosine 3',5'-monophosphate, but did not inhibit the stimulation of amylase secretion caused by secretagogues that increase inositol 1,4,5-trisphosphate. Finally, TG inhibited the sustained phase of cholecystokinin-stimulated amylase secretion and potentiated the time course of vasoactive intestinal peptide-stimulated amylase secretion. The present findings indicate that stimulation of amylase secretion by secretagogues that increase inositol 1,4,5-trisphosphate does not depend on increased free cytoplasmic calcium per se. In contrast, TG-induced potentiation of the stimulation of secretagogues that increase cellular cyclic adenosine 3',5'-monophosphate appears to result from increased free cytoplasmic calcium per se.

Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration

PubMed Central

Lana-Elola, Eva; Gibbins, Dorota; La Russa, Federica; Wiseman, Frances; Williamson, Matthew; Saccon, Rachele; Olerinyova, Anna; Mahmood, Radma; Nye, Emma; Cater, Heather; Yu, Y. Eugene; Bennett, David L. H.; Greensmith, Linda; Fisher, Elizabeth M. C.

2018-01-01

Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied—the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction. PMID:29746474

Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues

PubMed Central

Baena, Miguel; Sangüesa, Gemma; Dávalos, Alberto; Latasa, María-Jesús; Sala-Vila, Aleix; Sánchez, Rosa María; Roglans, Núria; Laguna, Juan Carlos; Alegret, Marta

2016-01-01

Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months’ supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake. PMID:27194405

Hypotension, lipodystrophy, and insulin resistance in generalized PPARγ-deficient mice rescued from embryonic lethality

PubMed Central

Duan, Sheng Zhong; Ivashchenko, Christine Y.; Whitesall, Steven E.; D’Alecy, Louis G.; Duquaine, Damon C.; Brosius, Frank C.; Gonzalez, Frank J.; Vinson, Charles; Pierre, Melissa A.; Milstone, David S.; Mortensen, Richard M.

2007-01-01

We rescued the embryonic lethality of global PPARγ knockout by breeding Mox2-Cre (MORE) mice with floxed PPARγ mice to inactivate PPARγ in the embryo but not in trophoblasts and created a generalized PPARγ knockout mouse model, MORE-PPARγ knockout (MORE-PGKO) mice. PPARγ inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPARγ agonists had the same effect. We showed that another mouse model of lipodystrophy was hypertensive, ruling out the lipodystrophy as a cause. Further, high salt loading did not correct the hypotension in MORE-PGKO mice. In vitro studies showed that the vasculature from MORE-PGKO mice was more sensitive to endothelial-dependent relaxation caused by muscarinic stimulation, but was not associated with changes in eNOS expression or phosphorylation. In addition, vascular smooth muscle had impaired contraction in response to α-adrenergic agents. The renin-angiotensin-aldosterone system was mildly activated, consistent with increased vascular capacitance or decreased volume. These effects are likely mechanisms contributing to the hypotension. Our results demonstrated that PPARγ is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPARγ function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation. PMID:17304352

Respiratory sensitization and allergy: Current research approaches and needs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boverhof, Darrell R.; Billington, Richard; Gollapudi, B. Bhaskar

2008-01-01

There are currently no accepted regulatory models for assessing the potential of a substance to cause respiratory sensitization and allergy. In contrast, a number of models exist for the assessment of contact sensitization and allergic contact dermatitis (ACD). Research indicates that respiratory sensitizers may be identified through contact sensitization assays such as the local lymph node assay, although only a small subset of the compounds that yield positive results in these assays are actually respiratory sensitizers. Due to the increasing health concerns associated with occupational asthma and the impending directives on the regulation of respiratory sensitizers and allergens, an approachmore » which can identify these compounds and distinguish them from contact sensitizers is required. This report discusses some of the important contrasts between respiratory allergy and ACD, and highlights several prominent in vivo, in vitro and in silico approaches that are being applied or could be further developed to identify compounds capable of causing respiratory allergy. Although a number of animal models have been used for researching respiratory sensitization and allergy, protocols and endpoints for these approaches are often inconsistent, costly and difficult to reproduce, thereby limiting meaningful comparisons of data between laboratories and development of a consensus approach. A number of emerging in vitro and in silico models show promise for use in the characterization of contact sensitization potential and should be further explored for their ability to identify and differentiate contact and respiratory sensitizers. Ultimately, the development of a consistent, accurate and cost-effective model will likely incorporate a number of these approaches and will require effective communication, collaboration and consensus among all stakeholders.« less

cap alpha. /sub 2/-Adrenergic receptor-mediated sensitization of forskolin-stimulated cyclic AMP production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, S.B.; Toews, M.L.; Turner, J.T.

1987-03-01

Preincubation of HT29 human colonic adenocarcinoma cells with ..cap alpha../sub 2/-adrenergic agonists resulted in a 10- to 20-fold increase in forskolin-stimulated cyclic AMP production as compared to cells preincubated without agonist. Similar results were obtained using either a (/sup 3/H)adenine prelabeling assay or a cyclic AMP radioimmunoassay to measure cyclic AMP levels. This phenomenon, which is termed sensitization, is ..cap alpha../sub 2/-adrenergic receptor-mediated and rapid in onset and reversal. Yohimbine, an ..cap alpha../sub 2/-adrenergic receptor-selective antagonist, blocked norepinephrine-induced sensitization, whereas prazosin (..cap alpha../sub 1/-adrenergic) and sotalol (..beta..-adrenergic) did not. The time for half-maximal sensitization was 5 min and the half-timemore » for reversal was 10 min. Only a 2-fold sensitization of cyclic AMP production stimulated by vasoactive intestinal peptide was observed, indicating that sensitization is relatively selective for forskolin. Sensitization reflects an increased production of cyclic AMP and not a decreased degradation of cyclic AMP, since incubation with a phosphodiesterase inhibitor and forskolin did not mimic sensitization. Increasing the levels of cyclic AMP during the preincubation had no effect on sensitization, indicating that sensitization is not caused by decreased cyclic AMP levels during the preincubation. This rapid and dramatic sensitization of forskolin-stimulated cyclic AMP production is a previously unreported effect that can be added to the growing list of ..cap alpha../sub 2/-adrenergic responses that are not mediated by a decrease in cyclic AMP.« less

Caffeine toxicity is inversely related to DNA repair in simian virus 40-transformed xeroderma pigmentosum cells irradiated with ultraviolet light

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cleaver, J.E.

1989-01-01

Human cells transformed by simian virus 40 (SV40) are more sensitive to killing by ultraviolet light when grown in caffeine after irradiation. The degree of sensitization at 2 mM caffeine (expressed as the ratio of the 37% survival dose for control cells divided by the 37% survival dose for cells grown in caffeine, i.e., the dose modification factor) was approximately 1.9 in transformed normal cells and 3.8-5.8 in excision-defective xeroderma pigmentosum (XP) groups A, C, and D cells. A large dose modification factor of 12 was observed in a transformed XP variant cell line. Chinese hamster ovary cells were notmore » significantly different from transformed normal human cells, with a maximum dose modification factor of 1.5. Two radioresistant XP revertants that do not excise cyclobutane dimers gave different responses; one resembled its group A parent in being sensitized by caffeine, and one did not. These results can be interpreted on the basis of a single hypothesis that cells are killed as a result of attempts to replicate damaged DNA. Increased replication rates caused by transformation, increased numbers of replication forks in DNA caused by caffeine, and increased numbers of damaged sites ahead of replication forks in excision-defective cells are all processes that will consequently increase killing according to this hypothesis. A corollary is that the XP variant may be highly sensitized to caffeine because of excision defects at the DNA replication forks, an idea that may be important in designing cloning strategies for the XP variant gene.« less

Developmental Programming: Impact of Prenatal Testosterone Excess on Insulin Sensitivity, Adiposity, and Free Fatty Acid Profile in Postpubertal Female Sheep

PubMed Central

Veiga-Lopez, A.; Moeller, J.; Patel, D.; Ye, W.; Pease, A.; Kinns, J.

2013-01-01

Prenatal T excess causes reproductive and metabolic disruptions including insulin resistance, attributes of women with polycystic ovary syndrome. This study tested whether increases in visceral adiposity, adipocyte size, and total free fatty acids underlie the insulin resistance seen in prenatal T-treated female sheep. At approximately 16 months of age, insulin resistance and adipose tissue partitioning were determined via hyperinsulinemic euglycemic clamp and computed tomography, respectively, in control and prenatal T-treated females. Three months later, adipocyte size and free fatty acid composition were determined. Results revealed that at the postpubertal time points tested, insulin sensitivity was increased, visceral adiposity and adipocyte size in both the sc and the visceral compartments were reduced, and circulating palmitic acid was increased in prenatal T-treated females relative to controls. In parallel studies, 20-month-old prenatal T-treated females tended to have increased basal insulin to glucose ratio. Relative to earlier findings of reduced insulin sensitivity of prenatal T-treated females during early life and adulthood, these findings of increased insulin sensitivity and reduced adiposity postpubertally are suggestive of a period of developmental adaptation. The disruption observed in free fatty acid metabolism a few months later correspond to a time point when the insulin sensitivity indices of prenatal T-treated animals appear to shift toward insulin resistance. In summary, current findings of improved insulin sensitivity and reduced visceral adiposity in postpubertal prenatal T-treated sheep relative to our earlier findings of reduced insulin sensitivity during early postnatal life and adulthood are indicative of a period of developmental adaptation. PMID:23525243

Can feedback analysis be used to uncover the physical origin of climate sensitivity and efficacy differences?

NASA Astrophysics Data System (ADS)

Rieger, Vanessa S.; Dietmüller, Simone; Ponater, Michael

2017-10-01

Different strengths and types of radiative forcings cause variations in the climate sensitivities and efficacies. To relate these changes to their physical origin, this study tests whether a feedback analysis is a suitable approach. For this end, we apply the partial radiative perturbation method. Combining the forward and backward calculation turns out to be indispensable to ensure the additivity of feedbacks and to yield a closed forcing-feedback-balance at top of the atmosphere. For a set of CO2-forced simulations, the climate sensitivity changes with increasing forcing. The albedo, cloud and combined water vapour and lapse rate feedback are found to be responsible for the variations in the climate sensitivity. An O3-forced simulation (induced by enhanced NOx and CO surface emissions) causes a smaller efficacy than a CO2-forced simulation with a similar magnitude of forcing. We find that the Planck, albedo and most likely the cloud feedback are responsible for this effect. Reducing the radiative forcing impedes the statistical separability of feedbacks. We additionally discuss formal inconsistencies between the common ways of comparing climate sensitivities and feedbacks. Moreover, methodical recommendations for future work are given.

Sensitivity of two salamander (Ambystoma) species to ultraviolet radiation

USGS Publications Warehouse

Calfee, R.D.; Bridges, C.M.; Little, E.E.

2006-01-01

Increased ultraviolet-B (UV-B) radiation reaching the Earth's surface has been implicated in amphibian declines. Recent studies have shown that many amphibian species have differences in sensitivity depending on developmental stage. Embryos and larvae of Ambystoma maculatum (Spotted Salamander) and larvae of Ambystoma talpoideum (Mole Salamander) were exposed to five simulated UV-B treatments in controlled laboratory experiments to determine the relative sensitivity of different lifestages. Hatching success of the embryos exceeded 95% in all treatments; however, the larvae of both species exhibited greater sensitivity to UV-B exposure. Older larvae of A. maculatum that were not exposed to UV-B as embryos were more sensitive than larvae that had hatched during exposure to UV-B. Growth of surviving larvae of A. maculatum was significantly reduced as UV-B intensity increased, whereas growth of A. talpoideum was unaffected. These results were compared to ambient UV-B conditions in natural environments. It appears that the embryo stage is relatively unaffected by UV-B levels observed in natural habitats, probably because of protection from vegetation, organic matter in the water column, oviposition depth, and egg jelly. The larval stage of these species may be at greater risk, particularly if there is an increase in UV-B radiation exposure caused by increases in water clarity and/or decreases in dissolved organic carbon.

Age Dependent Variability in Gene Expression in Fischer 344 ...

EPA Pesticide Factsheets

Recent evidence suggests older adults may be a sensitive population with regard to environmental exposure to toxic compounds. One source of this sensitivity could be an enhanced variability in response. Studies on phenotypic differences have suggested that variation in response does increase with age. However, few reports address the question of variation in gene expression as an underlying cause for increased variability of phenotypic response in the aged. In this study, we utilized global analysis to compare variation in constitutive gene expression in the retinae of young (4 mos), middle-aged (11 mos) and aged (23 mos) Fischer 344 rats. Three hundred and forty transcripts were identified in which variance in expression increased from 4 to 23 mos of age, while only twelve transcripts were found for which it decreased. Functional roles for identified genes were clustered in basic biological categories including cell communication, function, metabolism and response to stimuli. Our data suggest that population stochastically-induced variability should be considered in assessing sensitivity due to old age. Recent evidence suggests older adults may be a sensitive population with regard to environmental exposure to toxic compounds. One source of this sensitivity could be an enhanced variability in response. Studies on phenotypic differences have suggested that variation in response does increase with age. However, few reports address the question of variation in

Hydrostatic Pressure–Induced Release of Stored Calcium in Cultured Rat Optic Nerve Head Astrocytes

PubMed Central

Mandal, Amritlal; Delamere, Nicholas A.

2010-01-01

Purpose. Elevated intraocular pressure is associated with glaucomatous optic nerve damage. Other investigators have shown functional changes in optic nerve head astrocytes subjected to elevated hydrostatic pressure (HP) for 1 to 5 days. Recently, the authors reported ERK1/2, p90RSK and NHE1 phosphorylation after 2 hours. Here they examine calcium responses at the onset of HP to determine what precedes ERK1/2 phosphorylation. Methods. Cytoplasmic calcium concentration ([Ca2+]i) was measured in cultured rat optic nerve astrocytes loaded with fura-2. The cells were placed in a closed imaging chamber and subjected to an HP increase of 15 mm Hg. Protein phosphorylation was detected by Western blot analysis. Results. The increase of HP caused an immediate slow increase in [Ca2+]i. The response persisted in calcium-free solution and when nickel chloride (4 mM) was added to suppress channel-mediated calcium entry. Previous depletion of the ER calcium stores by cyclopiazonic acid abolished the HP-induced calcium level increase. The HP-induced increase persisted in cells exposed to xestospongin C, an inhibitor of IP3R-mediated calcium release. In contrast, ryanodine receptor (RyR) antagonist ruthenium red (10 μM) or dantrolene (25 μM) inhibited the HP-induced calcium increase. The HP-induced calcium increase was abolished when ryanodine-sensitive calcium stores were pre-depleted with caffeine (3 mM). HP caused ERK1/2 phosphorylation. The magnitude of the ERK1/2 phosphorylation response was reduced by ruthenium red and dantrolene. Conclusions. Increasing HP causes calcium release from a ryanodine-sensitive cytoplasmic store and subsequent ERK1/2 activation. Calcium store release appears to be a required early step in the initial astrocyte response to an HP increase. PMID:20071675

Consequences of implementing a cardiac troponin assay with improved sensitivity at Swedish coronary care units: an analysis from the SWEDEHEART registry.

PubMed

Eggers, Kai M; Lindahl, Bertil; Melki, Dina; Jernberg, Tomas

2016-08-07

Cardiac troponin (cTn) assays with improved sensitivity are increasingly utilized for the assessment of patients admitted because of suspected acute coronary syndrome (ACS). However, data on the clinical consequences of the implementation of such assays are limited. In a retrospective register-based study (37 710 coronary care unit admissions; SWEDEHEART registry), we compared the case mix, the use of diagnostic procedures, treatments, and 1-year all-cause mortality 1 year before the implementation of a cTn assay with improved sensitivity (study period 1) and 1 year thereafter (study period 2). During study period 2, more at-risk patients were admitted and more patients had cTn levels above the myocardial infarction cut-off (ACS patients +13.1%; non-ACS patients +160.1%). cTn levels above this cut-off exhibited stronger associations with mortality risk in study period 2 (adjusted HR 4.45 [95% confidence interval, CI, 3.36-5.89]) compared with period 1 (adjusted HR 2.43 [95% CI 2.11-2.80]), similar as for the cTn ratio relative to the respective 99th percentile. While there was no multivariable-adjusted increase in the use of diagnostic procedures, significant trends towards more differentiated treatment depending on the cause of cTn elevation, i.e. ACS or non-ACS, were noted. The implementation of a cTn assay with improved sensitivity was associated with an increase in the number of patients who due to their cTn-status were identified as suitable for beneficial therapies. There was no inappropriate increase in hospital resource utilization. As such, cTn assays with improved sensitivity provide an opportunity to improve the clinical management of patients with suspected ACS. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Accelerometer-Determined Physical Activity and Mortality in a National Prospective Cohort Study: Considerations by Hearing Sensitivity.

PubMed

Loprinzi, Paul D

2015-12-01

Previous work demonstrates that hearing impairment and physical inactivity are associated with premature all-cause mortality. The purpose of this study was to discern whether increased physical activity among those with hearing impairment can produce survival benefits. Data from the 2003-2006 National Health and Nutrition Examination Survey were used, with follow-up through 2011. Physical activity was objectively measured over 7 days via accelerometry. Hearing sensitivity was objectively measured using a modified Hughson Westlake procedure. Among the 1,482 participants, 152 died during the follow-up period (10.26%, unweighted); the unweighted median follow-up period was 89 months (interquartile range = 74-98 months). For those with normal hearing and after adjustments, for every 60-min increase in physical activity, adults had a 19% (HR [Hazard Ratio] = 0.81; 95% confidence interval [CI] [0.48-1.35]; p = .40) reduced risk of all-cause mortality; however, this association was not statistically significant. In a similar manner, physical activity was not associated with all-cause mortality among those with mild hearing loss (HR = 0.76; 95% CI [0.51-1.13]; p = .17). However, after adjustments, and for every 60-min increase in physical activity for those with moderate or greater hearing loss, there was a 20% (HR = 0.20; 95% CI [0.67-0.95]; p = .01) reduced risk of all-cause mortality. Physical activity may help to prolong survival among those with greater hearing impairment.

Glycine and GABAA Ultra-Sensitive Ethanol Receptors as Novel Tools for Alcohol and Brain Research

PubMed Central

Naito, Anna; Muchhala, Karan H.; Asatryan, Liana; Trudell, James R.; Homanics, Gregg E.; Perkins, Daya I.; Alkana, Ronald L.

2014-01-01

A critical obstacle to developing effective medications to prevent and/or treat alcohol use disorders is the lack of specific knowledge regarding the plethora of molecular targets and mechanisms underlying alcohol (ethanol) action in the brain. To identify the role of individual receptor subunits in ethanol-induced behaviors, we developed a novel class of ultra-sensitive ethanol receptors (USERs) that allow activation of a single receptor subunit population sensitized to extremely low ethanol concentrations. USERs were created by mutating as few as four residues in the extracellular loop 2 region of glycine receptors (GlyRs) or γ-aminobutyric acid type A receptors (GABAARs), which are implicated in causing many behavioral effects linked to ethanol abuse. USERs, expressed in Xenopus oocytes and tested using two-electrode voltage clamp, demonstrated an increase in ethanol sensitivity of 100-fold over wild-type receptors by significantly decreasing the threshold and increasing the magnitude of ethanol response, without altering general receptor properties including sensitivity to the neurosteroid, allopregnanolone. These profound changes in ethanol sensitivity were observed across multiple subunits of GlyRs and GABAARs. Collectively, our studies set the stage for using USER technology in genetically engineered animals as a unique tool to increase understanding of the neurobiological basis of the behavioral effects of ethanol. PMID:25245406

Interactions between creep, fatigue and strain aging in two refractory alloys

NASA Technical Reports Server (NTRS)

Sheffler, K. D.

1972-01-01

The application of low-amplitude, high-frequency fatigue vibrations during creep testing of two strain-aging refractory alloys (molybdenum-base TZC and tantalum-base T-111) significantly reduced the creep strength of these materials. This strength reduction caused dramatic increases in both the first stage creep strain and the second stage creep rate. The magnitude of the creep rate acceleration varied directly with both frequency and A ratio (ratio of alternating to mean stress), and also varied with temperature, being greatest in the range where the strain-aging phenomenon was most prominent. It was concluded that the creep rate acceleration resulted from a negative strain rate sensitivity which is associated with the strain aging phenomenon in these materials. (A negative rate sensitivity causes flow stress to decrease with increasing strain rate, instead of increasing as in normal materials). By combining two analytical expressions which are normally used to describe creep and strain aging behavior, an expression was developed which correctly described the influence of temperature, frequency, and A ratio on the TZC creep rate acceleration.

Are amino groups advantageous to insensitive high explosives (IHEs)?

PubMed

Cao, Xia; Wen, Yushi; Xiang, Bin; Long, Xinping; Zhang, Chaoyang

2012-10-01

There is usually a contradiction between increasing energy densities and reducing sensitivities of explosives. The explosives with both high energy densities and low sensitivities, or the so-called insensitive high explosives (IHEs), are desirable in most cases. It seems from applied explosives that amino groups are advantageous to IHE but the amount of amino groups contained IHEs is very limited. To make this clear, we present systemic examinations of the effects on the two properties stressed in IHEs after introducing amino groups to different molecular skeletons. As a result, the amino groups on resonant sites to nitro groups in conjugated systems can improve distinctly sensitivities and change energy densities in terms of oxygen balance; while the amino groups in unconjugated systems can hardly increase energy densities and usually cause increased sensitivities. It agrees well with a fact that almost all the molecules of applied amino group contained explosives possess conjugated skeletons. We therefore confirm that if amino groups are introduced resonantly to a nitro group in a conjugated system and the introduction improves OB, they are advantageous to IHEs.

Sensitive strata in Bootlegger Cove Formation

USGS Publications Warehouse

Olsen, Harold W.

1989-01-01

Sensitivity magnitudes are interpreted from remolded strength values in recent subsurface geologic, geotechnical, and geochemical data from the Bootlegger Cove Formation adjacent to the Turnagain Heights Landslide. The results show that strata composed of highly sensitive clays occur in both the middle and lower zones of the formation, and that between these strata the clays are generally of low-to-medium sensitivity. The most sensitive stratum is in the middle zone between two sand layers, and its sensitivity increases from both clay-sand interfaces to a maximum at the center of the stratum. The pore fluid chemistry of the highly sensitive materials differs from that in the materials of low to medium sensitivity only in their concentrations of organic carbon, chloride, bicarbonate, and sulfate. The total dissolved solids concentration is low, and the ratio of monovalent to divalent cations is very high throughout the middle and lower zones of the formation. Of the known causes of high and extremely high sensitivities, only organic and/or anionic dispersants are consistent with these findings.

Entropy of Masseter Muscle Pain Sensitivity: A New Technique for Pain Assessment.

PubMed

Castrillon, Eduardo E; Exposto, Fernando G; Sato, Hitoshi; Tanosoto, Tomohiro; Arima, Taro; Baad-Hansen, Lene; Svensson, Peter

2017-01-01

To test whether manipulation of mechanical pain sensitivity (MPS) of the masseter muscle is reflected in quantitative measures of entropy. In a randomized, single-blinded, placebo-controlled design, 20 healthy volunteers had glutamate, lidocaine, and isotonic saline injected into the masseter muscle. Self-assessed pain intensity on a numeric rating scale (NRS) was evaluated up to 10 minutes following the injection, and MPS was evaluated after application (at 5 minutes and 30 minutes) of three different forces (0.5 kg, 1 kg, and 2 kg) to 15 different sites of the masseter muscle. Finally, the entropy and center of gravity (COG) of the pain sensitivity scores were calculated. Analysis of variance was used to test differences in means of tested outcomes and Tukey post hoc tests were used to adjust for multiple comparisons. The main findings were: (1) Compared with both lidocaine and isotonic saline, glutamate injections caused an increase in peak, duration, and area under the NRS pain curve (P < .01); (2) A pressure of 2 kg caused the highest NRS pain scores (P < .03) and entropy values (P < .02); (3) Glutamate injections caused increases in entropy values when assessed with 0.5 kg and 1.0 kg but not with 2.0 kg of pressure; and (4) COG coordinates revealed differences between the x coordinates for time (P < .01) and time and force for the y coordinates (P < .01). These results suggest that manipulation of MPS of the masseter muscle with painful glutamate injections can increase the diversity of MPS, which is reflected in entropy measures. Entropy allows quantification of the diversity of MPS, which may be important in clinical assessment of pain states such as myofascial temporomandibular disorders.

Effects of changing climate on reference crop evapotranspiration over 1961-2013 in Xinjiang, China

NASA Astrophysics Data System (ADS)

Yao, Ning; Li, Yi; Sun, Changfeng

2018-01-01

To know the importance of different climate variables on reference crop evapotranspiration ( ET o), a step-by-step sensitivity analysis of ET o to single, two, and multi-climate variables ( C) was conducted. ET o in north, south, and entire Xinjiang Province, China, over 1961-2013 was estimated using the Penman-Monteith equation. Trends in the involved six Cs (i.e., minimum temperature— T min, average temperature— T ave, maximum temperature— T max, wind speed at 2 m— U 2, sunshine hour— n, and relative humidity— RH) were detected by the modified Mann-Kendall test. Nineteen scenarios of changed Cs were preset to obtain recalculated ET o values considering the actual trend in each C and the Pearson's correlation relationship between ET o and Cs. The results showed that ET o was mostly sensitive to T max, U 2, and n. Sensitivity of ET o to the two overlapped changes of T min and T max caused larger increases in ET o than T max and T ave, T ave and T max, T max and (- n), T max and RH, T max and (- U 2), and T min and T ave, but the overlapped changes (- U 2) and (- n) caused larger decreases in ET o than the other two C scenarios. The simultaneously increased T max, T min, T ave, and RH plus decreased U 2 and n had caused the actual decreases in ET o in Xinjiang. In general, the effects of decreased U 2 and n on decreasing ET o compensated the effects of increased T max on decreasing ET o in Xinjiang.

Role of calreticulin in the sensitivity of myocardiac H9c2 cells to oxidative stress caused by hydrogen peroxide.

PubMed

Ihara, Yoshito; Urata, Yoshishige; Goto, Shinji; Kondo, Takahito

2006-01-01

Calreticulin (CRT), a Ca2+-binding molecular chaperone in the endoplasmic reticulum, plays a vital role in cardiac physiology and pathology. Oxidative stress is a main cause of myocardiac apoptosis in the ischemic heart, but the function of CRT under oxidative stress is not fully understood. In the present study, the effect of overexpression of CRT on susceptibility to apoptosis under oxidative stress was examined using myocardiac H9c2 cells transfected with the CRT gene. Under oxidative stress due to H2O2, the CRT-overexpressing cells were highly susceptible to apoptosis compared with controls. In the overexpressing cells, the levels of cytoplasmic free Ca2+ ([Ca2+]i) were significantly increased by H2O2, whereas in controls, only a slight increase was observed. The H2O2-induced apoptosis was enhanced by the increase in [Ca2+]i caused by thapsigargin in control cells but was suppressed by BAPTA-AM, a cell-permeable Ca2+ chelator in the CRT-overexpressing cells, indicating the importance of the level of [Ca2+]i in the sensitivity to H2O2-induced apoptosis. Suppression of CRT by the introduction of the antisense cDNA of CRT enhanced cytoprotection against oxidative stress compared with controls. Furthermore, we found that the levels of activity of calpain and caspase-12 were elevated through the regulation of [Ca2+]i in the CRT-overexpressing cells treated with H2O2 compared with controls. Thus we conclude that the level of CRT regulates the sensitivity to apoptosis under oxidative stress due to H2O2 through a change in Ca2+ homeostasis and the regulation of the Ca2+-calpain-caspase-12 pathway in myocardiac cells.

B-type natriuretic peptides help in cardioembolic stroke diagnosis: pooled data meta-analysis.

PubMed

Llombart, Víctor; Antolin-Fontes, Albert; Bustamante, Alejandro; Giralt, Dolors; Rost, Natalia S; Furie, Karen; Shibazaki, Kensaku; Biteker, Murat; Castillo, José; Rodríguez-Yáñez, Manuel; Fonseca, Ana Catarina; Watanabe, Tetsu; Purroy, Francisco; Zhixin, Wu; Etgen, Thorleif; Hosomi, Naohisa; Jafarian Kerman, Scott Reza; Sharma, Jagdish C; Knauer, Carolin; Santamarina, Estevo; Giannakoulas, George; García-Berrocoso, Teresa; Montaner, Joan

2015-05-01

Determining the underlying cause of stroke is important to optimize secondary prevention treatment. Increased blood levels of natriuretic peptides (B-type natriuretic peptide/N-terminal pro-BNP [BNP/NT-proBNP]) have been repeatedly associated with cardioembolic stroke. Here, we evaluate their clinical value as pathogenic biomarkers for stroke through a literature systematic review and individual participants' data meta-analysis. We searched publications in PubMed database until November 2013 that compared BNP and NT-proBNP circulating levels among stroke causes. Standardized individual participants' data were collected to estimate predictive values of BNP/NT-proBNP for cardioembolic stroke. Dichotomized BNP/NT-proBNP levels were included in logistic regression models together with clinical variables to assess the sensitivity and specificity to identify cardioembolic strokes and the additional value of biomarkers using area under the curve and integrated discrimination improvement index. From 23 selected articles, we collected information of 2834 patients with a defined cause. BNP/NT-proBNP levels were significantly elevated in cardioembolic stroke until 72 hours from symptoms onset. Predictive models showed a sensitivity >90% and specificity >80% when BNP/NT-proBNP were added considering the lowest and the highest quartile, respectively. Both peptides also increased significantly the area under the curve and integrated discrimination improvement index compared with clinical models. Sensitivity, specificity, and precision of the models were validated in 197 patients with initially undetermined stroke with final pathogenic diagnosis after ancillary follow-up. Natriuretic peptides are strongly increased in cardioembolic strokes. Future multicentre prospective studies comparing BNP and NT-proBNP might aid in finding the optimal biomarker, the best time point, and the optimal cutoff points for cardioembolic stroke identification. © 2015 American Heart Association, Inc.

Interaction of ozone exposure with airway hyperresponsiveness and inflammation induced by trimellitic anhydride in sensitized guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Jian; Chung, K.Fan

1997-09-01

The effect of prior ozone (O{sub 3}) exposure on airway hyperresponsiveness and inflammation induced by trimellitic anhydride (TMA) has been investigated in TMA-sensitized guinea pigs. Airway responsiveness was measured as the concentration of acetylcholine needed to increase baseline lung resistance (RL) by 300% (PC300). Ozone (3 ppm, for 3 h) caused an increase in-log PC300 at 1 h after exposure, with return of -log PC300 to control levels at 8 h. Ozone also increased baseline RL at 8 h. TMA challenge increase -log PC300 in TMA-sensitized guinea pigs at 8 h after challenge from 3.85 {+-} 0.09 to 4.11 {+-}more » 0.09. Ozone exposure prior to TMA challenge prevented the induction of airway hyperresponsiveness with a mean -log PC300 of 3.51 {+-} 0.20, which was not different from that of control TMA-Sensitized group. Baseline RL was significantly higher in ozone-pretreated animals after TMA challenge when compared to those of either control or challenged with TMA alone. Ozone had no effect on TMA challenge-induced BAL eosinophilia and neutrophilia. We conclude that a single exposure to ozone inhibits the increase in airway responsiveness, but increases the bronchoconstrictor response induced by TMA in TMA-Sensitized guinea pigs; however, the inflammatory airway response to TMA is unchanged by preexposure to ozone. 29 refs., 2 figs., 1 tab.« less

Thermoluminescence and Antarctic meteorites

NASA Technical Reports Server (NTRS)

Sears, D. W. G.; Hasan, F. A.

1986-01-01

The level of natural thermoluminescence (TL) in meteorites is the result of competition between build-up, due to exposure to cosmic radiation, and thermal decay. Antarctic meteorites tend to have lower natural TL than non-Antarctic meteorites because of their generally larger terrestrial ages. However, since a few observed falls have low TL due to a recent heating event, such as passage within approximately 0.7 astronomical units of the Sun, this could also be the case for some Antarctic meteorites. Dose rate variations due to shielding, heating during atmospheric passage, and anomalous fading also cause natural TL variations, but the effects are either relatively small, occur infrequently, or can be experimentally circumvented. The TL sensitivity of meteorites reflects the abundance and nature of the feldspar. Thus intense shock, which destroys feldspar, causes the TL sensitivity to decrease by 1 to 2 orders of magnitude, while metamorphism, which generates feldspar through the devitrification of glass, causes TL sensitivity to increase by a factor of approximately 10000. The TL-metamorphism relationship is particularly strong for the lowest levels of metamorphism. The order-disorder transformation in feldspar also affect the TL emission characteristics and thus TL provides a means of paleothermometry.

Change in activity of serine palmitoyltransferase affects sensitivity to syringomycin E in yeast Saccharomyces cerevisiae.

PubMed

Toume, Moeko; Tani, Motohiro

2014-09-01

Syringomycin E is a cyclic lipodepsipeptide produced by strains of the plant bacterium Pseudomonas syringae pv. syringae. Genetic studies involving the yeast Saccharomyces cerevisiae have revealed that complex sphingolipids play important roles in the action of syringomycin E. Here, we found a novel mutation that confers resistance to syringomycin E on yeast; that is, a deletion mutant of ORM1 and ORM2, which encode negative regulators of serine palmitoyltransferase catalyzing the initial step of sphingolipid biosynthesis, exhibited resistance to syringomycin E. On the contrary, overexpression of Orm2 resulted in high sensitivity to the toxin. Moreover, overexpression of Lcb1 and Lcb2, catalytic subunits of serine palmitoyltransferase, causes resistance to the toxin, whereas partial repression of expression of Lcb1 had the opposite effect. Partial reduction of complex sphingolipids by repression of expression of Aur1, an inositol phosphorylceramide synthase, also resulted in high sensitivity to the toxin. These results suggested that an increase in sphingolipid biosynthesis caused by a change in the activity of serine palmitoyltransferase causes resistance to syringomycin E. © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Subdiaphragmatic vagotomy increases the sensitivity of lumbar Aδ primary afferent neurons along with voltage-dependent potassium channels in rats.

PubMed

Furuta, Sadayoshi; Watanabe, Lisa; Doi, Seira; Horiuchi, Hiroshi; Matsumoto, Kenjiro; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru

2012-02-01

Subdiaphragmatic vagal dysfunction causes chronic pain. To verify whether this chronic pain is accompanied by enhanced peripheral nociceptive sensitivity, we evaluated primary afferent neuronal excitability in subdiaphragmatic vagotomized (SDV) rats. SDV rats showed a decrease in the electrical stimuli-induced hind limb-flexion threshold at 250 Hz, but showed no similar effect at 5 or 2000 Hz, which indicated that lumbar primary afferent Aδ sensitivity was enhanced in SDV rats. The whole-cell patch-clamp technique also revealed the hyper-excitability of acutely dissociated medium-sized lumbar dorsal root ganglion (DRG) neurons isolated from SDV rats. The contribution of changes in voltage-dependent potassium (Kv) channels was assessed, and transient A-type K(+) (I(A) ) current density was apparently decreased. Moreover, Kv4.3 immunoreactivity in medium-sized DRG neurons was significantly reduced in SDV rats compared to sham. These results indicate that SDV causes hyper-excitability of lumbar primary Aδ afferent neurons, which may be induced along with suppressing I(A) currents via the decreased expression of Kv4.3. Thus, peripheral Aδ neuroplasticity may contribute to the chronic lower limb pain caused by SDV. Copyright © 2011 Wiley Periodicals, Inc.

[Changes in pain sensitivity after the ablation of the somatosensory areas of the cerebral cortex in cats].

PubMed

Reshetniak, V K; Kukushkin, M L

1986-12-01

The effects of ablation of the first and second somatosensory cortex on pain sensitivity were studied in the behavioural experiments on adult cats. The ablation of the first somatosensory cortex (SI) was shown to cause an increase of the response thresholds at all the levels of a conventional scale, while the destruction of the second somatosensory cortex (S2) decreased the response thresholds. The role of SI and S2 in the evaluation of nociceptive information is discussed.

Biological water quality monitoring using chemiluminescent and bioluminescent techniques

NASA Technical Reports Server (NTRS)

Thomas, R. R.

1978-01-01

Automated chemiluminescence and bioluminescence sensors were developed for the continuous monitoring of microbial levels in water supplies. The optimal chemical procedures were determined for the chemiluminescence system to achieve maximum sensitivity. By using hydrogen peroxide, reaction rate differentiation, ethylene diamine tetraacetic acid (EDTA), and carbon monoxide pretreatments, factors which cause interference were eliminated and specificity of the reaction for living and dead bacteria was greatly increased. By employing existing technology with some modifications, a sensitive and specific bioluminescent system was developed.

Changes in hydraulic conductance cause the difference in growth response to short-term salt stress between salt-tolerant and -sensitive black gram (Vigna mungo) varieties.

PubMed

Win, Khin Thuzar; Oo, Aung Zaw; Ookawa, Taiichiro; Kanekatsu, Motoki; Hirasawa, Tadashii

2016-04-01

Black gram (Vigna mungo) is an important crop in Asia, However, most black gram varieties are salt-sensitive. The causes of varietal differences in salt-induced growth reduction between two black gram varieties, 'U-Taung-2' (salt-tolerant; BT) and 'Mut Pe Khaing To' (salt-sensitive; BS), were examined the potential for the first step toward the genetic improvement of salt tolerance. Seedlings grown in vermiculite irrigated with full-strength Hoagland solution were treated with 0mM NaCl (control) or 225 mM NaCl for up to 10 days. In the 225 mM NaCl treatment, plant growth rate, net assimilation rate, mean leaf area, leaf water potential, and leaf photosynthesis were reduced more in BS than in BT plants. Leaf water potential was closely related to leaf photosynthesis, net assimilation rate, and increase in leaf area. In response to salinity stress, hydraulic conductance of the root, stem, and petiole decreased more strongly in BS than in BT plants. The reduction in stem and petiole hydraulic conductance was caused by cavitation, whereas the reduction in root hydraulic conductance in BS plants was caused by a reduction in root surface area and hydraulic conductivity. We conclude that the different reduction in hydraulic conductance is a cause of the differences in the growth response between the two black gram varieties under short-term salt stress. Copyright © 2016 Elsevier GmbH. All rights reserved.

Long-term performance evaluation of positron emission tomography: analysis and proposal of a maintenance protocol for long-term utilization.

PubMed

Watanuki, Shoichi; Tashiro, Manabu; Miyake, Masayasu; Ishikawa, Yoichi; Itoh, Masatoshi; Yanai, Kazuhiko; Sakemi, Yasuhiro; Fukuda, Hiroshi; Ishii, Keizo

2010-07-01

Positron emission tomography (PET) scanners require periodic monitoring in order to maintain scanner performance. The aim of the present study was to examine the deterioration of PET scanner performance caused by aging. We retrospectively examined PET scanner performance alterations in terms of sensitivity, spatial resolution, false coincidences due to scatter and random coincidences based on 13 years of follow-up data, including data when the PET scanner underwent an overhaul at the 10th year after installation. Sensitivity and scatter fraction were calculated by using cross calibration factor (CCF) measurement data, which are collected routinely. Efficacy of the examining the sensitivity and scatter was confirmed by NEMA measurements. Trans-axial resolution was measured as full width at half-maximum (FWHM) and full width at tenth-maximum (FWTM) at 0-20 cm offset from the field of view (FOV) center at the time of installation, 8 years after installation, and immediately after the overhaul. Random coincidence rate fraction was measured in a wide range of count rates before and after the overhaul. The results indicated that the total reduction of sensitivity during the first 10 years was 41% of the initial value in terms of NEMA measurement, and that the annual reduction of sensitivity progressed at a rate of 4.7% per year in terms of CCF measurement data. The changes in sensitivity can be calculated using CCF measurement data. Regarding the spatial resolution, mean FWHM and FWTM values were increased by 1.7 and 3.6%, respectively, in 8 years after installation. The relative scatter fraction was significantly increased compared with that before the overhaul. The random fraction decreased by 10-15% after the overhaul within a certain range of random count rates (1-120 kcps). In the case of our scanner, the parameter that displayed the largest change was the sensitivity, and this change was thought to be caused by the reduction of photomultiplier tube (PMT) gain, although the changes in PMT gain can cause various types of performance deterioration, as investigated in this study. We observed that the sensitivity of our PET scanner generally deteriorated due to aging. Sensitivity monitoring using CCF measurements can be an easy and useful method for monitoring and maintaining the performance of PET scanners against aging. Since the data were obtained from a single scanner, the authors would encourage the initiation of a follow-up study involving various scanners.

Comparing theories of reference-dependent choice.

PubMed

Bhatia, Sudeep

2017-09-01

Preferences are influenced by the presence or absence of salient choice options, known as reference points. This behavioral tendency is traditionally attributed to the loss aversion and diminishing sensitivity assumptions of prospect theory. In contrast, some psychological research suggests that reference dependence is caused by attentional biases that increase the subjective weighting of the reference point's primary attributes. Although both theories are able to successfully account for behavioral findings involving reference dependence, this article shows that these theories make diverging choice predictions when available options are inferior to the reference point. It presents the results of 2 studies that use settings with inferior choice options to compare these 2 theories. The analysis involves quantitative fits to participant-level choice data, and the results indicate that most participants are better described by models with attentional bias than they are by models with loss aversion and diminishing sensitivity. These differences appear to be caused by violations of loss aversion and diminishing sensitivity in losses. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

[The effect of N-stearoylethanolamine on liver phospholipid composition of rats with insulin resistance caused by alimentary obesity].

PubMed

Onopchenko, O V; Kosiakova, H V; Horid'ko, T M; Klimashevskyĭ, V M; Hula, N M

2014-01-01

We used alimentary obesity-induced insulin resistance (IR) model in rats to investigate the influence of N-stearoylethanolamine on the content of phospholipids and their fatty acid composition. Our results show that prolonged high-fat diet triggers considerable aberrations in the composition of main phospholipids in the liver and can be one of the causes of IR in rats. In particular, the increase of phosphatidylcholine, phosphatidylethanolamine and significant decrease of other phospholipids: lysophosphatidylcholine, lysophosphatidylethanolamine, sphingomyelin, phosphatidylinositol, phosphatidylserine and diphosphaglicerol were observed. The levels of monounsaturated (erucic, nervonic, oleic) and polyunsaturated (eicosatrienoic, docosatrienoic, arachidonic) fatty acids were increased; meanwhile the content of diunsaturated acids was decreased. The NSE administration (50 mg/kg of body weight) caused restoration of the phospholipids content in the liver of rats with diet-induced IR that highly correlated with the decrease in plasma insulin level and the improvement of insulin sensitivity. Moreover, the effect of NSE was accompanied by the normalization of fatty acids composition of phospholipids that could be related to modulating influence of NSE on the activity of the main fatty acid desaturases. It is known that the imbalance in phospholipid composition of the rat liver causes substantial metabolic alterations that are associated with the development of IR. Accordingly, the compensations of the imbalance by NSE can help to restore insulin sensitivity, inhibit the development of obesity, IR and type 2 diabetes.

Plasma metabolomic profiles predict near-term death among individuals with lower extremity peripheral arterial disease.

PubMed

Huang, Chiang-Ching; McDermott, Mary M; Liu, Kiang; Kuo, Ching-Hua; Wang, San-Yuan; Tao, Huimin; Tseng, Yufeng Jane

2013-10-01

Individuals with peripheral arterial disease (PAD) have a nearly two-fold increased risk of all-cause and cardiovascular disease mortality compared to those without PAD. This pilot study determined whether metabolomic profiling can accurately identify patients with PAD who are at increased risk of near-term mortality. We completed a case-control study using (1)H NMR metabolomic profiling of plasma from 20 decedents with PAD, without critical limb ischemia, who had blood drawn within 8 months prior to death (index blood draw) and within 10 to 28 months prior to death (preindex blood draw). Twenty-one PAD participants who survived more than 30 months after their index blood draw served as a control population. Results showed distinct metabolomic patterns between preindex decedent, index decedent, and survivor samples. The major chemical signals contributing to the differential pattern (between survivors and decedents) arose from the fatty acyl chain protons of lipoproteins and the choline head group protons of phospholipids. Using the top 40 chemical signals for which the intensity was most distinct between survivor and preindex decedent samples, classification models predicted near-term all-cause death with overall accuracy of 78% (32/41), a sensitivity of 85% (17/20), and a specificity of 71% (15/21). When comparing survivor with index decedent samples, the overall classification accuracy was optimal at 83% (34/41) with a sensitivity of 80% (16/20) and a specificity of 86% (18/21), using as few as the top 10 to 20 chemical signals. Our results suggest that metabolomic profiling of plasma may be useful for identifying PAD patients at increased risk for near-term death. Larger studies using more sensitive metabolomic techniques are needed to identify specific metabolic pathways associated with increased risk of near-term all-cause mortality among PAD patients. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Multiple chemical sensitivity caused by exposure to ignition coal fumes: a case report

PubMed Central

2013-01-01

Background Although multiple chemical sensitivity (MCS) is a well-known disorder caused by environmental exposures, MCS caused by occupational exposure has been reported in Korea. Therefore, we report a MCS case caused by environmental exposure to ignition coal after a differential diagnosis to exclude other diseases. Case report Since 2011, a 55-year-old woman had experienced edema, myalgia, and other symptoms when she smelled ignition coal near her workplace. She had been diagnosed with fibromyalgia syndrome(FMS) and was treated, with no improvement of symptoms. Since then, she showed the same symptoms after exposure to city gas, the smell of burning, and exhaust gas. To avoid triggering substances, she moved to a new house and used an air purifier. She quit her job in November 2012. After visiting our hospital, she underwent a differential diagnosis for FMS, chronic fatigue syndrome, and somatization disorder. She was diagnosed with MCS by the Korean version of the Quick Environment Exposure Sensitivity Inventory (QEESI). She was educated about the disease and to avoid triggering substances. She received ongoing treatment for her symptoms. Conclusion This case showed that symptoms began after smelling ignition coal. After that, her triggers was increased such as the smell of city gas, burning, and exhaust gas. This case is the first reported in Korea of MCS due to environmental exposure after ruling out other diseases. PMID:24472417

What makes a chemical an allergen?

PubMed

Kimber, Ian; Dearman, Rebecca J

2003-05-01

To consider the factors that confer on chemicals the ability to cause allergic sensitization, with particular emphasis on the induction of skin sensitization. Original and review articles available in the scientific literature. The expert opinion of the authors was used to select studies for inclusion in this review. A number of requirements must be met if a chemical is to induce skin sensitization. The most important requirements are access to the viable epidermis, the formation of stable conjugates with proteins, elicitation of cytokine production by skin cells, and the initiation of T-lymphocyte responses. In addition, qualitative aspects of induced immune responses influence the form of allergic sensitization. An increasingly sophisticated understanding of the factors required for the development of skin sensitization and other forms of chemical-induced allergy provides new opportunities for toxicological investigation and clinical management.

Pulmonary Sensitivity to Ozone Exposure in Sedentary Versus Chronically Trained, Female Rats

EPA Science Inventory

Epidemiological data suggest that a sedentary lifestyle may contribute to increased susceptibility to some environmental toxicants. The lack of adequate exercise combined with poor dietary choices are considered to be primary causes of obesity. To study the impact of an active ve...

Activities and effects of ergot alkaloids on livestock physiology and production

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids can have a broad impact on many different physiological mechanisms that can alter the homeostasis of livestock exposed to these toxins through consumption of infested feedstuffs. This altered homeostasis causes an increased sensitivity in livestock to perturbations in the ambient env...

Fungicide sensitivity in the wild rice pathogen Bipolaris oryzae

USDA-ARS?s Scientific Manuscript database

In recent years the occurrence of fungal brown spot, caused by Bipolaris oryzae has increased in cultivated wild rice (Zizania palustris) paddies in spite of the use of fungicides. To implement an efficient integrated disease management system, we are exploring whether field isolates have developed ...

Neonatal status epilepticus alters prefrontal-striatal circuitry and enhances methamphetamine-induced behavioral sensitization in adolescence.

PubMed

Lin, Tzu-Chao; Huang, Li-Tung; Huang, Ya-Ni; Chen, Gunng-Shinng; Wang, Jia-Yi

2009-02-01

Neonatal seizures may alter the developing neurocircuitry and cause behavioral abnormalities in adulthood. We found that rats previously subjected to lithium-pilocarpine (LiPC)-induced neonatal status epilepticus (NeoSE) exhibited enhanced behavioral sensitization to methamphetamine (MA) in adolescence. Neurochemically, dopamine (DA) and metabolites were markedly decreased in prefrontal cortex (PFC) and insignificantly changed in striatum by NeoSE, but were increased in both PFC and striatum by NeoSE+MA. Glutamate levels were increased in both PFC and striatum in the NeoSE+MA group. DA turnover, an index of utilization and activity, was increased by NeoSE but reversed by MA in PFC. Gene expression of the regulator of G-protein signaling 4 (RGS4) was downregulated in PFC and striatum by NeoSE and further suppressed by MA. These findings suggest NeoSE affects both dopaminergic and glutamatergic systems in the prefrontal-striatal circuitry that manifests as enhanced behavioral sensitization to MA in adolescence.

Two Cases of Occupational Contact Urticaria Caused by Percutaneous Sensitization to Parvalbumin

PubMed Central

Sano, Akiyo; Yagami, Akiko; Suzuki, Kayoko; Iwata, Yohei; Kobayashi, Tsukane; Arima, Masaru; Kondo, Yasuto; Yoshikawa, Tetsushi; Matsunaga, Kayoko

2015-01-01

Background In recent years, it has been proposed that the primary mechanism for the development of food allergies is percutaneous sensitization. Since 2010, in Japan, the number of immediate-type wheat allergy due to hydrolyzed wheat protein has dramatically increased among those who have been using soap containing hydrolyzed wheat. This incidence supports the hypothesis that food allergens arise through percutaneous sensitization. Clinical Summary A 25-year-old man (case 1) and an 18-year-old girl (case 2) with atopic dermatitis visited our Department because of food allergy and hand eczema. After starting their work with fish, severe itchy eczema appeared on their hands. They subsequently started to experience oral allergic symptoms, intraoral itchiness and dyspnea after eating fish. Specific IgE antibodies were detected for many fishes, and skin prick tests showed positive reactions for a variety of fishes in both cases. Furthermore, the fluorescence intensities of specific IgE antibodies against parvalbumin from various types of fish in microarray immunoassay analysis showed positive reactions. We diagnosed them as contact urticaria caused by percutaneous sensitization to parvalbumin through job-related physical contact with fish. Conclusion The patients' histories and findings indicate the possibility of percutaneous sensitization through occupational exposure to parvalbumin, leading to food allergy. PMID:26464568

KRAS Mutation Is a Predictor of Oxaliplatin Sensitivity in Colon Cancer Cells

PubMed Central

Lin, Yu-Lin; Ou, Da-Liang; Lin, Liang-In; Tseng, Li-Hui; Chang, Yih-Leong; Yeh, Kun-Huei; Cheng, Ann-Lii

2012-01-01

Molecular biomarkers to determine the effectiveness of targeted therapies in cancer treatment have been widely adopted in colorectal cancer (CRC), but those to predict chemotherapy sensitivity remain poorly defined. We tested our hypothesis that KRAS mutation may be a predictor of oxaliplatin sensitivity in CRC. KRAS was knocked-down in KRAS-mutant CRC cells (DLD-1G13D and SW480G12V) by small interfering RNAs (siRNA) and overexpressed in KRAS-wild-type CRC cells (COLO320DM) by KRAS-mutant vectors to generate paired CRC cells. These paired CRC cells were tested by oxaliplatin, irinotecan and 5FU to determine the change in drug sensitivity by MTT assay and flow cytometry. Reasons for sensitivity alteration were further determined by western blot and real-time quantitative reverse transcriptase polymerase chain reaction (qRT -PCR). In KRAS-wild-type CRC cells (COLO320DM), KRAS overexpression by mutant vectors caused excision repair cross-complementation group 1 (ERCC1) downregulation in protein and mRNA levels, and enhanced oxaliplatin sensitivity. In contrast, in KRAS-mutant CRC cells (DLD-1G13D and SW480G12V), KRAS knocked-down by KRAS-siRNA led to ERCC1 upregulation and increased oxaliplatin resistance. The sensitivity of irinotecan and 5FU had not changed in the paired CRC cells. To validate ERCC1 as a predictor of sensitivity for oxaliplatin, ERCC1 was knocked-down by siRNA in KRAS-wild-type CRC cells, which restored oxaliplatin sensitivity. In contrast, ERCC1 was overexpressed by ERCC1-expressing vectors in KRAS-mutant CRC cells, and caused oxaliplatin resistance. Overall, our findings suggest that KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells by the mechanism of ERCC1 downregulation. PMID:23209813

Inhibition of hyaluronic acid formation sensitizes chronic myelogenous leukemia to treatment with doxorubicin.

PubMed

Uchakina, Olga N; Ban, Hao; Hostetler, Bryan J; McKallip, Robert J

2016-11-01

In the current study we examined the ability of 4-methylumbelliferone (4-MU), which can inhibit hyaluronic acid synthesis, to sensitize K562 chronic myelogenous leukemia (CML) cells to doxorubicin therapy. Exposure of K562 cells to doxorubicin led to increased hyaluronic acid synthase (HAS) gene expression and increased levels of cell surface hyaluronic acid. Furthermore, exposure of K562 cells to exogenous HA caused resistance to doxorubicin-induced cell death. The combination of low dose 4-MU and doxorubicin led to increased apoptosis when compared to higher doses of any agent alone. Additionally, treatment with 4-MU led to a significant reduction in doxorubicin-induced increase in HA cell surface expression. Mechanistically, 4-MU treatment led to an increase in p38 activation and PARP cleavage. The role of p38 in 4-MU/doxorubicin-treated K562 cells was confirmed when p38 inhibitors led to protection from 4-MU/doxorubicin-induced apoptosis. Together, results from this study suggest that treatment with 4-MU increases the sensitivity of CML to chemotherapeutics by decreasing their HA-mediated resistance to apoptosis. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The mycotoxin deoxynivalenol facilitates allergic sensitization to whey in mice.

PubMed

Bol-Schoenmakers, M; Braber, S; Akbari, P; de Graaff, P; van Roest, M; Kruijssen, L; Smit, J J; van Esch, B C A M; Jeurink, P V; Garssen, J; Fink-Gremmels, J; Pieters, R H H

2016-11-01

Intestinal epithelial stress or damage may contribute to allergic sensitization against certain food antigens. Hence, the present study investigated whether impairment of intestinal barrier integrity by the mycotoxin deoxynivalenol (DON) contributes to the development of whey-induced food allergy in a murine model. C3H/HeOuJ mice, orally exposed to DON plus whey once a week for 5 consecutive weeks, showed whey-specific IgG1 and IgE in serum and an acute allergic skin response upon intradermal whey challenge, although early initiating mechanisms of sensitization in the intestine appeared to be different compared with the widely used mucosal adjuvant cholera toxin (CT). Notably, DON exposure modulated tight-junction mRNA and protein levels, and caused an early increase in IL-33, whereas CT exposure affected intestinal γδ T cells. On the other hand, both DON- and CT-sensitized mice induced a time-dependent increase in the soluble IL-33 receptor ST2 (IL-1R1) in serum, and enhanced local innate lymphoid cells type 2 cell numbers. Together, these results demonstrate that DON facilitates allergic sensitization to food proteins and that development of sensitization can be induced by different molecular mechanisms and local immune responses. Our data illustrate the possible contribution of food contaminants in allergic sensitization in humans.

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension.

PubMed

Ronzaud, Caroline; Loffing-Cueni, Dominique; Hausel, Pierrette; Debonneville, Anne; Malsure, Sumedha Ram; Fowler-Jaeger, Nicole; Boase, Natasha A; Perrier, Romain; Maillard, Marc; Yang, Baoli; Stokes, John B; Koesters, Robert; Kumar, Sharad; Hummler, Edith; Loffing, Johannes; Staub, Olivier

2013-02-01

The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK.

The use of the Petri net method in the simulation modeling of mitochondrial swelling.

PubMed

Danylovych, Yu V; Chunikhin, A Y; Danylovych, G V; Kolomiets, O V

2016-01-01

Using photon correlation spectroscopy, which allows investigating changes in the hydrodynamic dia­meter of the particles in suspension, it was shown that ultrahigh concentrations of Ca2+ (over 10 mM) induce swelling of isolated mitochondria. An increase in hydrodynamic diameter was caused by an increase of non-specific mitochondrial membrane permeability to Ca ions, matrix Ca2+ overload, activation of ATP- and Ca2+-sensitive K+-channels, as well as activation of cyclosporin-sensitive permeability transition pore. To formalize the experimental data and to assess conformity of experimental results with theoretical predictions we developed a simulation model using the hybrid functional Petri net method.

Baroreflex and neurovascular responses to skeletal muscle mechanoreflex activation in humans: an exercise in integrative physiology.

PubMed

Drew, Rachel C

2017-12-01

Cardiovascular adjustments to exercise resulting in increased blood pressure (BP) and heart rate (HR) occur in response to activation of several neural mechanisms: the exercise pressor reflex, central command, and the arterial baroreflex. Neural inputs from these feedback and feedforward mechanisms integrate in the cardiovascular control centers in the brain stem and modulate sympathetic and parasympathetic neural outflow, resulting in the increased BP and HR observed during exercise. Another specific consequence of the central neural integration of these inputs during exercise is increased sympathetic neural outflow directed to the kidneys, causing renal vasoconstriction, a key reflex mechanism involved in blood flow redistribution during increased skeletal muscle work. Studies in humans have shown that muscle mechanoreflex activation inhibits cardiac vagal outflow, decreasing the sensitivity of baroreflex control of HR. Metabolite sensitization of muscle mechanoreceptors can lead to reduced sensitivity of baroreflex control of HR, with thromboxane being one of the metabolites involved, via greater inhibition of cardiac vagal outflow without affecting baroreflex control of BP or baroreflex resetting. Muscle mechanoreflex activation appears to play a predominant role in causing renal vasoconstriction, both in isolation and in the presence of local metabolites. Limited investigations in older adults and patients with cardiovascular-related disease have provided some insight into how the influence of muscle mechanoreflex activation on baroreflex function and renal vasoconstriction is altered in these populations. However, future research is warranted to better elucidate the specific effect of muscle mechanoreflex activation on baroreflex and neurovascular responses with aging and cardiovascular-related disease. Copyright © 2017 the American Physiological Society.

VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity

PubMed Central

2012-01-01

Background This work tests the hypothesis that bladder instillation with vascular endothelial growth factor (VEGF) modulates sensory and motor nerve plasticity, and, consequently, bladder function and visceral sensitivity. In addition to C57BL/6J, ChAT-cre mice were used for visualization of bladder cholinergic nerves. The direct effect of VEGF on the density of sensory nerves expressing the transient receptor potential vanilloid subfamily 1 (TRPV1) and cholinergic nerves (ChAT) was studied one week after one or two intravesical instillations of the growth factor. To study the effects of VEGF on bladder function, mice were intravesically instilled with VEGF and urodynamic evaluation was assessed. VEGF-induced alteration in bladder dorsal root ganglion (DRG) neurons was performed on retrogradly labeled urinary bladder afferents by patch-clamp recording of voltage gated Na+ currents. Determination of VEGF-induced changes in sensitivity to abdominal mechanostimulation was performed by application of von Frey filaments. Results In addition to an overwhelming increase in TRPV1 immunoreactivity, VEGF instillation resulted in an increase in ChAT-directed expression of a fluorescent protein in several layers of the urinary bladder. Intravesical VEGF caused a profound change in the function of the urinary bladder: acute VEGF (1 week post VEGF treatment) reduced micturition pressure and longer treatment (2 weeks post-VEGF instillation) caused a substantial reduction in inter-micturition interval. In addition, intravesical VEGF resulted in an up-regulation of voltage gated Na+ channels (VGSC) in bladder DRG neurons and enhanced abdominal sensitivity to mechanical stimulation. Conclusions For the first time, evidence is presented indicating that VEGF instillation into the mouse bladder promotes a significant increase in peripheral nerve density together with alterations in bladder function and visceral sensitivity. The VEGF pathway is being proposed as a key modulator of neural plasticity in the pelvis and enhanced VEGF content may be associated with visceral hyperalgesia, abdominal discomfort, and/or pelvic pain. PMID:23249422

Soil organic matter decomposition and temperature sensitivity after forest fire in permafrost regions in Canada

NASA Astrophysics Data System (ADS)

Aaltonen, Heidi; Palviainen, Marjo; Köster, Kajar; Berninger, Frank; Pumpanen, Jukka

2017-04-01

On the Northern Hemisphere, 24% of soils are underlain by permafrost. These soils contain 50% of the global soil carbon pool. The Northern Hemisphere is also the region which is predicted to be most affected by climate warming and this causes uncertainties over the future of the permafrost. It has been estimated that 25% of permafrost might thaw by 2100, exposing previously frozen carbon pools to decomposition. In addition, global warming is expected to cause increase in the frequency of wild fires, which further increase permafrost melting by removing the insulating organic surface layer. The amount of released soil carbon from permafrost soils after forest fire is affected by degradability and temperature sensitivity of the soil organic matter, as well as soil depth and the stage of succession. Yet the common effect of these factors remains unclear. We studied how soil respiration and its temperature sensitivity (Q10) vary in different depths and within time by taking soil samples from different fire chronosequence areas (burned 3, 25, 46 and 100 years ago) from permafrost region in Northern Canada (Yukon and Northwest Territories, along Dempster Highway). The samples from three different depths (5, 10 and 30 cm) were incubated in four different temperatures (1, 7, 13 and 19°C) over 24h. Our results showed that the CO2 fluxes followed the stages of succession, with recently burned sites having lowest rates. The organic matter at 5 cm depth proved to be more labile and temperature sensitive than in deeper depths. The Q10 values, however, did not differ between sites, excluding 30 cm at the most recently burned site that had a significantly higher Q10 value than the other sites. The results implicate that heterotrophic soil respiration decreases on permafrost regions during the first stages after forest fire. At the same time the temperature sensitivity in deeper soil layers may increase.

EFFECT OF DIESEL EXHAUST EXPOSURE ON MUCOSAL SENSITIZATION TO OVALBUMIN ANTIGEN.

EPA Science Inventory

Several studies in humans and animals have shown that diesel exhaust (DE) can act as an immunological adjuvant to increase the severity of Type I hypersensitivity immune responses. The mechanism by which DE causes these effects is unknown but thought to be associated with lung in...

Alternaria leaf spot in Michigan and fungicide sensitivity issues

USDA-ARS?s Scientific Manuscript database

Since 2010 there has been an increase in identification of Alternaria leaf spot on sugar beet in Michigan and other growing regions in the US and Canada. In 2016, the disease was severe enough to cause economic losses in the Michigan growing region. Michigan isolates from sugar beet were examined ...

Novel insights on diagnosis, cause and treatment of diabetic neuropathy: focus on painful diabetic neuropathy

PubMed Central

Tavakoli, Mitra; Asghar, Omar; Alam, Uazman; Petropoulos, Ioannis N.; Fadavi, Hassan; Malik, Rayaz A.

2010-01-01

Diabetic neuropathy is common, under or misdiagnosed, and causes substantial morbidity with increased mortality. Defining and developing sensitive diagnostic tests for diabetic neuropathy is not only key to implementing earlier interventions but also to ensure that the most appropriate endpoints are employed in clinical intervention trials. This is critical as many potentially effective therapies may never progress to the clinic, not due to a lack of therapeutic effect, but because the endpoints were not sufficiently sensitive or robust to identify benefit. Apart from improving glycaemic control, there is no licensed treatment for diabetic neuropathy, however, a number of pathogenetic pathways remain under active study. Painful diabetic neuropathy is a cause of considerable morbidity and whilst many pharmacological and nonpharmacological interventions are currently used, only two are approved by the US Food and Drug Administration. We address the important issue of the ‘placebo effect’ and also consider potential new pharmacological therapies as well as nonpharmacological interventions in the treatment of painful diabetic neuropathy. PMID:23148152

Inhomogeneous Forcing and Transient Climate Sensitivity

NASA Technical Reports Server (NTRS)

Shindell, Drew T.

2014-01-01

Understanding climate sensitivity is critical to projecting climate change in response to a given forcing scenario. Recent analyses have suggested that transient climate sensitivity is at the low end of the present model range taking into account the reduced warming rates during the past 10-15 years during which forcing has increased markedly. In contrast, comparisons of modelled feedback processes with observations indicate that the most realistic models have higher sensitivities. Here I analyse results from recent climate modelling intercomparison projects to demonstrate that transient climate sensitivity to historical aerosols and ozone is substantially greater than the transient climate sensitivity to CO2. This enhanced sensitivity is primarily caused by more of the forcing being located at Northern Hemisphere middle to high latitudes where it triggers more rapid land responses and stronger feedbacks. I find that accounting for this enhancement largely reconciles the two sets of results, and I conclude that the lowest end of the range of transient climate response to CO2 in present models and assessments (less than 1.3 C) is very unlikely.

Layout-aware simulation of soft errors in sub-100 nm integrated circuits

NASA Astrophysics Data System (ADS)

Balbekov, A.; Gorbunov, M.; Bobkov, S.

2016-12-01

Single Event Transient (SET) caused by charged particle traveling through the sensitive volume of integral circuit (IC) may lead to different errors in digital circuits in some cases. In technologies below 180 nm, a single particle can affect multiple devices causing multiple SET. This fact adds the complexity to fault tolerant devices design, because the schematic design techniques become useless without their layout consideration. The most common layout mitigation technique is a spatial separation of sensitive nodes of hardened circuits. Spatial separation decreases the circuit performance and increases power consumption. Spacing should thus be reasonable and its scaling follows the device dimensions' scaling trend. This paper presents the development of the SET simulation approach comprised of SPICE simulation with "double exponent" current source as SET model. The technique uses layout in GDSII format to locate nearby devices that can be affected by a single particle and that can share the generated charge. The developed software tool automatizes multiple simulations and gathers the produced data to present it as the sensitivity map. The examples of conducted simulations of fault tolerant cells and their sensitivity maps are presented in this paper.

Highly sensitive wearable strain sensor based on silver nanowires and nanoparticles.

PubMed

Shengbo, Sang; Lihua, Liu; Aoqun, Jian; Qianqian, Duan; Jianlong, Ji; Qiang, Zhang; Wendong, Zhang

2018-06-22

Here, we propose a highly sensitive and stretchable strain sensor based on silver nanoparticles and nanowires (Ag NPs and NWs), advancing the rapid development of electronic skin. To improve the sensitivity of strain sensors based on silver nanowires (Ag NWs), Ag NPs and NWs were added to polydimethylsiloxane (PDMS) as an aid filler. Silver nanoparticles (Ag NPs) increase the conductive paths for electrons, leading to the low resistance of the resulting sensor (14.9 Ω). The strain sensor based on Ag NPs and NWs showed strong piezoresistivity with a tunable gauge factor (GF) at 3766, and a change in resistance as the strain linearly increased from 0% to 28.1%. The high GF demonstrates the irreplaceable role of Ag NPs in the sensor. Moreover, the applicability of our high-performance strain sensor has been demonstrated by its ability to sense movements caused by human talking, finger bending, wrist raising and walking.

Absence of cross-resistance between two alkylating agents: BCNU vs bifunctional galactitol.

PubMed

Institóris, E; Szikla, K; Otvös, L; Gál, F

1989-01-01

Dianhydrogalactitol (DAG) increased the life span of both BCNU-sensitive and -resistant L1210 tumor-bearing mice. However, the BCNU-resistant strain showed slightly lower sensitivity against DAG, which could be overcome by an increase in drug dose of ca. 20%. The somewhat lower sensitivity was proportional to a slightly reduced DNA cross-linking formation induced by DAG in BCNU-resistant cells. The amount of DNA cross-links was determined by measurement of the 1,6-di(guaninyl)-galactitol content of DNA. The slight reduction in cross-links is not attributable to DNA repair but rather to other factors that seem to prevent the formation of DNA-drug adducts. The absence of cross-resistance is explained by different kinds of DNA damage caused by the two alkylating agents and the presumably different defense mechanisms developed by cells against these lesions.

Sensitivity to neurotoxic stress is not increased in progranulin-deficient mice.

PubMed

Petkau, Terri L; Zhu, Shanshan; Lu, Ge; Fernando, Sarah; Cynader, Max; Leavitt, Blair R

2013-11-01

Loss-of-function mutations in the progranulin (GRN) gene are a common cause of autosomal dominant frontotemporal lobar degeneration, a fatal and progressive neurodegenerative disorder common in people less than 65 years of age. In the brain, progranulin is expressed in multiple regions at varying levels, and has been hypothesized to play a neuroprotective or neurotrophic role. Four neurotoxic agents were injected in vivo into constitutive progranulin knockout (Grn(-/-)) mice and their wild-type (Grn(+/+)) counterparts to assess neuronal sensitivity to toxic stress. Administration of 3-nitropropionic acid, quinolinic acid, kainic acid, and pilocarpine induced robust and measurable neuronal cell death in affected brain regions, but no differential cell death was observed between Grn(+/+) and Grn(-/-) mice. Thus, constitutive progranulin knockout mice do not have increased sensitivity to neuronal cell death induced by the acute chemical models of neuronal injury used in this study. Copyright © 2013. Published by Elsevier Inc.

Highly sensitive wearable strain sensor based on silver nanowires and nanoparticles

NASA Astrophysics Data System (ADS)

Shengbo, Sang; Lihua, Liu; Aoqun, Jian; Qianqian, Duan; Jianlong, Ji; Qiang, Zhang; Wendong, Zhang

2018-06-01

Here, we propose a highly sensitive and stretchable strain sensor based on silver nanoparticles and nanowires (Ag NPs and NWs), advancing the rapid development of electronic skin. To improve the sensitivity of strain sensors based on silver nanowires (Ag NWs), Ag NPs and NWs were added to polydimethylsiloxane (PDMS) as an aid filler. Silver nanoparticles (Ag NPs) increase the conductive paths for electrons, leading to the low resistance of the resulting sensor (14.9 Ω). The strain sensor based on Ag NPs and NWs showed strong piezoresistivity with a tunable gauge factor (GF) at 3766, and a change in resistance as the strain linearly increased from 0% to 28.1%. The high GF demonstrates the irreplaceable role of Ag NPs in the sensor. Moreover, the applicability of our high-performance strain sensor has been demonstrated by its ability to sense movements caused by human talking, finger bending, wrist raising and walking.

Flow Line, Durafill VS, and Dycal toxicity to dental pulp cells: effects of growth factors

PubMed Central

Furey, Alyssa; Hjelmhaug, Julie; Lobner, Doug

2010-01-01

Introduction The objective was to determine the effects of growth factor treatment on dental pulp cell sensitivity to toxicity of two composite restoration materials, Flow Line and Durafill VS, and a calcium hydroxide pulp capping material, Dycal. Methods Toxicity of the dental materials to cultures of primary dental pulp cells was determined by the MTT metabolism assay. The ability of six different growth factors to influence the toxicity was tested. Results A 24 hour exposure to either Flow Line or Durafill VS caused approximately 40% cell death, while Dycal exposure caused approximately 80% cell death. The toxicity of Flow Line and Durafill VS was mediated by oxidative stress. Four of the growth factors tested (BMP-2, BMP-7, EGF, and TGF-β) decreased the basal MTT values while making the cells resistant to Flow Line and Durafill VS toxicity, except BMP-2 which made the cells more sensitive to Flow Line. Treatment with FGF-2 caused no change in basal MTT metabolism, prevented the toxicity of Durafill VS, but increased the toxicity of Flow Line. Treatment with IGF-I increased basal MTT metabolism and made the cells resistant to Flow Line and Durafill VS toxicity. None of the growth factors made the cells resistant to Dycal toxicity. Conclusions The results indicate that growth factors can be used to alter the sensitivity of dental pulp cells to commonly used restoration materials. The growth factors BMP-7, EGF, TGF-β, and IGF-I provided the best profile of effects, making the cells resistant to both Flow Line and Durafill VS toxicity. PMID:20630288

Acrolein increases airway sensitivity to substance P and decreases NEP activity in guinea pigs.

PubMed

Turner, C R; Stow, R B; Hubbs, S J; Gomes, B C; Williams, J C

1993-04-01

The effects of acrolein exposure on airway responses to intravenous substance P were determined in guinea pigs exposed to vehicle or 1.6 ppm acrolein for 7.5 h on 2 consecutive days and examined 1, 4, 8, 15, and 28 days after exposure by use of pulmonary mechanics and bronchoalveolar lavage (BAL). Lung, trachea, liver, and BAL fluid were also assayed for neutral endopeptidase (NEP) activity 1, 7, and 28 days after exposure. Pulmonary inflammation and epithelial damage were prominent 1 day after acrolein exposure. NEP activity was decreased in the lungs, trachea, and liver 1 and 7 days after acrolein. Twenty-eight days after exposure, NEP activity in the lungs and liver was not significantly different in vehicle- and acrolein-exposed guinea pigs but was still reduced in tracheal tissue. The BAL NEP activity in acrolein-exposed guinea pigs was approximately twice that of vehicle control guinea pigs at all three time points. Acrolein caused a prolonged increase in airway sensitivity to substance P. Experiments performed in the presence of thiorphan suggested that the acrolein-induced reduction in NEP may contribute to increased airway sensitivity to aerosolized substance P, but the increase in airway sensitivity to intravenous substance P may occur by additional mechanisms.

Differential Expression of FAK and Pyk2 in Metastatic and Non-metastatic EL4 Lymphoma Cell Lines

PubMed Central

Zhang, Zhihong; Knoepp, Stewart M.; Ku, Hsun; Sansbury, Heather M.; Xie, Yuhuan; Chahal, Manpreet S.; Tomlinson, Stephen; Meier, Kathryn E.

2011-01-01

The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to phorbol 12-myristate 13-acetate (PMA). In sensitive cells, PMA causes Erk MAPK activation and Erk-mediated growth arrest. In resistant cells, PMA induces a low level of Erk activation, without growth arrest. A relatively unexplored aspect of the phenotypes is that resistant cells are more adherent to culture substrate than are sensitive cells. In this study, the roles of the protein tyrosine kinases FAK and Pyk2 in EL4 phenotype were examined, with a particular emphasis on the role of these proteins in metastasis. FAK is expressed only in PMA-resistant (or intermediate phenotype) EL4 cells, correlating with enhanced cell-substrate adherence, while Pyk2 is more highly expressed in non-adherent PMA-sensitive cells. PMA treatment causes modulation of mRNA for FAK (up-regulation) and Pyk2 (down-regulation) in PMA-sensitive but not PMA-resistant EL4 cells. The increase in Pyk2 mRNA is correlated with an increase in Pyk2 protein expression. The roles of FAK in cell phenotype were further explored using transfection and knockdown experiments. The results showed that FAK does not play a major role in modulating PMA-induced Erk activation in EL4 cells. However, the knockdown studies demonstrated that FAK expression is required for proliferation and migration of PMA-resistant cells. In an experimental metastasis model using syngeneic mice, only FAK-expressing (PMA-resistant) EL4 cells form liver tumors. Taken together, these studies suggest that FAK expression promotes metastasis of EL4 lymphoma cells. PMID:21533871

Differential expression of FAK and Pyk2 in metastatic and non-metastatic EL4 lymphoma cell lines.

PubMed

Zhang, Zhihong; Knoepp, Stewart M; Ku, Hsun; Sansbury, Heather M; Xie, Yuhuan; Chahal, Manpreet S; Tomlinson, Stephen; Meier, Kathryn E

2011-08-01

The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to phorbol 12-myristate 13-acetate (PMA). In sensitive cells, PMA causes Erk MAPK activation and Erk-mediated growth arrest. In resistant cells, PMA induces a low level of Erk activation, without growth arrest. A relatively unexplored aspect of the phenotypes is that resistant cells are more adherent to culture substrate than are sensitive cells. In this study, the roles of the protein tyrosine kinases FAK and Pyk2 in EL4 phenotype were examined, with a particular emphasis on the role of these proteins in metastasis. FAK is expressed only in PMA-resistant (or intermediate phenotype) EL4 cells, correlating with enhanced cell-substrate adherence, while Pyk2 is more highly expressed in non-adherent PMA-sensitive cells. PMA treatment causes modulation of mRNA for FAK (up-regulation) and Pyk2 (down-regulation) in PMA-sensitive but not PMA-resistant EL4 cells. The increase in Pyk2 mRNA is correlated with an increase in Pyk2 protein expression. The roles of FAK in cell phenotype were further explored using transfection and knockdown experiments. The results showed that FAK does not play a major role in modulating PMA-induced Erk activation in EL4 cells. However, the knockdown studies demonstrated that FAK expression is required for proliferation and migration of PMA-resistant cells. In an experimental metastasis model using syngeneic mice, only FAK-expressing (PMA-resistant) EL4 cells form liver tumors. Taken together, these studies suggest that FAK expression promotes metastasis of EL4 lymphoma cells.

Human T-Cell Leukemia Virus I Tax Protein Sensitizes p53-Mutant Cells to DNA Damage

PubMed Central

Mihaylova, Valia T.; Green, Allison M.; Khurgel, Moshe; Semmes, Oliver J.; Kupfer, Gary M.

2018-01-01

Mutations in p53 are a common cause of resistance of cancers to standard chemotherapy and, thus, treatment failure. Reports have shown that Tax, a human T-cell leukemia virus type I encoded protein that has been associated with genomic instability and perturbation of transcription and cell cycle, sensitizes HeLa cells to UV treatment. The extent to which Tax can sensitize cells and the mechanism by which it exerts its effect are unknown. In this study, we show that Tax sensitizes p53-mutant cells to a broad range of DNA-damaging agents, including mitomycin C, a bifunctional alkylator, etoposide, a topoisomerase II drug, and UV light, but not ionizing radiation, a double-strand break agent, or vinblastine, a tubulin poison. Tax caused hypersensitivity in all p53-deleted cell lines and several, but not all, mutant-expressed p53–containing cell lines, while unexpectedly being protective in p53 wild-type (wt) cells. The effect observed in p53-deleted lines could be reversed for this by transfection of wt p53. We also show that Tax activates a p53-independent proapoptotic program through decreased expression of the retinoblastoma protein and subsequent increased E2F1 expression. The expression of several proapoptotic proteins was also induced by Tax, including Puma and Noxa, culminating in a substantial increase in Bax dimerization. Our results show that Tax can sensitize p53-mutant cells to DNA damage while protecting p53 wt cells, a side benefit that might result in reduced toxicity in normal cells. Such studies hold the promise of a novel adjunctive therapy that could make cancer chemotherapy more effective. PMID:18559532

North-south differences in Chinese agricultural losses due to climate-change-influenced droughts

NASA Astrophysics Data System (ADS)

Qiang, Zhang; Lanying, Han; Jingjing, Lin; Qingyan, Cheng

2018-01-01

One of the effects of global climate change is increase in the frequency and severity of drought, which strongly affects the Chinese agricultural production. In order to cope these changes more effectively, it is important to document and analyze the agricultural losses caused by drought. We collected and analyzed conventional meteorological data and agricultural statistics data, in order to outline trends in drought occurrence and decline in agricultural yield. Data were assembled for the period 1960-2010. The study pays particular attention to regional differences between northern and southern China. Our results show the drought-caused agricultural loss rates (DCALR) in China have increased by approximately 0.5% per decade in the past 50 years. The study area in this paper is for the whole of the People's Republic of China, minus the Qinghai-Tibetan Plateau; when we analyzed regional differences, we found that losses increased by approximately 0.6% per decade in northern China, close to twice the increase in southern China. Moreover, drought risks and agricultural losses are rising faster in northern China. Our results also indicate that the agriculture in northern China is more sensitive to changes in precipitation, whereas the agriculture in southern China is more sensitive to temperature changes.

Assessment of the sensitizing potency of preservatives with chance of skin contact by the loose-fit coculture-based sensitization assay (LCSA).

PubMed

Sonnenburg, Anna; Schreiner, Maximilian; Stahlmann, Ralf

2015-12-01

Parabens, methylisothiazolinone (MI) and its derivative methylchloroisothiazolinone (MCI), are commonly used as preservatives in personal care products. They can cause hypersensitivity reactions of the human skin. We have tested a set of nine parabens, MI alone and in combination with MCI in the loose-fit coculture-based sensitization assay (LCSA). The coculture of primary human keratinocytes and allogenic dendritic cell-related cells (DC-rc) in this assay emulates the in vivo situation of the human skin. Sensitization potency of the test substances was assessed by flow cytometric analysis of the DC-rc maturation marker CD86. Determination of the concentration required to cause a half-maximal increase in CD86-expression (EC50sens) allowed a quantitative evaluation. The cytotoxicity of test substances as indicator for irritative potency was measured by 7-AAD (7-amino-actinomycin D) staining. Parabens exhibited weak (methyl-, ethyl-, propyl- and isopropylparaben) or strong (butyl-, isobutyl-, pentyl- and benzylparaben) effects, whereas phenylparaben was found to be a moderate sensitizer. Sensitization potencies of parabens correlated with side chain length. Due to a pronounced cytotoxicity, we could not estimate an EC50sens value for MI, whereas MI/MCI was classified as sensitizer and also showed cytotoxic effects. Parabens showed no (methyl- and ethylparaben) or weak irritative potencies (propyl-, isopropyl-, butyl-, isobutyl-, phenyl- and benzylparaben), only pentylparaben was rated to be irritative. Overall, we were able to demonstrate and compare the sensitizing potencies of parabens in this in vitro test. Furthermore, we showed an irritative potency for most of the preservatives. The data further support the usefulness of the LCSA for comparison of the sensitizing potencies of xenobiotics.

Metabolic effects of cortisol, ACTH, adrenalin and insulin in the marsupial sugar glider, Petaurus breviceps.

PubMed

Bradley, A J; Stoddart, D M

1990-11-01

The effects of cortisol, ACTH, adrenalin and insulin on indices of carbohydrate, fat and protein metabolism were investigated in the conscious marsupial sugar glider Petaurus breviceps. Short-term i.v. infusion of cortisol at dose rates of 0.02, 0.2 and 1.0 mg/kg per h caused the plasma glucose concentration to rise sharply from the normal range of 3.3-4.4 to 8.1-8.7 mmol/l at the end of the infusion period without significant alteration in plasma free fatty acid (FFA), amino acid or urea concentrations. Infusions of ACTH at dose rates of 0.02, 0.06 and 0.45 IU/kg per h caused a similar rise in plasma glucose concentration; however, this was now accompanied by an elevation in plasma FFA concentration, but again without significant changes in either plasma amino acid or urea concentrations. Infusion of adrenalin at 10 micrograms/kg per h caused an increase in the plasma concentrations of both glucose and FFA. Intravenous injections of 0.15 IU insulin/kg caused a rapid and marked decrease in the plasma glucose concentration within 30 min and an increase in the plasma free cortisol concentration. Associated with this change was a marked rise in the plasma concentration of both FFA and free cortisol. The rise in free cortisol was, however, significantly reduced by infusion of glucose. Pretreatment with five daily i.m. injections of 1 mg cortisol acetate/kg, which produced an increase in plasma free cortisol concentration to near the maximum of the physiological range, caused a marked reduction in insulin sensitivity. Cortisol pretreatment caused an increase in the plasma FFA and amino acid concentrations. Petaurus breviceps is highly sensitive to the metabolic effects of glucocorticoids and is similar in this respect to the brush-tailed possum Trichosurus vulpecula. The interactive effects between insulin and glucocorticoids on carbohydrate, fat and protein metabolism in Petaurus breviceps are similar to those shown by Trichosurus vulpecula and some eutherian mammals but contrast with the pattern described for two macropodid marsupials, the red kangaroo Macropus rufus and the quokka Setonix brachyurus.

Comparative evaluation of sea-urchin larval stage sensitivity to ocean acidification.

PubMed

Passarelli, M C; Cesar, A; Riba, I; DelValls, T A

2017-10-01

Changes in the marine carbonate system may affect various calcifying organisms. This study is aimed to compare the sensitivity of embryo-larval development of two species of sea urchins (Paracentrutos lividus and Lytechinus variegatus) collected and exposed to samples from different coastal zone (Spain and Brazil) to ocean acidification. The results showed that the larval stages are very sensitive to small changes in the seawater's pH. The larvae from P. lividus species showed to be more sensitive to acidified elutriate sediments than larvae from L. variegatus sea urchin. Furthermore, this study has demonstrated that the CO 2 enrichment in aquatic ecosystems cause changes on the mobility of the metals: Zn, Cu, Fe, Al and As, which was presented different behavior among them. Although an increase on the mobility of metals was found, the results using the principal component analysis showed that the pH reduction show the highest correlations with the toxicity and is the main cause of embryo-larval development inhibition. In this comparative study it is demonstrated that both species are able to assess potential effects of the ocean acidification related to CO 2 enrichment by both near future scenarios and the risk associated with CO 2 leakages in the Carbon Capture and Storage (CCS) process, and the importance of comparative studies in different zones to improve the understanding of the impacts caused by ocean acidification. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sensitization of TRPV1 by protein kinase C in rats with mono-iodoacetate-induced joint pain.

PubMed

Koda, K; Hyakkoku, K; Ogawa, K; Takasu, K; Imai, S; Sakurai, Y; Fujita, M; Ono, H; Yamamoto, M; Fukuda, I; Yamane, S; Morita, A; Asaki, T; Kanemasa, T; Sakaguchi, G; Morioka, Y

2016-07-01

To assess the functional changes of Transient receptor potential vanilloid 1 (TRPV1) receptor and to clarify its mechanism in a rat mono-iodoacetate (MIA)-induced joint pain model (MIA rats), which has joint degeneration with cartilage loss similar to osteoarthritis. Sensitization of TRPV1 in MIA rats was assessed by transient spontaneous pain behavior induced by capsaicin injection in knee joints and electrophysiological changes of dorsal root ganglion (DRG) neurons innervating knee joints in response to capsaicin. Mechanisms of TRPV1 sensitization were analyzed by a newly developed sandwich enzyme-linked immunosorbent assay that detects phosphorylated TRPV1, followed by functional and expression analyses of protein kinase C (PKC) in vivo and in vitro, which involves TRPV1 phosphorylation. Pain-related behavior induced by intra-articular injection of capsaicin was significantly increased in MIA rats compared with sham rats. In addition, capsaicin sensitivity, evaluated by capsaicin-induced inward currents, was significantly increased in DRG neurons of MIA rats. Protein levels of TRPV1 remained unchanged, but phosphorylated TRPV1 at Ser800 increased in DRG neurons of MIA rats. Phosphorylated-PKCɛ (p-PKCɛ) increased and co-localized with TRPV1 in DRG neurons of MIA rats. Capsaicin-induced pain-related behavior in MIA rats was inhibited by intra-articular pretreatment of the PKC inhibitor bisindolylmaleimide I. In addition, intra-articular injection of the PKC activator phorbol 12-myristate 13-acetate increased capsaicin-induced pain-related behavior in normal rats. TRPV1 was sensitized at the knee joint and at DRG neurons of MIA rats through PKC activation. Thus, TRPV1 sensitization might be involved in chronic pain caused by osteoarthritis. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Sensitivity of the equilibrium surface temperature of a GCM to systematic changes in atmospheric carbon dioxide

NASA Technical Reports Server (NTRS)

Oglesby, Robert J.; Saltzman, Barry

1990-01-01

The equilibrium response of surface temperature to atmospheric CO2 concentration, for six values between 100 and 1000 ppm, is calculated from a series of GCM experiments. This response is nonlinear, showing greater sensitivity for lower values of CO2 than for the higher values. It is suggested that changes in CO2 concentration of a given magnitude (e.g., 100 ppm) played a larger role in the Pleistocene ice-age-type temperature variations than in causing global temperature changes due to anthropogenic increases.

Evaluation of clinical coding data to determine causes of critical bleeding in patients receiving massive transfusion: a bi-national, multicentre, cross-sectional study.

PubMed

McQuilten, Z K; Zatta, A J; Andrianopoulos, N; Aoki, N; Stevenson, L; Badami, K G; Bird, R; Cole-Sinclair, M F; Hurn, C; Cameron, P A; Isbister, J P; Phillips, L E; Wood, E M

2017-04-01

To evaluate the use of routinely collected data to determine the cause(s) of critical bleeding in patients who receive massive transfusion (MT). Routinely collected data are increasingly being used to describe and evaluate transfusion practice. Chart reviews were undertaken on 10 randomly selected MT patients at 48 hospitals across Australia and New Zealand to determine the cause(s) of critical bleeding. Diagnosis-related group (DRG) and International Classification of Diseases (ICD) codes were extracted separately and used to assign each patient a cause of critical bleeding. These were compared against chart review using percentage agreement and kappa statistics. A total of 427 MT patients were included with complete ICD and DRG data for 427 (100%) and 396 (93%), respectively. Good overall agreement was found between chart review and ICD codes (78·3%; κ = 0·74, 95% CI 0·70-0·79) and only fair overall agreement with DRG (51%; κ = 0·45, 95% CI 0·40-0·50). Both ICD and DRG were sensitive and accurate for classifying obstetric haemorrhage patients (98% sensitivity and κ > 0·94). However, compared with the ICD algorithm, DRGs were less sensitive and accurate in classifying bleeding as a result of gastrointestinal haemorrhage (74% vs 8%; κ = 0·75 vs 0·1), trauma (92% vs 62%; κ = 0·78 vs 0·67), cardiac (80% vs 57%; κ = 0·79 vs 0·60) and vascular surgery (64% vs 56%; κ = 0·69 vs 0·65). Algorithms using ICD codes can determine the cause of critical bleeding in patients requiring MT with good to excellent agreement with clinical history. DRG are less suitable to determine critical bleeding causes. © 2016 British Blood Transfusion Society.

Characterization of a Novel MMS-Sensitive Allele of Schizosaccharomyces pombe mcm4+

PubMed Central

Ranatunga, Nimna S.; Forsburg, Susan L.

2016-01-01

The minichromosome maintenance (MCM) complex is the conserved helicase motor of the eukaryotic replication fork. Mutations in the Mcm4 subunit are associated with replication stress and double strand breaks in multiple systems. In this work, we characterize a new temperature-sensitive allele of Schizosaccharomyces pombe mcm4+. Uniquely among known mcm4 alleles, this mutation causes sensitivity to the alkylation damaging agent methyl methanesulfonate (MMS). Even in the absence of treatment or temperature shift, mcm4-c106 cells show increased repair foci of RPA and Rad52, and require the damage checkpoint for viability, indicating genome stress. The mcm4-c106 mutant is synthetically lethal with mutations disrupting fork protection complex (FPC) proteins Swi1 and Swi3. Surprisingly, we found that the deletion of rif1+ suppressed the MMS-sensitive phenotype without affecting temperature sensitivity. Together, these data suggest that mcm4-c106 destabilizes replisome structure. PMID:27473316

Temperature Sensitivity as a Microbial Trait Using Parameters from Macromolecular Rate Theory

PubMed Central

Alster, Charlotte J.; Baas, Peter; Wallenstein, Matthew D.; Johnson, Nels G.; von Fischer, Joseph C.

2016-01-01

The activity of soil microbial extracellular enzymes is strongly controlled by temperature, yet the degree to which temperature sensitivity varies by microbe and enzyme type is unclear. Such information would allow soil microbial enzymes to be incorporated in a traits-based framework to improve prediction of ecosystem response to global change. If temperature sensitivity varies for specific soil enzymes, then determining the underlying causes of variation in temperature sensitivity of these enzymes will provide fundamental insights for predicting nutrient dynamics belowground. In this study, we characterized how both microbial taxonomic variation as well as substrate type affects temperature sensitivity. We measured β-glucosidase, leucine aminopeptidase, and phosphatase activities at six temperatures: 4, 11, 25, 35, 45, and 60°C, for seven different soil microbial isolates. To calculate temperature sensitivity, we employed two models, Arrhenius, which predicts an exponential increase in reaction rate with temperature, and Macromolecular Rate Theory (MMRT), which predicts rate to peak and then decline as temperature increases. We found MMRT provided a more accurate fit and allowed for more nuanced interpretation of temperature sensitivity in all of the enzyme × isolate combinations tested. Our results revealed that both the enzyme type and soil isolate type explain variation in parameters associated with temperature sensitivity. Because we found temperature sensitivity to be an inherent and variable property of an enzyme, we argue that it can be incorporated as a microbial functional trait, but only when using the MMRT definition of temperature sensitivity. We show that the Arrhenius metrics of temperature sensitivity are overly sensitive to test conditions, with activation energy changing depending on the temperature range it was calculated within. Thus, we propose the use of the MMRT definition of temperature sensitivity for accurate interpretation of temperature sensitivity of soil microbial enzymes. PMID:27909429

Sensitivity of spiral ganglion neurons to damage caused by mobile phone electromagnetic radiation will increase in lipopolysaccharide-induced inflammation in vitro model.

PubMed

Zuo, Wen-Qi; Hu, Yu-Juan; Yang, Yang; Zhao, Xue-Yan; Zhang, Yuan-Yuan; Kong, Wen; Kong, Wei-Jia

2015-05-29

With the increasing popularity of mobile phones, the potential hazards of radiofrequency electromagnetic radiation (RF-EMR) on the auditory system remain unclear. Apart from RF-EMR, humans are also exposed to various physical and chemical factors. We established a lipopolysaccharide (LPS)-induced inflammation in vitro model to investigate whether the possible sensitivity of spiral ganglion neurons to damage caused by mobile phone electromagnetic radiation (at specific absorption rates: 2, 4 W/kg) will increase. Spiral ganglion neurons (SGN) were obtained from neonatal (1- to 3-day-old) Sprague Dawley® (SD) rats. After the SGN were treated with different concentrations (0, 20, 40, 50, 100, 200, and 400 μg/ml) of LPS, the Cell Counting Kit-8 (CCK-8) and alkaline comet assay were used to quantify cellular activity and DNA damage, respectively. The SGN were treated with the moderate LPS concentrations before RF-EMR exposure. After 24 h intermittent exposure at an absorption rate of 2 and 4 W/kg, DNA damage was examined by alkaline comet assay, ultrastructure changes were detected by transmission electron microscopy, and expression of the autophagy markers LC3-II and Beclin1 were examined by immunofluorescence and confocal laser scanning microscopy. Reactive oxygen species (ROS) production was quantified by the dichlorofluorescin-diacetate assay. LPS (100 μg/ml) induced DNA damage and suppressed cellular activity (P < 0.05). LPS (40 μg/ml) did not exhibit cellular activity changes or DNA damage (P > 0.05); therefore, 40 μg/ml was used to pretreat the concentration before exposure to RF-EMR. RF-EMR could not directly induce DNA damage. However, the 4 W/kg combined with LPS (40 μg/ml) group showed mitochondria vacuoles, karyopyknosis, presence of lysosomes and autophagosome, and increasing expression of LC3-II and Beclin1. The ROS values significantly increased in the 4 W/kg exposure, 4 W/kg combined with LPS (40 μg/ml) exposure, and H2O2 groups (P < 0.05, 0.01). Short-term exposure to radiofrequency electromagnetic radiation could not directly induce DNA damage in normal spiral ganglion neurons, but it could cause the changes of cellular ultrastructure at special SAR 4.0 W/kg when cells are in fragile or micro-damaged condition. It seems that the sensitivity of SGN to damage caused by mobile phone electromagnetic radiation will increase in a lipopolysaccharide-induced inflammation in vitro model.

Time course of ongoing activity during neuritis and following axonal transport disruption.

PubMed

Satkeviciute, Ieva; Goodwin, George; Bove, Geoffrey M; Dilley, Andrew

2018-05-01

Local nerve inflammation (neuritis) leads to ongoing activity and axonal mechanical sensitivity (AMS) along intact nociceptor axons and disrupts axonal transport. This phenomenon forms the most feasible cause of radiating pain, such as sciatica. We have previously shown that axonal transport disruption without inflammation or degeneration also leads to AMS but does not cause ongoing activity at the time point when AMS occurs, despite causing cutaneous hypersensitivity. However, there have been no systematic studies of ongoing activity during neuritis or noninflammatory axonal transport disruption. In this study, we present the time course of ongoing activity from primary sensory neurons following neuritis and vinblastine-induced axonal transport disruption. Whereas 24% of C/slow Aδ-fiber neurons had ongoing activity during neuritis, few (<10%) A- and C-fiber neurons showed ongoing activity 1-15 days following vinblastine treatment. In contrast, AMS increased transiently at the vinblastine treatment site, peaking on days 4-5 (28% of C/slow Aδ-fiber neurons) and resolved by day 15. Conduction velocities were slowed in all groups. In summary, the disruption of axonal transport without inflammation does not lead to ongoing activity in sensory neurons, including nociceptors, but does cause a rapid and transient development of AMS. Because it is proposed that AMS underlies mechanically induced radiating pain, and a transient disruption of axonal transport (as previously reported) leads to transient AMS, it follows that processes that disrupt axonal transport, such as neuritis, must persist to maintain AMS and the associated symptoms. NEW & NOTEWORTHY Many patients with radiating pain lack signs of nerve injury on clinical examination but may have neuritis, which disrupts axonal transport. We have shown that axonal transport disruption does not induce ongoing activity in primary sensory neurons but does cause transient axonal mechanical sensitivity. The present data complete a profile of key axonal sensitivities following axonal transport disruption. Collectively, this profile supports that an active peripheral process is necessary for maintained axonal sensitivities.

Optimization of conventional water treatment plant using dynamic programming.

PubMed

Mostafa, Khezri Seyed; Bahareh, Ghafari; Elahe, Dadvar; Pegah, Dadras

2015-12-01

In this research, the mathematical models, indicating the capability of various units, such as rapid mixing, coagulation and flocculation, sedimentation, and the rapid sand filtration are used. Moreover, cost functions were used for the formulation of conventional water and wastewater treatment plant by applying Clark's formula (Clark, 1982). Also, by applying dynamic programming algorithm, it is easy to design a conventional treatment system with minimal cost. The application of the model for a case reduced the annual cost. This reduction was approximately in the range of 4.5-9.5% considering variable limitations. Sensitivity analysis and prediction of system's feedbacks were performed for different alterations in proportion from parameters optimized amounts. The results indicated (1) that the objective function is more sensitive to design flow rate (Q), (2) the variations in the alum dosage (A), and (3) the sand filter head loss (H). Increasing the inflow by 20%, the total annual cost would increase to about 12.6%, while 20% reduction in inflow leads to 15.2% decrease in the total annual cost. Similarly, 20% increase in alum dosage causes 7.1% increase in the total annual cost, while 20% decrease results in 7.9% decrease in the total annual cost. Furthermore, the pressure decrease causes 2.95 and 3.39% increase and decrease in total annual cost of treatment plants. © The Author(s) 2013.

Sensitivity of water resources in the Delaware River basin to climate variability and change

USGS Publications Warehouse

Ayers, Mark A.; Wolock, David M.; McCabe, Gregory J.; Hay, Lauren E.; Tasker, Gary D.

1994-01-01

Because of the greenhouse effect, projected increases in atmospheric carbon dioxide levels might cause global warming, which in turn could result in changes in precipitation patterns and evapotranspiration and in increases in sea level. This report describes the greenhouse effect; discusses the problems and uncertainties associated with the detection, prediction, and effects of climate change; and presents the results of sensitivity analyses of how climate change might affect water resources in the Delaware River basin. Sensitivity analyses suggest that potentially serious shortfalls of certain water resources in the basin could result if some scenarios for climate change come true . The results of model simulations of the basin streamflow demonstrate the difficulty in distinguishing the effects that climate change versus natural climate variability have on streamflow and water supply . The future direction of basin changes in most water resources, furthermore, cannot be precisely determined because of uncertainty in current projections of regional temperature and precipitation . This large uncertainty indicates that, for resource planning, information defining the sensitivities of water resources to a range of climate change is most relevant . The sensitivity analyses could be useful in developing contingency plans for evaluating and responding to changes, should they occur.

Sound-by-sound thalamic stimulation modulates midbrain auditory excitability and relative binaural sensitivity in frogs

PubMed Central

Ponnath, Abhilash; Farris, Hamilton E.

2014-01-01

Descending circuitry can modulate auditory processing, biasing sensitivity to particular stimulus parameters and locations. Using awake in vivo single unit recordings, this study tested whether electrical stimulation of the thalamus modulates auditory excitability and relative binaural sensitivity in neurons of the amphibian midbrain. In addition, by using electrical stimuli that were either longer than the acoustic stimuli (i.e., seconds) or presented on a sound-by-sound basis (ms), experiments addressed whether the form of modulation depended on the temporal structure of the electrical stimulus. Following long duration electrical stimulation (3–10 s of 20 Hz square pulses), excitability (spikes/acoustic stimulus) to free-field noise stimuli decreased by 32%, but returned over 600 s. In contrast, sound-by-sound electrical stimulation using a single 2 ms duration electrical pulse 25 ms before each noise stimulus caused faster and varied forms of modulation: modulation lasted <2 s and, in different cells, excitability either decreased, increased or shifted in latency. Within cells, the modulatory effect of sound-by-sound electrical stimulation varied between different acoustic stimuli, including for different male calls, suggesting modulation is specific to certain stimulus attributes. For binaural units, modulation depended on the ear of input, as sound-by-sound electrical stimulation preceding dichotic acoustic stimulation caused asymmetric modulatory effects: sensitivity shifted for sounds at only one ear, or by different relative amounts for both ears. This caused a change in the relative difference in binaural sensitivity. Thus, sound-by-sound electrical stimulation revealed fast and ear-specific (i.e., lateralized) auditory modulation that is potentially suited to shifts in auditory attention during sound segregation in the auditory scene. PMID:25120437

Sound-by-sound thalamic stimulation modulates midbrain auditory excitability and relative binaural sensitivity in frogs.

PubMed

Ponnath, Abhilash; Farris, Hamilton E

2014-01-01

Descending circuitry can modulate auditory processing, biasing sensitivity to particular stimulus parameters and locations. Using awake in vivo single unit recordings, this study tested whether electrical stimulation of the thalamus modulates auditory excitability and relative binaural sensitivity in neurons of the amphibian midbrain. In addition, by using electrical stimuli that were either longer than the acoustic stimuli (i.e., seconds) or presented on a sound-by-sound basis (ms), experiments addressed whether the form of modulation depended on the temporal structure of the electrical stimulus. Following long duration electrical stimulation (3-10 s of 20 Hz square pulses), excitability (spikes/acoustic stimulus) to free-field noise stimuli decreased by 32%, but returned over 600 s. In contrast, sound-by-sound electrical stimulation using a single 2 ms duration electrical pulse 25 ms before each noise stimulus caused faster and varied forms of modulation: modulation lasted <2 s and, in different cells, excitability either decreased, increased or shifted in latency. Within cells, the modulatory effect of sound-by-sound electrical stimulation varied between different acoustic stimuli, including for different male calls, suggesting modulation is specific to certain stimulus attributes. For binaural units, modulation depended on the ear of input, as sound-by-sound electrical stimulation preceding dichotic acoustic stimulation caused asymmetric modulatory effects: sensitivity shifted for sounds at only one ear, or by different relative amounts for both ears. This caused a change in the relative difference in binaural sensitivity. Thus, sound-by-sound electrical stimulation revealed fast and ear-specific (i.e., lateralized) auditory modulation that is potentially suited to shifts in auditory attention during sound segregation in the auditory scene.

Spectra analysis of coating antigen: A possible explanation for difference in anti-AFB1 polyclonal antibody sensitivity

NASA Astrophysics Data System (ADS)

Ye, Yang; Liu, Aiping; Wang, Xiaohong; Chen, Fusheng

2016-10-01

For the detection of small hapten molecules, indirect competitive enzyme-linked immunosorbent assay (icELISA) is a preferred method. However, diverse coating antigen might bring different antiserum titer and sensitivity for the identical antiserum. In the present study, four AFB1-protein (aflatoxin B1-carrier protein) conjugates were prepared by activated ester method (AFB1O-BSA/AFB1O-OVA) and mannich method (AFB1-cBSA/AFB1-cOVA), and then applied as coating antigen for titer and sensitivity detection of the identical antiserum obtained from rabbit immunized by AFB1-KLH. Afterwards, the ultraviolet-visible, fluorescence and far-ultraviolet circular dichroism (far-UV CD) spectra were recorded for understanding the difference in titer and sensitivity obtained. Results revealed that AFB1O-BSA/AFB1O-OVA showed a strong intrinsic fluorescence band centered at 450 nm that originated from the emission of AFB1, which differed from AFB1-cBSA/AFB1-cOVA, while the decrease of α-helical and increase of β-sheet in AFB1-cBSA was the most remarkable. This indicated that the better sensitivity obtained by using AFB1O-BSA as coating antigen might be caused by its extended structure, because such structure affect the binding between AFB1 and antibody. The study might offer structural information for understanding the titer and sensitivity difference caused by coating antigen.

Making A D-Latch Sensitive To Alpha Particles

NASA Technical Reports Server (NTRS)

Buehler, Martin G.; Blaes, Brent R.; Nixon, Robert H.

1994-01-01

Standard complementary metal oxide/semiconductor (CMOS) D-latch integrated circuit modified to increase susceptibility to single-event upsets (SEU's) (changes in logic state) caused by impacts of energetic alpha particles. Suitable for use in relatively inexpensive bench-scale SEU tests of itself and of related integrated circuits like static random-access memories.

Influence of Varroa mite (Varroa destructor) infestation levels and management practices on insecticide sensitivity in the honey bee (Apis mellifera)

USDA-ARS?s Scientific Manuscript database

Because Varroa mites may cause devastating losses of honey bees through direct feeding, transmitting diseases, and increasing pathogen susceptibility, chemical and mechanical practices commonly are used to reduce mite infestation. While miticide applications are typically the most consistent and eff...

Amplification volume reduction on DNA database samples using FTA™ Classic Cards.

PubMed

Wong, Hang Yee; Lim, Eng Seng Simon; Tan-Siew, Wai Fun

2012-03-01

The DNA forensic community always strives towards improvements in aspects such as sensitivity, robustness, and efficacy balanced with cost efficiency. Therefore our laboratory decided to study the feasibility of PCR amplification volume reduction using DNA entrapped in FTA™ Classic Card and to bring cost savings to the laboratory. There were a few concerns the laboratory needed to address. First, the kinetics of the amplification reaction could be significantly altered. Second, an increase in sensitivity might affect interpretation due to increased stochastic effects even though they were pristine samples. Third, statics might cause FTA punches to jump out of its allocated well into another thus causing sample-to-sample contamination. Fourth, the size of the punches might be too small for visual inspection. Last, there would be a limit to the extent of volume reduction due to evaporation and the possible need of re-injection of samples for capillary electrophoresis. The laboratory had successfully optimized a reduced amplification volume of 10 μL for FTA samples. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Sensitivity experiments with a one-dimensional coupled plume - iceflow model

NASA Astrophysics Data System (ADS)

Beckmann, Johanna; Perette, Mahé; Alexander, David; Calov, Reinhard; Ganopolski, Andrey

2016-04-01

Over the last few decades Greenland Ice sheet mass balance has become increasingly negative, caused by enhanced surface melting and speedup of the marine-terminating outlet glaciers at the ice sheet margins. Glaciers speedup has been related, among other factors, to enhanced submarine melting, which in turn is caused by warming of the surrounding ocean and less obviously, by increased subglacial discharge. While ice-ocean processes potentially play an important role in recent and future mass balance changes of the Greenland Ice Sheet, their physical understanding remains poorly understood. In this work we performed numerical experiments with a one-dimensional plume model coupled to a one-dimensional iceflow model. First we investigated the sensitivity of submarine melt rate to changes in ocean properties (ocean temperature and salinity), to the amount of subglacial discharge and to the glacier's tongue geometry itself. A second set of experiments investigates the response of the coupled model, i.e. the dynamical response of the outlet glacier to altered submarine melt, which results in new glacier geometry and updated melt rates.

Google Glass Glare: disability glare produced by a head-mounted visual display.

PubMed

Longley, Chris; Whitaker, David

2016-03-01

Head mounted displays are a type of wearable technology - a market that is projected to expand rapidly over the coming years. Probably the most well known example is the device Google Glass (or 'Glass'). Here we investigate the extent to which the device display can interfere with normal visual function by producing monocular disability glare. Contrast sensitivity was measured in two normally sighted participants, 32 and 52 years of age. Data were recorded for the right eye, the left eye and then again in a binocular condition. Measurements were taken both with and without the Glass in place, across a range of stimulus luminance levels using a two-alternative forced-choice methodology. The device produced a significant reduction in contrast sensitivity in the right eye (>0.5 log units). The level of disability glare increased as stimulus luminance was reduced in a manner consistent with intraocular light scatter, resulting in a veiling retinal illuminance. Sensitivity in the left eye was unaffected. A significant reduction in binocular contrast sensitivity occurred at lower luminance levels due to a loss of binocular summation, although binocular sensitivity was not found to fall below the sensitivity of the better monocular level (binocular inhibition). Head mounted displays such as Google Glass have the potential to cause significant disability glare in the eye exposed to the visual display, particularly under conditions of low luminance. They can also cause a more modest binocular reduction in sensitivity by eliminating the benefits of binocular summation. © 2015 The Authors Ophthalmic & Physiological Optics © 2015 The College of Optometrists.

Potent homocysteine-induced ERK phosphorylation in cultured neurons depends on self-sensitization via system Xc{sup -}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gu Li; Hu Xiaoling; Xue Zhanxia

2010-01-15

Homocysteine is increased during pathological conditions, endangering vascular and cognitive functions, and elevated homocysteine during pregnancy may be correlated with an increased incidence of schizophrenia in the offspring. This study showed that millimolar homocysteine concentrations in saline medium cause phosphorylation of extracellular-signal regulated kinases 1 and 2 (ERK{sub 1/2}) in cerebellar granule neurons, inhibitable by metabotropic but not ionotropic glutamate receptor antagonists. These findings are analogous to observations by , that similar concentrations cause neuronal death. However, these concentrations are much higher than those occurring clinically during hyperhomocysteinemia. It is therefore important that a approx 10-fold increase in potency occurredmore » in the presence of the glutamate precursor glutamine, when ERK{sub 1/2} phosphorylation became inhibitable by NMDA or non-NMDA antagonists and dependent upon epidermal growth factor (EGF) receptor transactivation. However, glutamate release to the medium was reduced, suggesting that reversal of the cystine/glutamate antiporter, system X{sub c}{sup -} could be involved in potentiation of the response by causing a localized release of initially accumulated homocysteine. In agreement with this hypothesis further enhancement of ERK{sub 1/2} phosphorylation occurred in the additional presence of cystine. Pharmacological inhibition of system X{sub c}{sup -} prevented the effect of micromolar homocysteine concentrations, and U0126-mediated inhibition of ERK{sub 1/2} phosphorylation enhanced homocysteine-induced death. In conclusion, homocysteine interacts with system X{sub c}{sup -} like quisqualate (Venkatraman et al. 1994), by 'self-sensitization' with initial accumulation and subsequent release in exchange with cystine and/or glutamate, establishing high local homocysteine concentrations, which activate adjacent ionotropic glutamate receptors and cause neurotoxicity.« less

[Comutagenic action of sodium selenite and caffeine on S. typhimurium TA 1535 with its subsequent treatment by N-nitrosomethylurea].

PubMed

Balanski, R M

1988-01-01

The comutagenic activity of sodium selenite and caffeine was studied by the Ames test. Reproduction of S. typhimurium TA1535 for 4 h at 37 degrees C in the nutrient broth with sodium selenide (5 micrograms/ml) significantly increased sensitivity of bacterial cells to the mutagenic action of 2-3 mM N-nitrosomethylurea (NMU). When using threshold concentrations of NMU the potentiation of mutagenesis reached 625.2%. The addition of 0.19 mg/ml of caffeine to the nutrient medium also led (though the action was less pronounced) to an increase in sensitivity of bacterial cells to the NMU mutagenic action. Reproduction of S. typhimurium TA1535 in the medium containing sodium selenide and caffeine did not cause an increase in the frequency of spontaneous his+-revertant mutations.

Effects of increased temperature on metabolic activity and oxidative stress in the first life stages of marble trout (Salmo marmoratus).

PubMed

Simčič, Tatjana; Jesenšek, Dušan; Brancelj, Anton

2015-08-01

Climate change may result in future alterations in thermal regime which could markedly affect the early developmental stages of cold water fish due to their expected high sensitivity to increasing temperature. In the present study, the effect of temperature increase of 2, 4 and 6°C on the oxygen consumption rate (R), the activity of respiratory electron transport system (ETS) and oxidative stress have been studied in four developmental stages of the marble trout (Salmo marmoratus)-eyed eggs, yolk-sac larvae and juveniles of 1 and 3 months. Oxygen consumption rate and ETS activity increased with level of development and with temperature in all four stages. ETS/R ratios decreased during development and correlated with temperature in eyed eggs, larvae and juveniles of 1 month, but not in juveniles of 3 months. Low ETS/R ratios at higher temperatures indicate stress response in eyed eggs, the most temperature sensitive developmental stage. Catalase (CAT) and glutathione reductase (GR) activities increased during development, but responded differently to elevated temperature in the different developmental stages. Stress in eyed eggs, caused by higher temperatures, resulted in increased oxygen consumption rate and increased activities of CAT and GR. Larvae were sensitive to increased temperature only at the highest experimental temperature of 16°C. Increased temperature did not stress the metabolism of the juveniles, since they were able to compensate their metabolic activity. The earlier developmental stages of marble trout are thus more sensitive to temperature increase than juveniles and therefore more endangered by higher water temperatures. This is the first report connecting oxygen consumption, ETS activity and ETS/R ratio with the activities of antioxidant enzymes in relation to increased temperature in salmonids.

A neural hypothesis for stress-induced headache.

PubMed

Cathcart, Stuart

2009-12-01

The mechanisms by which stress contributes to CTH are not clearly understood. The commonly accepted notion of muscle hyper-reactivity to stress in CTH sufferers is not supported in the research data. We propose a neural model whereby stress acts supra-spinally to aggravate already increased pain sensitivity in CTH sufferers. Indirect support for the model comes from emerging research elucidating complex supra-spinal networks through which psychological stress may contribute to and even cause pain. Similarly, emerging research demonstrates supra-spinal pain processing abnormalities in CTH sufferers. While research with CTH sufferers offering direct support for the model is lacking at present, initial work by our group is consistent with the models predictions, particularly, that stress aggravates already increased pain sensitivity in CTH sufferers.

Allergic contact dermatitis caused by isobornyl acrylate in OmniPod, an innovative tubeless insulin pump.

PubMed

Raison-Peyron, Nadia; Mowitz, Martin; Bonardel, Nathalie; Aerts, Olivier; Bruze, Magnus

2018-04-10

The frequency of allergic contact dermatitis caused by (meth)acrylates is increasing worldwide, and isobornyl acrylate (IBOA) has been identified as a culprit sensitizer in FreeStyle Libre, a medical device used by diabetic patients. To report on 4 patients sensitized to IBOA contained in OmniPod, a new, tubeless insulin pump, and to describe the clinical and chemical analytical work-up. Four patients with eczematous skin eruptions after using OmniPod, including 2 with previous adverse skin reactions to FreeStyle Libre, were patch tested with a baseline series and additional (meth)acrylates, including IBOA in several concentrations and/or vehicles. Gas chromatography-mass spectrometry (GC-MS) was used to identify the presence of IBOA in OmniPod. All patients were shown to be sensitized to IBOA. GC-MS identified IBOA in OmniPod, with the highest concentrations being found in the unit itself and not in the adhesive patch. The OmniPod tubeless insulin pump is another source of IBOA, and its use may lead to primary sensitization to this acrylate, or may provoke elicitation of allergic contact dermatitis in previously sensitized patients. Our cases highlight the need to obtain satisfactory cooperation from pharmaceutical companies involved in the manufacture of these widely used medical devices. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Heart rate and blood pressure variabilities in salt-sensitive hypertension.

PubMed

Piccirillo, G; Bucca, C; Durante, M; Santagada, E; Munizzi, M R; Cacciafesta, M; Marigliano, V

1996-12-01

In salt-sensitive hypertension, a high sodium intake causes plasma catecholamines to rise and pulmonary baroreceptor plasticity to fall. In salt-sensitive and salt-resistant hypertensive subjects during low and high sodium intakes, we studied autonomic nervous system activity by power spectral analysis of heart rate and arterial pressure variabilities and baroreceptor sensitivity. In all subjects, high sodium intake significantly enhanced the low-frequency power of heart rate and arterial pressures at rest and after sympathetic stress. It also increased heart rate and arterial pressure variabilities. During high sodium intake, salt-sensitive hypertensive subjects had significantly higher low-frequency powers of systolic arterial pressure (7.5 mm Hg2, P < .05) and of heart rate at rest (59.2 +/- 2.4 normalized units [NU], P < .001) than salt-resistant subjects (6.6 +/- 0.3 mm Hg2, 55.0 +/- 3.2 NU) and normotensive control subjects (5.1 +/- 0.5 mm Hg2, 41.6 +/- 2.9 NU). In salt-sensitive subjects, low sodium intake significantly reduced low-frequency normalized units (P < .001) and the ratio of low- to high-power frequency (P < .001). High-sodium intake significantly increased baroreflex sensitivity in control subjects (from 10.0 +/- 0.7 to 17.5 +/- 0.7 ms/mm Hg, P < .001) and salt-resistant subjects (from 6.9 +/- 0.7 to 13.9 +/- 0.9, P < .05) but not in salt-sensitive subjects (7.4 +/- 0.3 to 7.9 +/- 0.4). In conclusion, a high sodium intake markedly enhances cardiac sympathetic activity in salt-sensitive and salt-resistant hypertension. In contrast, although reduced sodium intake lowers arterial pressure and sympathetic activity, it does so only in salt-sensitive subjects. Hence, in salt-resistant subjects, neither arterial pressure nor sympathetic activity depends on salt intake. During a high sodium intake in normotensive subjects and salt-resistant hypertensive subjects, increased sympathetic activity is probably compensated by enhanced baroreflex sensitivity.

Participation of the peripheral taste system in aging-dependent changes in taste sensitivity.

PubMed

Narukawa, Masataka; Kurokawa, Azusa; Kohta, Rie; Misaka, Takumi

2017-09-01

Previous studies have shown that aging modifies taste sensitivity. However, the factors affecting the changes in taste sensitivity remain unclear. To investigate the cause of the age-related changes in taste sensitivity, we compared the peripheral taste detection systems in young and old mice. First, we examined whether taste sensitivity varied according to age using behavioral assays. We confirmed that the taste sensitivities to salty and bitter tastes decreased with aging. In other assays, the gustatory nerve responses to salty and sweet tastes increased significantly with aging, while those to bitter taste did not change. Thus, the profile of the gustatory nerve responses was inconsistent with the profile of the behavioral responses. Next, we evaluated the expressions of taste-related molecules in the taste buds. Although no apparent differences in the expressions of representative taste receptors were observed between the two age groups, the mRNA expressions of signaling effectors were slightly, but significantly, decreased in old mice. No significant differences in the turnover rates of taste bud cells were observed between the two age groups. Thus, we did not observe any large decreases in the expressions of taste-related molecules and turnover rates of taste bud cells with aging. Based on these findings, we conclude that changes in taste sensitivity with aging were not caused by aging-related degradation of peripheral taste organs. Meanwhile, the concentrations of several serum components that modify taste responses changed with age. Thus, taste signal-modifying factors such as serum components may have a contributing role in aging-related changes in taste sensitivity. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Acute stress-induced sensitization of the pituitary-adrenal response to heterotypic stressors: independence of glucocorticoid release and activation of CRH1 receptors.

PubMed

Belda, Xavier; Daviu, Núria; Nadal, Roser; Armario, Antonio

2012-09-01

A single exposure to some severe stressors causes sensitization of the hypothalamic-pituitary-adrenal (HPA) response to novel stressors. However, the putative factors involved in stress-induced sensitization are not known. In the present work we studied in adult male rats the possible role of glucocorticoids and CRH type 1 receptor (CRH-R1), using an inhibitor of glucocorticoid synthesis (metyrapone, MET), the glucocorticoid receptor (GR) antagonist RU38486 (mifepristone) and the non-peptide CRH-R1 antagonist R121919. In a first experiment we demonstrated with different doses of MET (40-150 mg/kg) that the highest dose acted as a pharmacological stressor greatly increasing ACTH release and altering the normal circadian pattern of HPA hormones, but no dose affected ACTH responsiveness to a novel environment as assessed 3 days after drug administration. In a second experiment, we found that MET, at a dose (75 mg/kg) that blocked the corticosterone response to immobilization (IMO), did not alter IMO-induced ACTH sensitization. Finally, neither the GR nor the CRH-R1 antagonists blocked IMO-induced ACTH sensitization on the day after IMO. Thus, a high dose of MET, in contrast to IMO, was unable to sensitize the HPA response to a novel environment despite the huge activation of the HPA axis caused by the drug. Neither a moderate dose of MET that markedly reduced corticosterone response to IMO, nor the blockade of GR or CRH-R1 receptors was able to alter stress-induced HPA sensitization. Therefore, stress-induced sensitization is not the mere consequence of a marked HPA activation and does not involve activation of glucocorticoid or CRH-R1 receptors. Copyright © 2012 Elsevier Inc. All rights reserved.

The binding of analogs of porphyrins and chlorins with elongated side chains to albumin

PubMed Central

Ben Dror, Shimshon; Bronshtein, Irena; Weitman, Hana; Smith, Kevin M.; O’Neal, William G.; Jacobi, Peter A.; Ehrenberg, Benjamin

2012-01-01

In previous studies, we demonstrated that elongation of side chains of several sensitizers endowed them with higher affinity for artificial and natural membranes and caused their deeper localization in membranes. In the present study, we employed eight hematoporphyrin and protoporphyrin analogs and four groups containing three chlorin analogs each, all synthesized with variable numbers of methylenes in their alkyl carboxylic chains. We show that these tetrapyrroles’ affinity for bovine serum albumin (BSA) and their localization in the binding site are also modulated by chain lengths. The binding constants of the hematoporphyrins and protoporphyrins to BSA increased as the number of methylenes was increased. The binding of the chlorins depended on the substitution at the meso position opposite to the chains. The quenching of the sensitizers’ florescence by external iodide ions decreased as the side chains became longer, indicating to deeper insertion of the molecules into the BSA binding pocket. To corroborate this conclusion, we studied the efficiency of photodamage caused to tryptophan in BSA upon illumination of the bound sensitizers. The efficiency was found to depend on the side-chain lengths of the photosensitizer. We conclude that the protein site that hosts these sensitizers accommodates different analogs at positions that differ slightly from each other. These differences are manifested in the ease of access of iodide from the external aqueous phase, and in the proximity of the photosensitizers to the tryptophan. In the course of this study, we developed the kinetic equations that have to be employed when the sensitizer itself is being destroyed. PMID:19330323

Atypical antipsychotics, insulin resistance and weight; a meta-analysis of healthy volunteer studies.

PubMed

Burghardt, Kyle J; Seyoum, Berhane; Mallisho, Abdullah; Burghardt, Paul R; Kowluru, Renu A; Yi, Zhengping

2018-04-20

Atypical antipsychotics increase the risk of diabetes and cardiovascular disease through their side effects of insulin resistance and weight gain. The populations for which atypical antipsychotics are used carry a baseline risk of metabolic dysregulation prior to medication which has made it difficult to fully understand whether atypical antipsychotics cause insulin resistance and weight gain directly. The purpose of this work was to conduct a systematic review and meta-analysis of atypical antipsychotic trials in healthy volunteers to better understand their effects on insulin sensitivity and weight gain. Furthermore, we aimed to evaluate the occurrence of insulin resistance with or without weight gain and with treatment length by using subgroup and meta-regression techniques. Overall, the meta-analysis provides evidence that atypical antipsychotics decrease insulin sensitivity (standardized mean difference=-0.437, p<0.001) and increase weight (standardized mean difference=0.591, p<0.001) in healthy volunteers. It was found that decreases in insulin sensitivity were potentially dependent on treatment length but not weight gain. Decreases in insulin sensitivity occurred in multi-dose studies <13days while weight gain occurred in studies 14days and longer (max 28days). These findings provide preliminary evidence that atypical antipsychotics cause insulin resistance and weight gain directly, independent of psychiatric disease and may be associated with length of treatment. Further, well-designed studies to assess the co-occurrence of insulin resistance and weight gain and to understand the mechanisms and sequence by which they occur are required. Copyright © 2018 Elsevier Inc. All rights reserved.

Cytochrome c conformations resolved by the photon counting histogram: Watching the alkaline transition with single-molecule sensitivity

PubMed Central

Perroud, Thomas D.; Bokoch, Michael P.; Zare, Richard N.

2005-01-01

We apply the photon counting histogram (PCH) model, a fluorescence technique with single-molecule sensitivity, to study pH-induced conformational changes of cytochrome c. PCH is able to distinguish different protein conformations based on the brightness of a fluorophore sensitive to its local environment. We label cytochrome c through its single free cysteine with tetramethylrhodamine-5-maleimide (TMR), a fluorophore with specific brightnesses that we associate with specific protein conformations. Ensemble measurements demonstrate two different fluorescence responses with increasing pH: (i) a decrease in fluorescence intensity caused by the alkaline transition of cytochrome c (pH 7.0–9.5), and (ii) an increase in intensity when the protein unfolds (pH 9.5–10.8). The magnitudes of these two responses depend strongly on the molar ratio of TMR used to label cytochrome c. Using PCH we determine that this effect arises from the proportion of a nonfunctional conformation in the sample, which can be differentiated from the functional conformation. We further determine the causes of each ensemble fluorescence response: (i) during the alkaline transition, the fluorophore enters a dark state and discrete conformations are observed, and (ii) as cytochrome c unfolds, the fluorophore incrementally brightens, but discrete conformations are no longer resolved. Moreover, we also show that functional TMR-cytochrome c undergoes a response of identical magnitude regardless of the proportion of nonfunctional protein in the sample. As expected for a technique with single-molecule sensitivity, we demonstrate that PCH can directly observe the most relevant conformation, unlike ensemble fluorometry. PMID:16314563

Mechanisms of disease: the role of GRK4 in the etiology of essential hypertension and salt sensitivity.

PubMed

Felder, Robin A; Jose, Pedro A

2006-11-01

Hypertension and salt sensitivity of blood pressure are two conditions the etiologies of which are still elusive because of the complex influences of genes, environment, and behavior. Recent understanding of the molecular mechanisms that govern sodium homeostasis is shedding new light on how genes, their protein products, and interacting metabolic pathways contribute to disease. Sodium transport is increased in the proximal tubule and thick ascending limb of Henle of the kidney in human essential hypertension. This Review focuses on the counter-regulation between the dopaminergic and renin-angiotensin systems in the renal proximal tubule, which is the site of about 70% of total renal sodium reabsorption. The inhibitory effect of dopamine is most evident under conditions of moderate sodium excess, whereas the stimulatory effect of angiotensin II is most evident under conditions of sodium deficit. Dopamine and angiotensin II exert their actions via G protein-coupled receptors, which are in turn regulated by G protein-coupled receptor kinases (GRKs). Polymorphisms that lead to aberrant action of GRKs cause a number of conditions, including hypertension and salt sensitivity. Polymorphisms in one particular member of this family-GRK4-have been shown to cause hyperphosphorylation, desensitization and internalization of a member of the dopamine receptor family, the dopamine 1 receptor, while increasing the expression of a key receptor of the renin-angiotensin system, the angiotensin II type 1 receptor. Novel diagnostic and therapeutic approaches for identifying at-risk subjects, followed by selective treatment of hypertension and salt sensitivity, might center on restoring normal receptor function through blocking the effects of GRK4 polymorphisms.

Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells

PubMed Central

Janssen, Aniek; Kops, Geert J. P. L.; Medema, René H.

2009-01-01

The mitotic checkpoint has evolved to prevent chromosome mis-segregations by delaying mitosis when unattached chromosomes are present. Inducing severe chromosome segregation errors by ablating the mitotic checkpoint causes cell death. Here we have analyzed the consequences of gradual increases in chromosome segregation errors on the viability of tumor cells and normal human fibroblasts. Partial reduction of essential mitotic checkpoint components in four tumor cell lines caused mild chromosome mis-segregations, but no lethality. These cells were, however, remarkably more sensitive to low doses of taxol, which enhanced the amount and severity of chromosome segregation errors. Sensitization to taxol was achieved by reducing levels of Mps1 or BubR1, proteins having dual roles in checkpoint activation and chromosome alignment, but not by reducing Mad2, functioning solely in the mitotic checkpoint. Moreover, we find that untransformed human fibroblasts with reduced Mps1 levels could not be sensitized to sublethal doses of taxol. Thus, targeting the mitotic checkpoint and chromosome alignment simultaneously may selectively kill tumor cells by enhancing chromosome mis-segregations. PMID:19855003

Effect of Genetic Information Regarding Salt-Sensitive Hypertension on the Intent to Maintain a Reduced Salt Diet: Implications for Health Communication in Japan.

PubMed

Miyamoto, Keiko; Iwakuma, Miho; Nakayama, Takeo

2017-03-01

The authors investigated the relationship between the awareness of dietary salt and genetics and the intent to maintain a low-salt diet. In particular, they assessed whether hypothetical genetic information regarding salt-sensitive hypertension motivates the intent to reduce dietary salt for communicating the health benefits of lower salt consumption to citizens. A self-administered questionnaire survey was conducted with 2500 randomly sampled residents aged 30 to 69 years living in Nagahama, Japan. Genetic information regarding higher salt sensitivity increased motivation to reduce salt intake for both those who agreed that genes cause hypertension and those who did not. Less than 50% of those who agreed that genes cause hypertension lost their intention to lower their salt consumption when they found they did not possess the susceptibility gene. Communicating genetic information positively affected motivation to reduce salt intake. The present study clarifies the difficulty in changing the behavioral intent of those who have significantly less incentive to reduce salt intake. Therefore, a multidimensional approach is crucial to reduce salt consumption. ©2016 Wiley Periodicals, Inc.

Underground structures increasing the intrinsic vulnerability of urban groundwater: Sensitivity analysis and development of an empirical law based on a groundwater age modelling approach

NASA Astrophysics Data System (ADS)

Attard, Guillaume; Rossier, Yvan; Eisenlohr, Laurent

2017-09-01

In a previous paper published in Journal of Hydrology, it was shown that underground structures are responsible for a mixing process between shallow and deep groundwater that can favour the spreading of urban contamination. In this paper, the impact of underground structures on the intrinsic vulnerability of urban aquifers was investigated. A sensitivity analysis was performed using a 2D deterministic modelling approach based on the reservoir theory generalized to hydrodispersive systems to better understand this mixing phenomenon and the mixing affected zone (MAZ) caused by underground structures. It was shown that the maximal extent of the MAZ caused by an underground structure is reached approximately 20 years after construction. Consequently, underground structures represent a long-term threat for deep aquifer reservoirs. Regarding the construction process, draining operations have a major impact and favour large-scale mixing between shallow and deep groundwater. Consequently, dewatering should be reduced and enclosed as much as possible. The role played by underground structures' dimensions was assessed. The obstruction of the first aquifer layer caused by construction has the greatest influence on the MAZ. The cumulative impact of several underground structures was assessed. It was shown that the total MAZ area increases linearly with underground structures' density. The role played by materials' properties and hydraulic gradient were assessed. Hydraulic conductivity, anisotropy and porosity have the strongest influence on the development of MAZ. Finally, an empirical law was derived to estimate the MAZ caused by an underground structure in a bi-layered aquifer under unconfined conditions. This empirical law, based on the results of the sensitivity analysis developed in this paper, allows for the estimation of MAZ dimensions under known material properties and underground structure dimensions. This empirical law can help urban planners assess the area of influence of underground structures and protect urban strategic reservoirs.

Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients

PubMed Central

Marston, Steven; Memo, Massimiliano; Messer, Andrew; Papadaki, Maria; Nowak, Kristen; McNamara, Elyshia; Ong, Royston; El-Mezgueldi, Mohammed; Li, Xiaochuan; Lehman, William

2013-01-01

The congenital myopathies include a wide spectrum of clinically, histologically and genetically variable neuromuscular disorders many of which are caused by mutations in genes for sarcomeric proteins. Some congenital myopathy patients have a hypercontractile phenotype. Recent functional studies demonstrated that ACTA1 K326N and TPM2 ΔK7 mutations were associated with hypercontractility that could be explained by increased myofibrillar Ca2+ sensitivity. A recent structure of the complex of actin and tropomyosin in the relaxed state showed that both these mutations are located in the actin–tropomyosin interface. Tropomyosin is an elongated molecule with a 7-fold repeated motif of around 40 amino acids corresponding to the 7 actin monomers it interacts with. Actin binds to tropomyosin electrostatically at two points, through Asp25 and through a cluster of amino acids that includes Lys326, mutated in the gain-of-function mutation. Asp25 interacts with tropomyosin K6, next to K7 that was mutated in the other gain-of-function mutation. We identified four tropomyosin motifs interacting with Asp25 (K6-K7, K48-K49, R90-R91 and R167-K168) and three E-E/D-K/R motifs interacting with Lys326 (E139, E181 and E218), and we predicted that the known skeletal myopathy mutations ΔK7, ΔK49, R91G, ΔE139, K168E and E181K would cause a gain of function. Tests by an in vitro motility assay confirmed that these mutations increased Ca2+ sensitivity, while mutations not in these motifs (R167H, R244G) decreased Ca2+ sensitivity. The work reported here explains the molecular mechanism for 6 out of 49 known disease-causing mutations in the TPM2 and TPM3 genes, derived from structural data of the actin–tropomyosin interface. PMID:23886664

Sensitivity of tropical forest aboveground productivity to climate anomalies in SW Costa Rica

NASA Astrophysics Data System (ADS)

Hofhansl, Florian; Kobler, Johannes; Ofner, Joachim; Drage, Sigrid; Pölz, Eva-Maria; Wanek, Wolfgang

2014-12-01

The productivity of tropical forests is driven by climate (precipitation, temperature, and light) and soil fertility (geology and topography). While large-scale drivers of tropical productivity are well established, knowledge on the sensitivity of tropical lowland net primary production to climate anomalies remains scarce. We here analyze seven consecutive years of monthly recorded tropical forest aboveground net primary production (ANPP) in response to a recent El Niño-Southern Oscillation (ENSO) anomaly. The ENSO transition period resulted in increased temperatures and decreased precipitation during the El Niño dry period, causing a decrease in ANPP. However, the subsequent La Niña wet period caused strong increases in ANPP such that drought-induced reductions were overcompensated. Most strikingly, the climatic controls differed between canopy production (CP) and wood production (WP). Whereas CP showed strong seasonal variation but was not affected by ENSO, WP decreased significantly in response to a 3°C increase in annual maximum temperatures during the El Niño period but subsequently recovered to above predrought levels during the La Niña period. Moreover, the climate sensitivity of tropical forest ANPP components was affected by local topography (water availability) and disturbance history (species composition). Our results suggest that projected increases in temperature and dry season length could impact tropical carbon sequestration by shifting ANPP partitioning toward decreased WP, thus decreasing the carbon storage of highly productive lowland forests. We conclude that the impact of climate anomalies on tropical forest productivity is strongly related to local site characteristics and will therefore likely prevent uniform responses of tropical lowland forests to projected global changes.

Impact of Nrf2 on tumour growth and drug sensitivity in oncogenic K-ras-transformed cells in vitro and in vivo.

PubMed

Shao, Jiajia; Glorieux, Christophe; Liao, Jianwei; Chen, Ping; Lu, Wenhua; Liang, Zhenhao; Wen, Shijun; Hu, Yumin; Huang, Peng

2018-06-01

K-ras is one of the most common oncogenes in human cancers, and its aberrant activation may lead to malignant transformation associated with oxidative stress and activation of the transcription factor Nrf2 that regulates multiple detoxification enzymes. The purpose of this research was to use gene editing technology to evaluate the role of Nrf2 in affecting tumour growth and drug sensitivity of K-ras G12V -transformed cells. We showed that induction of K-ras G12V caused a significant activation of Nrf2 associated with increased expression of its target genes NAD(P)H:quinone oxidoreductase 1 (NQO1) and haem oxygenase-1 (HO-1). Interestingly, knock-out of Nrf2 by CRISPR/Cas9 in K-ras G12V -expressing cells only impacted the expression of NQO1 but not HO-1. We also found that Nrf2 knock-out caused high reactive oxygen species (ROS) stress, suppression of cell proliferation, increased apoptosis in vitro, and a decrease of tumour growth in vivo. Furthermore, abrogation of Nrf2 significantly increased the sensitivity of K-ras G12V cells to multiple anticancer agents including phenethyl isothiocyanate (PEITC), doxorubicin, etoposide, and cisplatin. These results show that genetic abrogation of Nrf2 impairs the malignant phenotype of K-Ras G12V -transformed cells in vitro and in vivo, and demonstrates the critical role of Nrf2 in promoting cell survival and drug resistance in cells harbouring oncogenic K-ras. As such, inhibition of Nrf2 would be an attractive strategy to increase the therapeutic effect and overcome drug resistance in cancer with oncogenic K-ras activation.

The pilosebaceous unit—a phthalate-induced pathway to skin sensitization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simonsson, Carl, E-mail: carl.simonsson@chem.gu.se; Stenfeldt, Anna-Lena; Karlberg, Ann-Therese

2012-10-01

Allergic contact dermatitis (ACD) is caused by low-molecular weight compounds called haptens. It has been shown that the potency of haptens can depend on the formulation in which they are applied on the skin. Specifically the sensitization potency of isothiocyanates, a group of haptens which can be released from e.g. adhesive tapes and neoprene materials, increases with the presence of phthalates; however, the underlying mechanisms are not clear. A better understanding of the mechanisms governing the potency of haptens is important, e.g. to improve the risk assessment and the formulation of chemicals in consumer products. In this study we havemore » explored phthalate-induced effects on the sensitization potency, skin distribution, and reactivity of fluorescent model isothiocyanate haptens using non-invasive two-photon microscopy to provide new insights regarding vehicle effects in ACD. The data presented in this paper indicate that the sensitization potency of isothiocyanates increases when applied in combination with dibutylphthalate due to a specific uptake via the pilosebaceous units. The results highlight the importance of shunt pathways when evaluating the bioavailability of skin sensitizers. The findings also indicate that vehicle-dependent hapten reactivity towards stratum corneum proteins regulates the bioavailability, and thus the potency, of skin sensitizers. -- Highlights: ► Vehicle effects on sensitization potency were investigated in the LLNA. ► In vivo cutaneous absorption of contact sensitizers was visualized using TPM. ► Sensitizing potency of isothiocyanates depends on the presence of a phthalate. ► Phthalate induced cutaneous absorption via the pilosebaceous units. ► Vehicle-dependent reactivity regulates sensitization potency.« less

A single exposure to immobilization causes long-lasting pituitary-adrenal and behavioral sensitization to mild stressors.

PubMed

Belda, Xavier; Fuentes, Silvia; Nadal, Roser; Armario, Antonio

2008-11-01

We have previously reported that a single exposure to immobilization (IMO) in rats causes a long-term desensitization of the hypothalamic-pituitary-adrenal (HPA) response to the same (homotypic) stressor. Since there are reports showing that a single exposure to other stressors causes sensitization of the HPA response to heterotypic stressors and increases anxiety-like behavior, we studied in the present work the long-term effects of IMO on behavioral and HPA response to mild superimposed stressors. In Experiments 1 and 2, adult male Sprague-Dawley rats were subjected to 2 h of IMO and then exposed for 5 min to the elevated plus-maze (EPM) at 1, 3 or 7 days after IMO. Blood samples were taken at 15 min after initial exposure to the EPM. Increases in anxiety-like behavior and HPA responsiveness to the EPM were found at all times post-IMO. Changes in the resting levels of HPA hormones did not explain the enhanced HPA responsiveness to the EPM (Experiment 3). In Experiments 4 and 5, we studied the effects of a single exposure to a shorter session of IMO (1 h) on behavioral and HPA responses to a brief and mild session of foot-shocks done 10 days after IMO. Neither previous IMO nor exposure to shocks in control rats modified behavior in the EPM. However, a brief session of shocks in previously IMO-exposed rats dramatically increased anxiety in the EPM. HPA and freezing responses to shocks were similar in control and previous IMO groups. Therefore, a single exposure to IMO appears to induce long-lasting HPA and behavioral sensitization to mild superimposed stressors, although the two responses are likely to be at least partially independent. Long-term effects of IMO on the susceptibility to stress-induced endocrine and emotional disturbances may be relevant to the characterization of animal models of post-traumatic stress.

Computational studies of transthoracic and transvenous defibrillation in a detailed 3-D human thorax model.

PubMed

Jorgenson, D B; Haynor, D R; Bardy, G H; Kim, Y

1995-02-01

A method for constructing and solving detailed patient-specific 3-D finite element models of the human thorax is presented for use in defibrillation studies. The method utilizes the patient's own X-ray CT scan and a simplified meshing scheme to quickly and efficiently generate a model typically composed of approximately 400,000 elements. A parameter sensitivity study on one human thorax model to examine the effects of variation in assigned tissue resistivity values, level of anatomical detail included in the model, and number of CT slices used to produce the model is presented. Of the seven tissue types examined, the average left ventricular (LV) myocardial voltage gradient was most sensitive to the values of myocardial and blood resistivity. Incorrectly simplifying the model, for example modeling the heart as a homogeneous structure by ignoring the blood in the chambers, caused the average LV myocardial voltage gradient to increase by 12%. The sensitivity of the model to variations in electrode size and position was also examined. Small changes (< 2.0 cm) in electrode position caused average LV myocardial voltage gradient values to increase by up to 12%. We conclude that patient-specific 3-D finite element modeling of human thoracic electric fields is feasible and may reduce the empiric approach to insertion of implantable defibrillators and improve transthoracic defibrillation techniques.

Multiple Chemical Sensitivity (MCS) - Scientific and Public-Health Aspects

PubMed Central

Schwenk, Michael

2004-01-01

Multiple Chemical Sensitivity (MCS) is a phenomenon which the ENT-doctor should be familiar with. It has its roots in the description of a syndrome in 1987. A worker spilled chemicals at his workplace and from then on he reacted highly sensitive to chemicals. Today, there are many people who explain their complaints with self-suspected MCS. Various pathopysiological models have been proposed, including toxicological, immunological or behaviorial models. But no-one could be proved so far. Since controlled provocation tests have also provided unclear results, an increasing number of doctors assumes today, that MCS reflects a psychic condition. In 1996, an expert team of the WHO has suggested the renaming of MCS to "idiopathic environmental illness" (IEI). However, other doctors still assume a chemical cause. Since there are neither straightforward diagnostic methods to proof MCS, nor reliable therapeutic concepts, treatment of MCS-patients is usually difficult. The MCS-debate (somatic vs psychic causes) seems to reflect the dilemma of the medical profession today, that somatic disorders of known origin can be well treated, whereas the increasing number of psychosomatic/ somatoform disorders is often resistant to medical help. The ENT-doctor should pay attention to changes of the nasal mucous membrane, nasal resistance and the sense of smell. Moreover he should know about the peculiarities of MCS-patients. The manuscript describes the present knowledge and state of discussion with special regard to the situation in Germany. PMID:22073047

The sensitivity of Bacillus subtilis to diverse antimicrobial compounds is influenced by Abh.

PubMed

Murray, Ewan J; Stanley-Wall, Nicola R

2010-12-01

Abh is a transition state regulator of Bacillus subtilis that controls biofilm formation and the production of several diverse antimicrobial compounds. Using a high-throughput non-biased technique, we show for the first time that Abh influences the sensitivity of B. subtilis to diverse antimicrobial compounds. Following up on these findings with a combination of classical genetics and antibiotic susceptibility assays, we demonstrate that Abh influences cellular processes such as the remodelling of the cell wall. We present data demonstrating that the extracytoplasmic function sigma factor σ(X) controls resistance to β-lactam antibiotics by activating abh transcription. Downstream from Abh, activation of slrR expression by Abh is responsible for controlling the sensitivity of B. subtilis to such antibiotics due to the role that SlrR plays in regulating autolysin biosynthesis. The abh mutant additionally exhibits increased resistance to aminoglycoside antimicrobials. We confirm that aminoglycoside killing of B. subtilis is likely to be caused by oxidative damage but rule out the possibility that the increased resistance of the abh mutant to aminoglycosides is due to a general increase in resistance to oxidative stress.

Fast Atmosphere-Ocean Model Runs with Large Changes in CO2

NASA Technical Reports Server (NTRS)

Russell, Gary L.; Lacis, Andrew A.; Rind, David H.; Colose, Christopher; Opstbaum, Roger F.

2013-01-01

How does climate sensitivity vary with the magnitude of climate forcing? This question was investigated with the use of a modified coupled atmosphere-ocean model, whose stability was improved so that the model would accommodate large radiative forcings yet be fast enough to reach rapid equilibrium. Experiments were performed in which atmospheric CO2 was multiplied by powers of 2, from 1/64 to 256 times the 1950 value. From 8 to 32 times, the 1950 CO2, climate sensitivity for doubling CO2 reaches 8 C due to increases in water vapor absorption and cloud top height and to reductions in low level cloud cover. As CO2 amount increases further, sensitivity drops as cloud cover and planetary albedo stabilize. No water vapor-induced runaway greenhouse caused by increased CO2 was found for the range of CO2 examined. With CO2 at or below 1/8 of the 1950 value, runaway sea ice does occur as the planet cascades to a snowball Earth climate with fully ice covered oceans and global mean surface temperatures near 30 C.

A cellular automata traffic flow model for three-phase theory

NASA Astrophysics Data System (ADS)

Qian, Yong-Sheng; Feng, Xiao; Zeng, Jun-Wei

2017-08-01

This paper presents a newly-modified KKW model including the subdivided vehicles types, and introduces the changes for a driver's sensitivity into the speed fluctuation. By means of the numerical simulation the following conclusions are obtained herewith: 1. Velocity disturbance propagation in traffic flow is caused by the speed adaptation among vehicles. 2. In free flow phase, very fewer vehicles are affected by the velocity disturbance and the effect can be dissipated quickly thus the time of disturbance in a single vehicle is quite shorter. On the contrary, the impact duration time of the disturbance on a single vehicle is longer in synchronous flow phase, thus, it will affect more vehicles accordingly. 3. Under the free flow phase, the continuous deceleration behavior of a high speed vehicle to adapt the preceding car with slow speed can cause the reduction of the driver's sensitivity, lead to the vehicle over-deceleration and aggravate the effects of velocity perturbations While in the synchronous flow phase, though the reaction delay caused by the driver's sensitivity reduction can induce speed wave dissolving in essence, it increases the impact of disturbance on the traffic flow. 4. The large acceleration and deceleration tendency of an aggressive driver in the free flow phase always increase the influence of the velocity disturbance, while a conservative driver often weakens the influence. However, in the synchronized flow, since the high traffic density and the synchronization between vehicles is very strong, also the main factor which affects the driver's speed choice is the distance among vehicles, therefore the effect of a driver's behavior tendency to the spread of velocity perturbation is not obvious under this state.

Altered pain sensitivity and axioscapular muscle activity in neck pain patients compared with healthy controls.

PubMed

Christensen, S W; Hirata, R P; Graven-Nielsen, T

2017-11-01

Previous studies have indicated that neck pain patients feel increased symptoms following upper limb activities, and altered axioscapular muscle function has been proposed as a contributing factor. Pain sensitivity and muscle activity, during arm movements, were assessed in neck pain patients and controls. Patients with ongoing insidious-onset neck pain (IONP, N = 16) and whiplash-associated disorders (WAD, N = 9) were included along with sex- and age-matched controls (N = 25). Six series of repeated arm abductions were performed during electromyographic (EMG) recordings from eight bilateral muscles. The first and last three series were separated by 8 min and 42 s, respectively. Each series consisted of three slow and three fast movements. Pressure pain thresholds (PPTs) were recorded bilaterally from neck, head and arm at baseline, after the third and sixth movement series. Pain intensity was recorded on an electronic visual analogue scale (VAS). Larger pain areas and higher VAS scores were found in patients compared with controls (p < 0.001), and in patients, the VAS scores increased in the course of movements (p < 0.02). PPTs were lower in patients compared with controls at all sites (p < 0.03), and these decreased during arm movements in the IONP group (p < 0.03), while increasing at head and neck sites in controls (p < 0.04). During the slow movements, increasing serratus anterior EMG activity was found in the series with short breaks in-between for the WAD group compared with IONP and controls (p < 0.001). Axioscapular movement caused different responses in pain sensitivity and muscle activity between neck pain patient groups compared with controls. Neck pain patients report increased symptoms following upper limb activities. This study shows that repeated arm movements caused differentiated responses in pain sensitivity and muscle activity between subgroups of neck pain patient and asymptomatic controls. Such findings may be of great clinical significance when planning rehabilitation for this patient population. © 2017 European Pain Federation - EFIC®.

Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons

PubMed Central

Yang, Shi-Bing; Tien, An-Chi; Boddupalli, Gayatri; Xu, Allison W.; Jan, Yuh Nung; Jan, Lily Yeh

2012-01-01

Summary The prevalence of obesity in older people is the leading cause of metabolic syndromes. Central neurons serving as homeostatic sensors for bodyweight control include hypothalamic neurons that express pro-opiomelanocortin (POMC) or neuropeptide-Y (NPY) and agouti-related protein (AgRP). Here we report an age-dependent increase of mammalian target of rapamycin (mTOR) signaling in POMC neurons that elevates the ATP-sensitive potassium (KATP) channel activity cell-autonomously to silence POMC neurons. Systemic or intracerebral administration of the mTOR inhibitor rapamycin causes weight loss in old mice. Intracerebral rapamycin infusion into old mice enhances the excitability and neurite projection of POMC neurons, thereby causing a reduction of food intake and bodyweight. Conversely, young mice lacking the mTOR negative regulator TSC1 in POMC neurons, but not those lacking TSC1 in NPY/AgRP neurons, were obese. Our study reveals that an increase in mTOR signaling in hypothalamic POMC neurons contributes to age-dependent obesity. PMID:22884327

Thin films composed of multiwalled carbon nanotubes, gold nanoparticles and myoglobin for humidity detection at room temperature.

PubMed

Qi, Zhi-mei; Wei, Mingdeng; Honma, Itaru; Zhou, Haoshen

2007-02-02

Optically transparent and electrically conductive nanocomposite thin films consisting of multiwalled carbon nanotubes (MWCNTs), gold nanoparticles (GNPs) and myoglobin molecules that glue GNPs and MWCNTs together are fabricated for the first time on glass substrates from aqueous solution. The nanocomposite thin film is capable of varying its resistance, impedance or optical transmittance at room temperature in response to changes in ambient humidity. The conductometric sensitivity to relative humidity (RH) of the nanocomposite thin film is compared with those of the pure and Mb-functionalized MWCNT layers. The pure MWCNT layer shows a small increase in its resistance with increasing RH due to the effect of p-type semiconducting nanotubes present in the film. In contrast, a four times higher sensitivity to RH is observed for both the nanocomposite and Mb-functionalized MWCNT thin films. The sensitivity enhancement is attributable to swelling of the thin films induced by water absorption in the presence of Mb molecules, which increases the inter-nanotube spacing and thereby causes a further increase of the film resistance. A humidity change as low as DeltaRH=0.3 % has been readily detected by conductometry using the nanocomposite thin film.

Influence of increased mechanical loading by hypergravity on the microtubule cytoskeleton and prostaglandin E2 release in primary osteoblasts

NASA Technical Reports Server (NTRS)

Searby, Nancy D.; Steele, Charles R.; Globus, Ruth K.

2005-01-01

Cells respond to a wide range of mechanical stimuli such as fluid shear and strain, although the contribution of gravity to cell structure and function is not understood. We hypothesized that bone-forming osteoblasts are sensitive to increased mechanical loading by hypergravity. A centrifuge suitable for cell culture was developed and validated, and then primary cultures of fetal rat calvarial osteoblasts at various stages of differentiation were mechanically loaded using hypergravity. We measured microtubule network morphology as well as release of the paracrine factor prostaglandin E2 (PGE2). In immature osteoblasts, a stimulus of 10x gravity (10 g) for 3 h increased PGE2 2.5-fold and decreased microtubule network height 1.12-fold without affecting cell viability. Hypergravity (3 h) caused dose-dependent (5-50 g) increases in PGE2 (5.3-fold at 50 g) and decreases (1.26-fold at 50 g) in microtubule network height. PGE2 release depended on duration but not orientation of the hypergravity load. As osteoblasts differentiated, sensitivity to hypergravity declined. We conclude that primary osteoblasts demonstrate dose- and duration-dependent sensitivity to gravitational loading, which appears to be blunted in mature osteoblasts.

Mounting a thermocouple of type E onto a Cu single crystal for use in a magnetically sensitive environment below 77 K

DOE Office of Scientific and Technical Information (OSTI.GOV)

Potzuweit, Alexander; Schaffner, Anuschka; Jänsch, Heinz Julius, E-mail: heinz.jaensch@physik.uni-marburg.de

2014-09-01

Type E thermocouples show magnetic effects at liquid nitrogen temperature and below. This may cause trouble in experiments that are sensitive to magnetic stray fields like nuclear magnetic resonance, photoemission or high resolution electron energy loss spectroscopy. Here, a solution for the temperature measurement of a single crystal is presented. The authors weld a copper rod onto the back side of the single crystal, thereby relocating the sensitive sample from the thermocouple attachment position. They show that it is possible to measure the crystal temperature at the end of the rod while significantly reducing the ferromagnetic influence due to themore » increased distance.« less

Mechanical impact tests of materials in oxygen effects of contamination. [Teflon, stainless steel, and aluminum

NASA Technical Reports Server (NTRS)

Ordin, P. M.

1980-01-01

The effect of contaminants on the mechanical impact sensitivity of Teflon, stainless steel, and aluminum in a high-pressure oxygen environment was investigated. Uncontaminated Teflon did not ignite under the test conditions. The liquid contaminants - cutting oil, motor lubricating oil, and toolmaker dye - caused Teflon to ignite. Raising the temperature lowered the impact energy required for ignition. Stainless steel was insensitive to ignition under the test conditions with the contaminants used. Aluminum appeared to react without contaminants under certain test conditions; however, contamination with cutting oil, motor lubricating oil, and toolmakers dye increased the sensitivity of aluminum to mechanical impact. The grit contaminants silicon dioxide and copper powder did not conclusively affect the sensitivity of aluminum.

Antioxidative Defense System, Pigment Composition, and Photosynthetic Efficiency in Two Wheat Cultivars Subjected to Drought1

PubMed Central

Loggini, Barbara; Scartazza, Andrea; Brugnoli, Enrico; Navari-Izzo, Flavia

1999-01-01

We analyzed antioxidative defenses, photosynthesis, and pigments (especially xanthophyll-cycle components) in two wheat (Triticum durum Desf.) cultivars, Adamello and Ofanto, during dehydration and rehydration to determine the difference in their sensitivities to drought and to elucidate the role of different protective mechanisms against oxidative stress. Drought caused a more pronounced inhibition in growth and photosynthetic rates in the more sensitive cv Adamello compared with the relatively tolerant cv Ofanto. During dehydration the glutathione content decreased in both wheat cultivars, but only cv Adamello showed a significant increase in glutathione reductase and hydrogen peroxide-glutathione peroxidase activities. The activation states of two sulfhydryl-containing chloroplast enzymes, NADP+-dependent glyceraldehyde-3-phosphate dehydrogenase and fructose-1,6-bisphosphatase, were maintained at control levels during dehydration and rehydration in both cultivars. This indicates that the defense systems involved are efficient in the protection of sulfhydryl groups against oxidation. Drought did not cause significant effects on lipid peroxidation. Upon dehydration, a decline in chlorophyll a, lutein, neoxanthin, and β-carotene contents, and an increase in the pool of de-epoxidized xanthophyll-cycle components (i.e. zeaxanthin and antheraxanthin), were evident only in cv Adamello. Accordingly, after exposure to drought, cv Adamello showed a larger reduction in the actual photosystem II photochemical efficiency and a higher increase in nonradiative energy dissipation than cv Ofanto. Although differences in zeaxanthin content were not sufficient to explain the difference in drought tolerance between the two cultivars, zeaxanthin formation may be relevant in avoiding irreversible damage to photosystem II in the more sensitive cultivar. PMID:10069848

Targeted disruption of FANCC and FANCG in human cancer provides a preclinical model for specific therapeutic options.

PubMed

Gallmeier, Eike; Calhoun, Eric S; Rago, Carlo; Brody, Jonathan R; Cunningham, Steven C; Hucl, Tomas; Gorospe, Myriam; Kohli, Manu; Lengauer, Christoph; Kern, Scott E

2006-06-01

How specifically to treat pancreatic and other cancers harboring Fanconi anemia gene mutations has raised great interest recently, yet preclinical studies have been hampered by the lack of well-controlled human cancer models. We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and determined the impact of these genes on drug sensitivity, irradiation sensitivity, and genome maintenance. FANCC and FANCG disruption abrogated FANCD2 monoubiquitination, confirming an impaired Fanconi anemia pathway function. On treatment with DNA interstrand-cross-linking agents, FANCC and FANCG disruption caused increased clastogenic damage, G2/M arrest, and decreased proliferation. The extent of hypersensitivity varied among agents, with ratios of inhibitory concentration 50% ranging from 2-fold for oxaliplatin to 14-fold for melphalan, a drug infrequently used in solid tumors. No hypersensitivity was observed on gemcitabine, etoposide, 3-aminobenzamide, NU1025, or hydrogen peroxide. FANCC and FANCG disruption also resulted in increased clastogenic damage on irradiation, but only FANCG disruption caused a subsequent decrease in relative survival. Finally, FANCC and FANCG disruption increased spontaneous chromosomal breakage, supporting the role of these genes in genome maintenance and likely explaining why they are mutated in sporadic cancer. Our human cancer cell model provides optimal controls to elucidate fundamental biologic features of individual Fanconi anemia gene defects and facilitates preclinical studies of therapeutic options. The impact of Fanconi gene defects on drug and irradiation sensitivity renders these genes promising targets for a specific, genotype-based therapy for individual cancer patients, providing a strong rationale for clinical trials.

Short-term weight loss attenuates local tissue inflammation and improves insulin sensitivity without affecting adipose inflammation in obese mice.

PubMed

Jung, Dae Young; Ko, Hwi Jin; Lichtman, Eben I; Lee, Eunjung; Lawton, Elizabeth; Ong, Helena; Yu, Kristine; Azuma, Yoshihiro; Friedline, Randall H; Lee, Ki Won; Kim, Jason K

2013-05-01

Obesity is a major cause of insulin resistance, and weight loss is shown to improve glucose homeostasis. But the underlying mechanism and the role of inflammation remain unclear. Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 wk. After HFD, weight loss was induced by changing to a low-fat diet (LFD) or exercise with continuous HFD. The weight loss effects on energy balance and insulin sensitivity were determined using metabolic cages and hyperinsulinemic euglycemic clamps in awake mice. Diet and exercise intervention for 3 wk caused a modest weight loss and improved glucose homeostasis. Weight loss dramatically reduced local inflammation in skeletal muscle, liver, and heart but not in adipose tissue. Exercise-mediated weight loss increased muscle glucose metabolism without affecting Akt phosphorylation or lipid levels. LFD-mediated weight loss reduced lipid levels and improved insulin sensitivity selectively in liver. Both weight loss interventions improved cardiac glucose metabolism. These results demonstrate that a short-term weight loss with exercise or diet intervention attenuates obesity-induced local inflammation and selectively improves insulin sensitivity in skeletal muscle and liver. Our findings suggest that local factors, not adipose tissue inflammation, are involved in the beneficial effects of weight loss on glucose homeostasis.

Evolution of the incidence of pollen grains and sensitivity to pollen in the city of Elche (Spain).

PubMed

Javier, Fernandez; Emilio, Flores; Montserrat, Varea; Victor, Soriano; Purificaci N, Gonzalez

2015-09-01

Environment-mediated pollen production varies over time and space, influencing pollen exposure risk and ultimately patient sensitization trends. In order to assess temporal variation of pollen incidence and patient sensitization, we set up a pollen incidence and patient sensitization survey in the city of Elche, Spain, over a 10-years interval. Pollen counts were obtained from a Burkard-type collector located in the city of Elche. We studied consecutive patients attending the outpatient consulting room at the Elche Hospital for suspected pollinosis (276 in 2005), and compared observed trends with cases from 1995 (200). Skin tests were performed for most of the common pollen in our area. The total pollen count increased by 41% from 1995 (13,219) to 2005 (22,854). There were significant counts differences between 1995 and 2005 in Olea europaea (2,018 vs. 4,433), Phoenix dactylifera (3,130 vs. 3,891), and Cupressaceae (1,212 vs. 3,115). The differences between sensitization to pollen in both years were mainly for those in relation to Olea europaea (51.4% vs. 74.9%), Salsola kali (53.7% vs. 71.8%), Parietaria judaica (10.3% vs. 21.5%), Phoenix dactylifera (5.6% vs. 22.3%), Plantago lanceolata (17.8% vs. 38.5%), and Poaceae (47.7% vs. 44.1%). The percentage of monosensitized patients was similar in both years, 16% in 1995 and 17% in 2005. Increased pollen counts in the environment may have led to increased sensitization to pollen. Possible causes may be due to changes in the weather, although the improvements of the extracts used in skin testing, increased air pollution, and/or climate change are factors to consider.

Weather sensitivity for zoo visitation in Toronto, Canada: a quantitative analysis of historical data

NASA Astrophysics Data System (ADS)

Hewer, Micah J.; Gough, William A.

2016-11-01

Based on a case study of the Toronto Zoo (Canada), multivariate regression analysis, involving both climatic and social variables, was employed to assess the relationship between daily weather and visitation. Zoo visitation was most sensitive to weather variability during the shoulder season, followed by the off-season and, then, the peak season. Temperature was the most influential weather variable in relation to zoo visitation, followed by precipitation and, then, wind speed. The intensity and direction of the social and climatic variables varied between seasons. Temperatures exceeding 26 °C during the shoulder season and 28 °C during the peak season suggested a behavioural threshold associated with zoo visitation, with conditions becoming too warm for certain segments of the zoo visitor market, causing visitor numbers to decline. Even light amounts of precipitation caused average visitor numbers to decline by nearly 50 %. Increasing wind speeds also demonstrated a negative influence on zoo visitation.

Sulfuric acid induces airway hyperresponsiveness to substance P in the guinea pig.

PubMed

Stengel, P W; Bendele, A M; Cockerham, S L; Silbaugh, S A

1993-01-01

We investigated whether sulfuric acid inhalation would cause hyperresponsiveness to substance P. Guinea pigs became dyspneic during a 1 h sulfuric acid exposure, but recovered by 24 h when they were challenged with substance P or histamine aerosols. Eight minutes after the start of challenge, animals were killed and excised lung gas volumes measured. Sulfuric acid slightly increased histamine responsiveness compared to controls. However, sulfuric acid caused a much more pronounced leftward shift in the dose response to substance P. Coadministration of the neutral endopeptidase (NEP) inhibitor, thiorphan, did not reduce sulfuric acid-related hyperresponsiveness to substance P. By 72 h, sensitization to substance P was absent. Histological evaluation of sulfuric acid-treated lungs revealed mild alveolitis at 24 h, but not at 72 h. We conclude that sulfuric acid produces a marked sensitization to substance P. Inactivation of NEP does not appear to account for this effect.

Zinc activates damage-sensing TRPA1 ion channels.

PubMed

Hu, Hongzhen; Bandell, Michael; Petrus, Matt J; Zhu, Michael X; Patapoutian, Ardem

2009-03-01

Zinc is an essential biological trace element. It is required for the structure or function of over 300 proteins, and it is increasingly recognized for its role in cell signaling. However, high concentrations of zinc have cytotoxic effects, and overexposure to zinc can cause pain and inflammation through unknown mechanisms. Here we show that zinc excites nociceptive somatosensory neurons and causes nociception in mice through TRPA1, a cation channel previously shown to mediate the pungency of wasabi and cinnamon through cysteine modification. Zinc activates TRPA1 through a unique mechanism that requires zinc influx through TRPA1 channels and subsequent activation via specific intracellular cysteine and histidine residues. TRPA1 is highly sensitive to intracellular zinc, as low nanomolar concentrations activate TRPA1 and modulate its sensitivity. These findings identify TRPA1 as an important target for the sensory effects of zinc and support an emerging role for zinc as a signaling molecule that can modulate sensory transmission.

Sensitivity to bites by the bedbug, Cimex lectularius.

PubMed

Reinhardt, K; Kempke, D; Naylor, R A; Siva-Jothy, M T

2009-06-01

Bedbugs are a public health problem and can cause significant economic losses, but little is known about the effects of bites on humans. We reviewed case reports and published papers on bedbug bites to assess the empirical basis of the commonly cited figure that only approximately 80% of the population are sensitive to bedbug bites. We found the sensitivity estimate to be based on only one study carried out 80 years ago. However, this study did not account for the now well-established fact that only repeated exposure to external allergens leads to skin reactions. In our sample, 18 of 19 persons showed a skin reaction after bedbug exposure, but in most cases only after repeated controlled exposure. With repeated exposure, the latency between bite and skin reactions decreased from approximately 10 days to a few seconds. Our results are relevant for the hospitality industry, where apparently increasing infestation rates are likely to lead to an increase in the number of tourists and hotel employees exposed to bedbugs. Medical and public health professionals may expect to see an increase in the prevalence of people with bedbug bite sensitivity. The significance of the delayed reaction time of skin to bites may also have implications in litigation cases where people seek compensation.

Increased sensitivity to thiopurines in methylthioadenosine phosphorylase-deleted cancers

PubMed Central

Coulthard, Sally A.; Redfern, Christopher P.F.; Vikingsson, Svante; Appell, Malin Lindqvist; Skoglund, Karin; Falk, Ingrid Jakobsen; Hall, Andrew G.; Taylor, Gordon A.; Hogarth, Linda A.

2011-01-01

The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used in the treatment of leukaemia. Incorporation of deoxythioguanosine nucleotides (dGs) into the DNA of thiopurine-treated cells causes cell death but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Since the growth of MTAP-deleted tumour cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukaemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP−ve) transfected to express MTAP constitutively (A549-MTAP+ve). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intra-cellularly to MeTIMP, was markedly higher in both cell lines under MTAP−ve conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dGs incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP. PMID:21282358

Excess processing of oxidative damaged bases causes hypersensitivity to oxidative stress and low dose rate irradiation.

PubMed

Yoshikawa, Y; Yamasaki, A; Takatori, K; Suzuki, M; Kobayashi, J; Takao, M; Zhang-Akiyama, Q-M

2015-10-01

Ionizing radiations such as X-ray and γ-ray can directly or indirectly produce clustered or multiple damages in DNA. Previous studies have reported that overexpression of DNA glycosylases in Escherichia coli (E. coli) and human lymphoblast cells caused increased sensitivity to γ-ray and X-ray irradiation. However, the effects and the mechanisms of other radiation, such as low dose rate radiation, heavy-ion beams, or hydrogen peroxide (H2O2), are still poorly understood. In the present study, we constructed a stable HeLaS3 cell line overexpressing human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) protein. We determined the survival of HeLaS3 and HeLaS3/hOGG1 cells exposed to UV, heavy-ion beams, γ-rays, and H2O2. The results showed that HeLaS3 cells overexpressing hOGG1 were more sensitive to γ-rays, OH(•), and H2O2, but not to UV or heavy-ion beams, than control HeLaS3. We further determined the levels of 8-oxoG foci and of chromosomal double-strand breaks (DSBs) by detecting γ-H2AX foci formation in DNA. The results demonstrated that both γ-rays and H2O2 induced 8-oxoguanine (8-oxoG) foci formation in HeLaS3 cells. hOGG1-overexpressing cells had increased amounts of γ-H2AX foci and decreased amounts of 8-oxoG foci compared with HeLaS3 control cells. These results suggest that excess hOGG1 removes the oxidatively damaged 8-oxoG in DNA more efficiently and therefore generates more DSBs. Micronucleus formation also supported this conclusion. Low dose-rate γ-ray effects were also investigated. We first found that overexpression of hOGG1 also caused increased sensitivity to low dose rate γ-ray irradiation. The rate of micronucleus formation supported the notion that low dose rate irradiation increased genome instability.

Phenazine derivatives cause proteotoxicity and stress in C. elegans

PubMed Central

Ray, Arpita; Rentas, Courtney; Caldwell, Guy A.; Caldwell, Kim A.

2014-01-01

It is widely recognized that bacterial metabolites have toxic effects in animal systems. Phenazines are a common bacterial metabolite within the redox-active exotoxin class. These compounds have been shown to be toxic to the soil invertebrate Caenorhabditis elegans with the capability of causing oxidative stress and lethality. Here we report that chronic, low-level exposure to three separate phenazine molecules (phenazine-1-carboxylic acid, pyocyanin and 1-hydroxyphenazine) upregulated ER stress response and enhanced expression of a superoxide dismutase reporter in vivo. Exposure to these molecules also increased of polyglutamine and α-synuclein in the bodywall muscle cells of C. elegans. Exposure of worms to these phenazines caused additional sensitivity in dopamine neurons expressing wild-type α-synuclein, indicating a possible defect in protein homeostasis. The addition of an anti-oxidant failed to rescue the neurotoxic and protein aggregation phenotypes caused by these compounds. Thus, increased production of superoxide radicals that occurs in whole animals in response to these phenazines appears independent from the toxicity phenotype observed. Collectively, these data provide cause for further consideration of the neurodegenerative impact of phenazines. PMID:25304539

Improvement of a PCR test to diagnose infection by Mansonella ozzardi.

PubMed

Vera, Luana Janaína Souza; Basano, Sergio de Almeida; Camargo, Juliana de Souza Almeida Aranha; França, Andonai Krauze de; Ferreira, Ricardo de Godoi Mattos; Casseb, Almeida Andrade; Medeiros, Jansen Fernandes; Fontes, Gilberto; Camargo, Luís Marcelo Aranha

2011-01-01

Mansonelliasis is caused by Mansonella ozzardi. It is widespread in the Amazon region, with a high prevalence. The common exam of thick blood smears stained with Giemsa shows low efficacy levels and has been an obstacle to diagnosing individuals with low blood parasitemia. In order to increase diagnosis efficacy, the PCR technique was improved. PCR demonstrated the best performance, with sensitivity and negative predictive values (NPV) of 100%, followed by blood filtration through membrane filters, which showed a sensitivity of 88.9% and a NPV of 84.6%, when compared to thick blood smears.

STUDIES ON THE USE OF MUTAGENIC AGENTS IN PLANT BREEDING. I. THE EFFECT OF SEED MOISTURE CONTENT ON SENSITIVITY TO X RAYS IN LUPINUS ANGUSTIFOLIUS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Francis, C.M.; Gladstones, J.S.

1963-01-01

Seeds of Lupinus angustifolius were exposed to doses of to 18.1% (fresh wt). X/sub 1/ plant damage was measured in terms of reduction in height at 110 days from sowing, delay in flowering, and reduction in mean seed yield per plant. The three measures were found to be highly correlated. Survival was not significantly affected within the range of treatments used. Radiosensitivity increased progressively with decreasing moisture contents below 11.6%, seeds with 8.1-7.6% being four to five times as sensitive as those with 11.6-16% moisture content. The latter range represented a plateau of min sensitivity. Between 18.0 and 18.1% moisture,more » sensitivity again increased. Flowering time was the most sensitive measure of plant damage in that it was the only one to register consistently an effect due to the lowest x-ray dose (2.5 kr). This indicates that flowering time could be the most reliable, for comparative purposes, of the indices used. In addition it has the important advantage of being quickly and accurately scored. The magnitude of the protection against x-ray damage afforded by increased seed moisture can be expressed quantitatively in terms of a dose reduction factor (DRF), i.e., the factor by which the dose tolerated by the most sensitive seeds is less than that required to cause the same level of damage in the most tolerant seeds. DRF (in the present experiments between four and five for all three indices of x-ray damage) represents the damage caused to the seeds by 5 kr at 6-7% moisture as being approximates the same as that caused by 20 kr at 11-16% seed moisture. This is similar to the factor of about four previously found for barley seedling height and survival, but differs from the value of 10 found for seedling leaf span and survival in tomato. It is possible, however, that the extremely low moisture contents obtained in tomato seeds (as low as 1.2%) contributed to the difference, and that greater DRF might have been found for barley and lupins had lower min seed moisture contents been obtained. It is proposed that in subsequent generations, a corresponding DRF be derived for mutation rates. This should show whether or not the protective effect of moisture against plant damage in the X/sub 1/ is paralleled by a similar protection against mutation. If it is not, as appears to be the case in barley, it should be possible to define a particular range of seed moisture contents at which the highest mutation rates can be obtained. (BBB)« less

Climate, Tree Growth, Forest Drought Stress, and Tree Mortality in Forests of Western North America: Long-Term Patterns and Recent Trends

NASA Astrophysics Data System (ADS)

Allen, C. D.; Williams, P.

2012-12-01

Ongoing climate changes are increasingly affecting the world's forests, particularly including high latitude and high elevation coniferous forests. Although forest growth has improved in some regions due to greater growing season length and warmth (perhaps along with increased atmospheric CO2 or N), large growth declines or increased mortality from droughts or hotter temperatures also are being observed. We present and interpret information on regional variation in climate-tree growth relationships and trends, and on patterns and trends of climate-related forest disturbances, from western North America. From 235 tree-ring chronologies in the Southwest US we show that tree-ring growth records from warmer southwestern sites are more sensitive to temperature than tree-ring growth records from cooler southwestern sites. Assessment of 59 tree-ring records from 11 species in the Cascade Mountains of the Pacific Northwest shows that trees growing in cool places respond positively to increased temperature and trees in warm places respond negatively, implying that trees historically not sensitive to temperature may become sensitive as mean temperatures warm. An analysis of 59 white spruce populations in Alaska supports the hypothesis that warming has caused tree growth to lose sensitivity to cold temperatures. Comparing ring widths to temperature during just the coldest 50% of years during the 20th century, tree growth was sensitive to cold temperatures, and this effect was strongest at the coldest sites; whereas during the warmest 50% of years, trees were not at all sensitive to cold temperatures, even at the cold sites. Drought and vapor pressure deficit are among the variables that emerge as being increasingly important to these Alaska boreal forests as mean temperatures rise. Most recently, from 346 tree-ring chronologies in the Southwest US we establish a tree-ring-based Forest Drought Stress Index (FDSI) for the three most widespread conifer species (Pinus edulis, Pinus ponderosa, and Pseudotsuga menziesii) in this region. FDSI responds sensitively and nonlinearly to growing season daily maximum temperatures which increase vapor pressure deficit, resulting in greater tree physiological stress and reduced tree growth. Drought conditions and warming temperatures in the Southwest since ca. 1996 have caused FDSI values in particular years since 2000 to start to exceed the most extreme values reconstructed from tree-rings for the past 1000 years for this region. FDSI demonstrates strong correlations with the spatial extent of major forest disturbances in the Southwest, including high-severity wildfire and bark beetle infestations, which over the past 20 years also have affected historically unprecedented levels. Similar trends of increasing extent and severity of forest disturbances are apparent across large portions of western North America. For the Southwest US, given relatively robust projections of substantial further increases in warmer temperatures and drought stress in coming decades, by ~2050 projected levels of FDSI and associated disturbances would reach extreme values, suggesting that current forest ecosystems likely would be forced to reorganize through wholesale tree mortality and the establishment of new dominant species.

Transferencia Linguistica y Multilinguismo (Linguistic Transfer and Multilingualism).

ERIC Educational Resources Information Center

Sanchez D., Anibal

1971-01-01

The problem of interference caused by linguistic transfer in second language learning does not increase with the number of languages that the student has acquired. The ability to learn a second, third, or fourth language depends on what Chomsky calls "the language acquisition device," which is a capacity or a sensitivity formed by a combination of…

Excessive exposure stimulates epicormic branching in young northern hardwoods

Treesearch

Barton M. Blum

1963-01-01

Sudden and excessive exposure of northern hardwood trees often causes growth responses that degrade tree quality, injuries that lead to tree deterioration, or both. The most sensitive and visible tree reaction to increased exposure is the formation of epicormic branches. Such branches may arise along the tree bole from either dormant or adventitious buds in response to...

Effect of zeolite nano-materials and artichoke (Cynara scolymus L.) leaf extract on increase in urinary clearance of systematically absorbed nicotine.

PubMed

Malekshah, R E; Mahjub, R; Rastgarpanah, M; Ghorbani, M; Partoazar, A R; Mehr, S E; Dehpour, A R; Dorkoosh, F A

2012-12-01

Nicotine, the main pharmacologically active component in tobacco and cigarette, has some toxic effects and also high potential for addiction. In this study, the effect of artichoke (Cynara scolymus L.) and zeolite nano-materials on urinary excretion of nicotine and consequently elimination of systematically absorbed nicotine was investigated. A simple, valid and highly sensitive high performance liquid chromatography method has been developed for determination of nicotine in rat urine according to guidelines for bioanalysis.It was found that nano-zeolites can cause increase in urinary concentration of nicotine due to its high surface adsorption. Artichoke leaf extract can cause increase in urinary excretion of nicotine in longer post administration times. It was observed that co-administration of nanozeolites and the leaf extract has the synergetic effect on increasing the urinary excretion of nicotine. © Georg Thieme Verlag KG Stuttgart · New York.

An Animal Model of Trichloroethylene-Induced Skin Sensitization in BALB/c Mice.

PubMed

Wang, Hui; Zhang, Jia-xiang; Li, Shu-long; Wang, Feng; Zha, Wan-sheng; Shen, Tong; Wu, Changhao; Zhu, Qi-xing

2015-01-01

Trichloroethylene (TCE) is a major occupational hazard and environmental contaminant that can cause multisystem disorders in the form of occupational medicamentosa-like dermatitis. Development of dermatitis involves several proinflammatory cytokines, but their role in TCE-mediated dermatitis has not been examined in a well-defined experimental model. In addition, few animal models of TCE sensitization are available, and the current guinea pig model has apparent limitations. This study aimed to establish a model of TCE-induced skin sensitization in BALB/c mice and to examine the role of several key inflammatory cytokines on TCE sensitization. The sensitization rate of dorsal painted group was 38.3%. Skin edema and erythema occurred in TCE-sensitized groups, as seen in 2,4-dinitrochlorobenzene (DNCB) positive control. Trichloroethylene sensitization-positive (dermatitis [+]) group exhibited increased thickness of epidermis, inflammatory cell infiltration, swelling, and necrosis in dermis and around hair follicle, but ear painted group did not show these histological changes. The concentrations of serum proinflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-2 were significantly increased in 24, 48, and 72 hours dermatitis [+] groups treated with TCE and peaked at 72 hours. Deposition of TNF-α, IFN-γ, and IL-2 into the skin tissue was also revealed by immunohistochemistry. We have established a new animal model of skin sensitization induced by repeated TCE stimulations, and we provide the first evidence that key proinflammatory cytokines including TNF-α, IFN-γ, and IL-2 play an important role in the process of TCE sensitization. © The Author(s) 2015.

Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake

PubMed Central

Krishna, Saritha; Lin, Zhoumeng; de La Serre, Claire B.; Wagner, John J.; Harn, Donald H.; Pepples, Lacey M.; Djani, Dylan M.; Weber, Matthew T.; Srivastava, Leena; Filipov, Nikolay M.

2016-01-01

High-fat diet (HFD) induced obesity is associated not only with metabolic dysregulation, e.g., impaired glucose homeostasis and insulin sensitivity, but also with neurological dysfunction manifested with aberrant behavior and/or neurotransmitter imbalance. Most studies have examined HFD's effects predominantly in male subjects, either in the periphery or on the brain, in isolation and after a finite feeding period. In this study, we evaluated the time-course of selected metabolic, behavioral, and neurochemical effects of HFD intake in parallel and at multiple time points in female (C57BL/6) mice. Peripheral effects were evaluated at three feeding intervals (short: 5–6 weeks, long: 20–22 weeks, and prolonged: 33–36 weeks). Central effects were evaluated only after long and prolonged feeding durations; we have previously reported those effects after the short (5–6 weeks) feeding duration) [1]. Ongoing HFD feeding resulted in an obese phenotype characterized by increased visceral adiposity and, after prolonged HFD intake, an increase in liver and kidney weights. Peripherally, 5 weeks of HFD intake was sufficient to impair glucose tolerance significantly, with the deleterious effects of HFD being greater with prolonged intake. Similarly, 5 weeks of HFD consumption was sufficient to impair insulin sensitivity. However, sensitivity to insulin after prolonged HFD intake was not different between control, low-fat diet (LFD) and HFD-fed mice, most likely due to age-dependent decrease in insulin sensitivity in the LFD-fed mice. HFD intake also induced bi-phasic hepatic inflammation and it increased gut permeability. Behaviorally, prolonged intake of HFD caused mice to be hypoactive and bury fewer marbles in a marble burying task; the latter was associated with significantly impaired hippocampal serotonin homeostasis. Cognitive (short-term recognition memory) function of mice was unaffected by chronic HFD feeding. Considering our prior findings of short-term (5–6 weeks) HFD-induced central (hyperactivity/anxiety and altered ventral hippocampal neurochemistry) effects and our current results, it seems that in female mice some metabolic/inflammatory dysregulations caused by HFD, such as gut permeability, appear early and persist, whereas others, such as glucose intolerance, are exaggerated with continuous HFD feeding; behaviorally, prolonged HFD consumption mainly affects locomotor activity and anxiety-like responses, likely due to the advanced obesity phenotype; neurochemically, the serotonergic system appears to be most sensitive to continued HFD feeding. PMID:26852949

Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake.

PubMed

Krishna, Saritha; Lin, Zhoumeng; de La Serre, Claire B; Wagner, John J; Harn, Donald H; Pepples, Lacey M; Djani, Dylan M; Weber, Matthew T; Srivastava, Leena; Filipov, Nikolay M

2016-04-01

High-fat diet (HFD) induced obesity is associated not only with metabolic dysregulation, e.g., impaired glucose homeostasis and insulin sensitivity, but also with neurological dysfunction manifested with aberrant behavior and/or neurotransmitter imbalance. Most studies have examined HFD's effects predominantly in male subjects, either in the periphery or on the brain, in isolation and after a finite feeding period. In this study, we evaluated the time-course of selected metabolic, behavioral, and neurochemical effects of HFD intake in parallel and at multiple time points in female (C57BL/6) mice. Peripheral effects were evaluated at three feeding intervals (short: 5-6 weeks, long: 20-22 weeks, and prolonged: 33-36 weeks). Central effects were evaluated only after long and prolonged feeding durations; we have previously reported those effects after the short (5-6 weeks) feeding duration. Ongoing HFD feeding resulted in an obese phenotype characterized by increased visceral adiposity and, after prolonged HFD intake, an increase in liver and kidney weights. Peripherally, 5 weeks of HFD intake was sufficient to impair glucose tolerance significantly, with the deleterious effects of HFD being greater with prolonged intake. Similarly, 5 weeks of HFD consumption was sufficient to impair insulin sensitivity. However, sensitivity to insulin after prolonged HFD intake was not different between control, low-fat diet (LFD) and HFD-fed mice, most likely due to age-dependent decrease in insulin sensitivity in the LFD-fed mice. HFD intake also induced bi-phasic hepatic inflammation and it increased gut permeability. Behaviorally, prolonged intake of HFD caused mice to be hypoactive and bury fewer marbles in a marble burying task; the latter was associated with significantly impaired hippocampal serotonin homeostasis. Cognitive (short-term recognition memory) function of mice was unaffected by chronic HFD feeding. Considering our prior findings of short-term (5-6 weeks) HFD-induced central (hyperactivity/anxiety and altered ventral hippocampal neurochemistry) effects and our current results, it seems that in female mice some metabolic/inflammatory dysregulations caused by HFD, such as gut permeability, appear early and persist, whereas others, such as glucose intolerance, are exaggerated with continuous HFD feeding; behaviorally, prolonged HFD consumption mainly affects locomotor activity and anxiety-like responses, likely due to the advanced obesity phenotype; neurochemically, the serotonergic system appears to be most sensitive to continued HFD feeding. Copyright © 2016 Elsevier Inc. All rights reserved.

The effects of IL-5 on airway physiology and inflammation in rats.

PubMed

Nag, Sammy S; Xu, Li Jing; Hamid, Qutayba; Renzi, Paolo M

2003-03-01

There is evidence that the cytokine IL-5 is a prominent feature of airway inflammation in asthma. The aim of this study was to determine whether exogenous IL-5 could cause changes in lung physiology, the early and late airway response after antigen challenge, and airway inflammation in rats that do not have a propensity to develop these changes after sensitization and challenge. Intratracheal administration of IL-5 to ovalbumin sensitized Brown Norway SSN rats increased the airway responsiveness to methacholine (AHR) 20 hours after administration of IL-5 at the same time as an increase in neutrophils occurred in the lung lavage. This effect was dose dependent and was not caused by endotoxin. Concurrent intratracheal administration of 50 ng of anti-IL-5 monoclonal antibody with 10 microg of recombinant human IL-5 decreased the AHR and neutrophil influx. Pretreatment with 3 microg of IL-5 had no effect on the early and late airway response or on AHR after ovalbumin challenge. However, IL-5 increased lung re-sistance 20 hours after antigen challenge. Although total lung cells and differential counts did not differ significantly 8 hours after antigen challenge, the blood lymphocyte CD4/CD8 ratio decreased in IL-5 pretreated rats (P <.05). In addition, in situ hybridization showed a significant increase in cells within the airway wall expressing IL-4 and IL-5 mRNA in IL-5 treated/challenged rats compared to controls (P <.05). The intratracheal administration of IL-5 causes only part of the physiologic changes that are associated with asthma. Other factors are necessary to obtain the complete asthma phenotype.

A 21st-century shift from fossil-fuel to biogenic methane emissions indicated by ¹³CH₄.

PubMed

Schaefer, Hinrich; Mikaloff Fletcher, Sara E; Veidt, Cordelia; Lassey, Keith R; Brailsford, Gordon W; Bromley, Tony M; Dlugokencky, Edward J; Michel, Sylvia E; Miller, John B; Levin, Ingeborg; Lowe, Dave C; Martin, Ross J; Vaughn, Bruce H; White, James W C

2016-04-01

Between 1999 and 2006, a plateau interrupted the otherwise continuous increase of atmospheric methane concentration [CH4] since preindustrial times. Causes could be sink variability or a temporary reduction in industrial or climate-sensitive sources. We reconstructed the global history of [CH4] and its stable carbon isotopes from ice cores, archived air, and a global network of monitoring stations. A box-model analysis suggests that diminishing thermogenic emissions, probably from the fossil-fuel industry, and/or variations in the hydroxyl CH4 sink caused the [CH4] plateau. Thermogenic emissions did not resume to cause the renewed [CH4] rise after 2006, which contradicts emission inventories. Post-2006 source increases are predominantly biogenic, outside the Arctic, and arguably more consistent with agriculture than wetlands. If so, mitigating CH4 emissions must be balanced with the need for food production. Copyright © 2016, American Association for the Advancement of Science.

Curcumin-Mediated HDAC Inhibition Suppresses the DNA Damage Response and Contributes to Increased DNA Damage Sensitivity

PubMed Central

Wang, Shu-Huei; Lin, Pei-Ya; Chiu, Ya-Chen; Huang, Ju-Sui; Kuo, Yi-Tsen; Wu, Jen-Chine; Chen, Chin-Chuan

2015-01-01

Chemo- and radiotherapy cause multiple forms of DNA damage and lead to the death of cancer cells. Inhibitors of the DNA damage response are candidate drugs for use in combination therapies to increase the efficacy of such treatments. In this study, we show that curcumin, a plant polyphenol, sensitizes budding yeast to DNA damage by counteracting the DNA damage response. Following DNA damage, the Mec1-dependent DNA damage checkpoint is inactivated and Rad52 recombinase is degraded by curcumin, which results in deficiencies in double-stand break repair. Additive effects on damage-induced apoptosis and the inhibition of damage-induced autophagy by curcumin were observed. Moreover, rpd3 mutants were found to mimic the curcumin-induced suppression of the DNA damage response. In contrast, hat1 mutants were resistant to DNA damage, and Rad52 degradation was impaired following curcumin treatment. These results indicate that the histone deacetylase inhibitor activity of curcumin is critical to DSB repair and DNA damage sensitivity. PMID:26218133

The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIM(EL).

PubMed

Guo, Y; Schoell, M C; Freeman, R S

2009-04-23

von Hippel-Lindau (VHL) disease is caused by germ-line mutations in the VHL tumor suppressor gene and is the most common cause of inherited renal cell carcinoma (RCC). Mutations in the VHL gene also occur in a large majority of sporadic cases of clear-cell RCC, which have high intrinsic resistance to chemotherapy and radiotherapy. Here we show that VHL-deficient RCC cells express lower levels of the proapoptotic Bcl-2 family protein BIM(EL) and are more resistant to etoposide and UV radiation-induced death compared to the same cells stably expressing the wild-type VHL protein (pVHL). Reintroducing pVHL into VHL-null cells increased the half-life of BIM(EL) protein without affecting its mRNA expression, and overexpressing pVHL inhibited BIM(EL) polyubiquitination. Suppressing pVHL expression with RNA interference resulted in a decrease in BIM(EL) protein and a corresponding decrease in the sensitivity of RCC cells to apoptotic stimuli. Directly inhibiting BIM(EL) expression in pVHL-expressing RCC cells caused a similar decrease in cell death. These results demonstrate that pVHL acts to promote BIM(EL) protein stability in RCC cells, and that destabilization of BIM(EL) in the absence of pVHL contributes to the increased resistance of VHL-null RCC cells to certain apoptotic stimuli.

Phenotypic analysis of NS5A variant from liver transplant patient with increased cyclosporine susceptibility

PubMed Central

Ansari, Israr-ul H.; Allen, Todd; Berical, Andrew; Stock, Peter G.; Barin, Burc; Striker, Rob

2013-01-01

Hepatitis C virus (HCV) replication is limited by cyclophilin inhibitors but it remains unclear how viral genetic variations influence susceptibility to cyclosporine (cyclosporine A, CsA), a cyclophilin inhibitor. In this study HCV from liver transplant patients was sequenced before and after CsA exposure. Phenotypic analysis of NS5A sequence was performed by using HCV sub genomic replicon to determine CsA susceptibility. The data indicates an atypical proline at position 328 in NS5A causes increases CsA sensitivity both in the context of genotype 1a and 1b residues. Point mutants mimicking other naturally occurring residues at this position also increased (Ala) or decreased (Arg) replicon sensitivity to CsA relative to the typical threonine (genotype 1a) or serine (genotype 1b) at this position. This work has implications for treatment of HCV by cyclophilin inhibitors. PMID:23290631

Effect of radiation on red cell membrane and intracellular oxidative defense systems.

PubMed

Katz, D; Mazor, D; Dvilansky, A; Meyerstein, N

1996-03-01

Ionizing radiation is currently used for prevention of transfusion associated graft versus host disease (TAGVHD). As radiation damage is associated with the production of activated oxygen species, the aim of this study was to observe the immediate effect of ionizing radiation on red cell membrane and intracellular oxidative defense systems. Neonatal and iron deficiency (IDA) cells, known for their increased sensitivity to oxidative stress, were chosen and compared with normal cells. Irradiation was performed in doses of 1500 cGy, 3000 cGy and 5000 cGy. GSH and methemoglobin levels and the activity of different antioxidant enzymes, measured under optimal in vitro conditions, were preserved in all cells after irradiation. Only radiation at the highest does of 5000 cGy, caused significant potassium leakage in neonatal cells and insignificant increase in IDA cells. Thus, cells with increased sensitivity to oxidative stress are more susceptible to damage by ionizing radiation than normal cells.

Oxidation-state sensitive imaging of cerium dioxide by atomic-resolution low-angle annular dark field scanning transmission electron microscopy.

PubMed

Johnston-Peck, Aaron C; Winterstein, Jonathan P; Roberts, Alan D; DuChene, Joseph S; Qian, Kun; Sweeny, Brendan C; Wei, Wei David; Sharma, Renu; Stach, Eric A; Herzing, Andrew A

2016-03-01

Low-angle annular dark field (LAADF) scanning transmission electron microscopy (STEM) imaging is presented as a method that is sensitive to the oxidation state of cerium ions in CeO2 nanoparticles. This relationship was validated through electron energy loss spectroscopy (EELS), in situ measurements, as well as multislice image simulations. Static displacements caused by the increased ionic radius of Ce(3+) influence the electron channeling process and increase electron scattering to low angles while reducing scatter to high angles. This process manifests itself by reducing the high-angle annular dark field (HAADF) signal intensity while increasing the LAADF signal intensity in close proximity to Ce(3+) ions. This technique can supplement STEM-EELS and in so doing, relax the experimental challenges associated with acquiring oxidation state information at high spatial resolutions. Published by Elsevier B.V.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, W.; Tuleya, R.E.; Ginis, I.

In this study, the effect of thermodynamic environmental changes on hurricane intensity is extensively investigated with the National Oceanic and Atmospheric Administration Geophysical Fluid Dynamics Laboratory hurricane model for a suite of experiments with different initial upper-tropospheric temperature anomalies up to {+-}4 C and sea surface temperatures ranging from 26 to 31 C given the same relative humidity profile. The results indicate that stabilization in the environmental atmosphere and sea surface temperature (SST) increase cause opposing effects on hurricane intensity. The offsetting relationship between the effects of atmospheric stability increase (decrease) and SST increase (decrease) is monotonic and systematic inmore » the parameter space. This implies that hurricane intensity increase due to a possible global warming associated with increased CO{sub 2} is considerably smaller than that expected from warming of the oceanic waters alone. The results also indicate that the intensity of stronger (weaker) hurricanes is more (less) sensitive to atmospheric stability and SST changes. The model-attained hurricane intensity is found to be well correlated with the maximum surface evaporation and the large-scale environmental convective available potential energy. The model-attained hurricane intensity if highly correlated with the energy available from wet-adiabatic ascent near the eyewall relative to a reference sounding in the undisturbed environment for all the experiments. Coupled hurricane-ocean experiments show that hurricane intensity becomes less sensitive to atmospheric stability and SST changes since the ocean coupling causes larger (smaller) intensity reduction for stronger (weaker) hurricanes. This implies less increase of hurricane intensity related to a possible global warming due to increased CO{sub 2}.« less

DNA repair properties of Escherichia coli tif-1, recAo281 and lexA1 strains deficient in single-strand DNA binding protein.

PubMed

Whittier, R F; Chase, J W

1983-01-01

Mutations affecting single-strand DNA binding protein (SSB) impair induction of mutagenic (SOS) repair. To further investigate the role of SSB in SOS induction and DNA repair, isogenic strains were constructed combining the ssb+, ssb-1 or ssb-113 alleles with one or more mutations known to alter regulation of damage inducible functions. As is true in ssb+ strains tif-1 (recA441) was found to allow thermal induction of prophage lambda + and Weigle reactivation in ssb-1 and ssb-113 strains. Furthermore, tif-1 decreased the UV sensitivity of the ssb-113 strain slightly and permitted UV induction of prophage lambda + at 30 degrees C. Strains carrying the recAo281 allele were also constructed. This mutation causes high constitutive levels of RecA protein synthesis and relieves much of the UV sensitivity conferred by lexA- alleles without restoring SOS (error-prone) repair. In contrast, the recAo281 allele failed to alleviate the UV sensitivity associated with either ssb- mutation. In a lexA1 recAo281 background the ssb-1 mutation increased the extent of postirradiation DNA degradation and concommitantly increased UV sensitivity 20-fold to the level exhibited by a recA1 strain. The ssb-113 mutation also increased UV sensitivity markedly in this background but did so without greatly increasing postirradiation DNA degradation. These results suggest a direct role for SSB in recombinational repair apart from and in addition to its role in facilitating induction of the recA-lexA regulon.

Cocaine sensitization does not alter SP effects on locomotion or excitatory synaptic transmission in the NAc of rats.

PubMed

Kombian, Samuel B; Ananthalakshmi, Kethireddy V V; Zidichouski, Jeffrey A; Saleh, Tarek M

2012-02-01

Substance P (SP) and cocaine employ similar mechanisms to modify excitatory synaptic transmission in the nucleus accumbens (NAc), a region implicated in substance abuse. Here we explored, using NAc slices, whether SP effects on these synaptic responses were altered in rats that have been sensitized to cocaine and whether SP could mimic cocaine in triggering increased locomotion in sensitized rats. Intraperitoneal (IP) injection of naïve rats with cocaine (15 mg/kg) caused increased locomotion by 408.5 ± 85.9% (n = 5) which further increased by 733.1 ± 157.8% (n = 5) following a week of cocaine sensitization. A similar challenge with 10 mg/kg of SP after cocaine sensitization did not produce significant changes in locomotion (170.6 ± 61.0%; n = 4). In contrast to cocaine, IP injection of rats with SP or SP(5-11) (10-100 mg/kg) with or without phosphoramidon did not elicit changes in locomotion. In electrophysiological studies, both cocaine and SP depressed evoked NMDA and non-NMDA receptor-mediated excitatory synaptic currents (EPSCs) in slices obtained from naïve rats. In slices derived from cocaine-sensitized rats, cocaine but not SP produced a more profound decrease in non-NMDA compared to NMDA responses. Similar to that in naïve rats, cocaine's effect on the EPSCs in these sensitized rats occluded those of SP. Thus, although SP and cocaine may employ similar mechanisms to depress EPSCs in the NAc, IP injection of SP does not mimic cocaine-induced hyperlocomotion indicating that not all of cocaine's effects are mimicked by SP. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Red wine polyphenols increase calcium in bovine aortic endothelial cells: a basis to elucidate signalling pathways leading to nitric oxide production

PubMed Central

Martin, Sophie; Andriambeloson, Emile; Takeda, Ken; Andriantsitohaina, Ramaroson

2002-01-01

The present study investigates the mechanisms by which polyphenolic compounds from red wine elicit Ca2+ mobilization in bovine aortic endothelial cells (BAECs). Two polyphenol-containing red wine extracts, red wine polyphenolic compounds (RWPC) and Provinols™, and delphinidin, an anthocyanin were used. RWPC stimulated a Ca2+-dependent release of nitric oxide (NO) from BAECs accounting for the relaxation of endothelium-denuded rat aortic rings as shown by cascade bioassay. RWPC, Provinols™ and delphinidin increased cytosolic free calcium ([Ca2+]i), by releasing Ca2+ from intracellular stores and by increasing Ca2+ entry. The RWPC-induced increase in [Ca2+]i was decreased by exposure to ryanodine (30 μM), whereas Provinols™ and delphinidin-induced increases in [Ca2+]i were decreased by bradykinin (0.1 μM) and thapsigargin (1 μM) pre-treatment. RWPC, Provinols™ and delphinidin-induced increases in [Ca2+]i were sensitive to inhibitors of phospholipase C (neomycin, 3 mM; U73122, 3 μM) and tyrosine kinase (herbimycin A, 1 μM). RWPC, Provinols™ and delphinidin induced herbimycin A (1 μM)-sensitive tyrosine phosphorylation of several intracellular proteins. Provinols™ released Ca2+ via both a cholera (CTX) and pertussis toxins (PTX)-sensitive pathway, whereas delphinidin released Ca2+ only via a PTX-sensitive mechanism. Our data contribute in defining the mechanisms of endothelial NO production caused by wine polyphenols including the increase in [Ca2+]i and the activation of tyrosine kinases. Furthermore, RWPC, Provinols™ and delphinidin display differences in the process leading to [Ca2+]i increases in endothelial cells illustrating multiple cellular targets of natural dietary polyphenolic compounds. PMID:11906973

Repair of Ultraviolet Radiation Damage in Sensitive Mutants of Micrococcus radiodurans

PubMed Central

Moseley, B. E. B.

1969-01-01

Various aspects of the repair of ultraviolet (UV) radiation-induced damage were compared in wild-type Micrococcus radiodurans and two UV-sensitive mutants. Unlike the wild type, the mutants are more sensitive to radiation at 265 nm than at 280 nm. The delay in deoxyribonucleic acid (DNA) synthesis following exposure to UV is about seven times as long in the mutants as in the wild type. All three strains excise UV-induced pyrimidine dimers from their DNA, although the rate at which cytosine-thymine dimers are excised is slower in the mutants. The three strains also mend the single-strand breaks that appear in the irradiated DNA as a result of dimer excision, although the process is less efficient in the mutants. It is suggested that the increased sensitivity of the mutants to UV radiation may be caused by a partial defect in the second step of dimer excision. PMID:5773016

Climate catastrophes

NASA Astrophysics Data System (ADS)

Budyko, Mikhail

1999-05-01

Climate catastrophes, which many times occurred in the geological past, caused the extinction of large or small populations of animals and plants. Changes in the terrestrial and marine biota caused by the catastrophic climate changes undoubtedly resulted in considerable fluctuations in global carbon cycle and atmospheric gas composition. Primarily, carbon dioxide and other greenhouse gas contents were affected. The study of these catastrophes allows a conclusion that climate system is very sensitive to relatively small changes in climate-forcing factors (transparency of the atmosphere, changes in large glaciations, etc.). It is important to take this conclusion into account while estimating the possible consequences of now occurring anthropogenic warming caused by the increase in greenhouse gas concentration in the atmosphere.

Use of long term dermal sensitization followed by intratracheal challenge method to identify low-dose chemical-induced respiratory allergic responses in mice.

PubMed

Fukuyama, Tomoki; Ueda, Hideo; Hayashi, Koichi; Tajima, Yukari; Shuto, Yasufumi; Saito, Toru R; Harada, Takanori; Kosaka, Tadashi

2008-10-01

The inhalation of many types of chemicals, including pesticides, perfumes, and other low-molecular weight chemicals, is a leading cause of allergic respiratory diseases. We attempted to develop a new test protocol to detect environmental chemical-related respiratory hypersensitivity at low and weakly immunogenic doses. We used long-term dermal sensitization followed by a low-dose intratracheal challenge to evaluate sensitization by the well-known respiratory sensitizers trimellitic anhydride (TMA) and toluene diisocyanate (TDI) and the contact sensitizer 2,4-dinitrochlorobenzene (DNCB). After topically sensitizing BALB/c mice (9 times in 3 weeks) and challenging them intratracheally with TMA, TDI, or DNCB, we assayed differential cell counts and chemokine levels in bronchoalveolar lavage fluid (BALF); lymphocyte counts, surface antigen expression of B cells, and local cytokine production in lung-associated lymph nodes (LNs); and antigen-specific IgE levels in serum and BALF. TMA induced marked increases in antigen-specific IgE levels in both serum and BALF, proliferation of eosinophils and chemokines (MCP-1, eotaxin, and MIP-1beta) in BALF, and proliferation of Th2 cytokines (interleukin (IL)-4, IL-10, and IL-13) in restimulated LN cells. TDI induced marked increases in levels of cytokines (IL-4, IL-10, IL-13, and IFN-gamma) produced by restimulated LN cells. In contrast, DNCB treatment yielded, at most, small, nonsignificant increases in all parameters. Our protocol thus detected respiratory allergic responses to low-molecular weight chemicals and may be useful for detecting environmental chemical-related respiratory allergy.

Enkephalin inhibition of angiotensin-stimulated release of oxytocin and vasopressin

NASA Technical Reports Server (NTRS)

Keil, L. C.; Chee, O.; Rosella-Dampman, L. M.; Emmert, S.; Summy-Long, J. Y.

1984-01-01

The effect of intracerebroventricular (ICV) pretreatment with 100 ng/5 microliter leucine(5)-enkephalin (LE) on the increase in plasma oxytocin (OT) and vasopressin (VP) caused by ICV injection of 10, 50, or 100 ng/5 microliter of angiotensin II (AII) is investigated experimentally in conscious adult male Sprague-Dawley rats; the effects of water-deprivation dehydration and lactation/suckling (in female rats) are also studied. An OT radioimmunoassay (RIA) with a sensitivity of 800 fg/ml (described in detail) and the VP RIA technique of Keil and Severs (1977) are employed. Administration of AII or dehydration for 48 or 72 h cause a significant increase in OT and VP without affecting the ratio, while lactation and suckling increase OT only. LE pretreatment inhibits significantly but does not suppress the AII-stimulated OT-VP response.

Prediction of skin sensitizers using alternative methods to animal experimentation.

PubMed

Johansson, Henrik; Lindstedt, Malin

2014-07-01

Regulatory frameworks within the European Union demand that chemical substances are investigated for their ability to induce sensitization, an adverse health effect caused by the human immune system in response to chemical exposure. A recent ban on the use of animal tests within the cosmetics industry has led to an urgent need for alternative animal-free test methods that can be used for assessment of chemical sensitizers. To date, no such alternative assay has yet completed formal validation. However, a number of assays are in development and the understanding of the biological mechanisms of chemical sensitization has greatly increased during the last decade. In this MiniReview, we aim to summarize and give our view on the recent progress of method development for alternative assessment of chemical sensitizers. We propose that integrated testing strategies should comprise complementary assays, providing measurements of a wide range of mechanistic events, to perform well-educated risk assessments based on weight of evidence. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Long-term changes in retinal contrast sensitivity in chicks from frosted occluders and drugs: relations to myopia?

PubMed

Diether, S; Schaeffel, F

1999-07-01

Experiments in animal models have shown that the retinal analyzes the image to identify the position of the plane of focus and fine-tunes the growth of the underlying sclera. It is fundamental to the understanding of the development of refractive errors to know which image features are processed. Since the position of the image plane fluctuates continuously with accommodative status and viewing distance, a meaningful control of refractive development can only occur by an averaging procedure with a long time constant. As a candidate for a retinal signal for enhanced eye growth and myopia we propose the level of contrast adaptation which varies with the average amount of defocus. Using a behavioural paradigm, we have found in chickens (1) that contrast adaptation (CA, here referred to as an increase in contrast sensitivity) occurs at low spatial frequencies (0.2 cyc/deg) already after 1.5 h of wearing frosted goggles which cause deprivation myopia, (2) that CA also occurs with negative lenses (-7.4D) and positive lenses (+6.9D) after 1.5 h, at least if accommodation is paralyzed and, (3) that CA occurs at a retinal level or has, at least, a retinal component. Furthermore, we have studied the effects of atropine and reserpine, which both suppress myopia development, on CA. Quisqualate, which causes retinal degeneration but leaves emmetropization functional, was also tested. We found that both atropine and reserpine increase contrast sensitivity to a level where no further CA could be induced by frosted goggles. Quisqualate increased only the variability of refractive development and of contrast sensitivity. Taken together, CA occurring during extended periods of defocus is a possible candidate for a retinal error signal for myopia development. However, the situation is complicated by the fact that there must be a second image processing mode generating a powerful inhibitory growth signal if the image is in front of the retina, even with poor images (Diether, S., & Schaeffel, F. (1999).

Substrate Metabolism and Insulin Sensitivity During Fasting in Obese Human Subjects: Impact of GH Blockade.

PubMed

Pedersen, Morten Høgild; Svart, Mads Vandsted; Lebeck, Janne; Bidlingmaier, Martin; Stødkilde-Jørgensen, Hans; Pedersen, Steen Bønløkke; Møller, Niels; Jessen, Niels; Jørgensen, Jens O L

2017-04-01

Insulin resistance and metabolic inflexibility are features of obesity and are amplified by fasting. Growth hormone (GH) secretion increases during fasting and GH causes insulin resistance. To study the metabolic effects of GH blockade during fasting in obese subjects. Nine obese males were studied thrice in a randomized design: (1) after an overnight fast (control), (2) after 72 hour fasting (fasting), and (3) after 72 hour fasting with GH blockade (pegvisomant) [fasting plus GH antagonist (GHA)]. Each study day consisted of a 4-hour basal period followed by a 2-hour hyperinsulinemic, euglycemic clamp combined with indirect calorimetry, assessment of glucose and palmitate turnover, and muscle and fat biopsies. GH levels increased with fasting (P < 0.01), and the fasting-induced reduction of serum insulin-like growth factor I was enhanced by GHA (P < 0.05). Fasting increased lipolysis and lipid oxidation independent of GHA, but fasting plus GHA caused a more pronounced suppression of lipid intermediates in response to hyperinsulinemic, euglycemic clamp. Fasting-induced insulin resistance was abrogated by GHA (P < 0.01) primarily due to reduced endogenous glucose production (P = 0.003). Fasting plus GHA also caused elevated glycerol levels and reduced levels of counterregulatory hormones. Fasting significantly reduced the expression of antilipolytic signals in adipose tissue independent of GHA. Suppression of GH activity during fasting in obese subjects reverses insulin resistance and amplifies insulin-stimulated suppression of lipid intermediates, indicating that GH is an important regulator of substrate metabolism, insulin sensitivity, and metabolic flexibility also in obese subjects. Copyright © 2017 by the Endocrine Society

Sensitivity of water resources in the Delaware River basin to climate variability and change

USGS Publications Warehouse

Ayers, Mark A.; Wolock, David M.; McCabe, Gregory J.; Hay, Lauren E.; Tasker, Gary D.

1993-01-01

Because of the "greenhouse effect," projected increases in atmospheric carbon dioxide levels might cause global warming, which in turn could result in changes in precipitation patterns and evapotranspiration and in increases in sea level. This report describes the greenhouse effect; discusses the problems and uncertainties associated with the detection, prediction, and effects of climatic change, and presents the results of sensitivity-analysis studies of the potential effects of climate change on water resources in the Delaware River basin. On the basis of sensitivity analyses, potentially serious shortfalls of certain water resources in the basin could result if some climatic-change scenarios become true. The results of basin streamflow-model simulations in this study demonstrate the difficulty in distinguishing effects of climatic change on streamflow and water supply from effects of natural variability in current climate. The future direction of basin changes in most water resources, furthermore, cannot be determined precisely because of uncertainty in current projections of regional temperature and precipitation. This large uncertainty indicates that, for resource planning, information defining the sensitivities of water resources to a range of climate change is most relevant. The sensitivity analyses could be useful in developing contingency plans on how to evaluate and respond to changes, should they occur.

Diet and Dermatitis: Food Triggers

PubMed Central

Schlichte, Megan

2014-01-01

Given increasing awareness of the link between diet and health, many patients are concerned that dietary factors may trigger dermatitis. Research has found that dietary factors can indeed exacerbate atopic dermatitis or cause dermatitis due to systemic contact dermatitis. In atopic dermatitis, dietary factors are more likely to cause an exacerbation among infants or children with moderate-to-severe atopic dermatitis relative to other populations. Foods may trigger rapid, immunoglobulin E-mediated hypersensitivity reactions or may lead to late eczematous reactions. While immediate reactions occur within minutes to hours of food exposure, late eczematous reactions may occur anywhere from hours to two days later. Screening methods, such as food allergen-specific serum immunoglobulin E tests or skin prick tests, can identify sensitization to specific foods, but a diagnosis of food allergy requires specific signs and symptoms that occur reproducibly upon food exposure. Many patients who are sensitized will not develop clinical findings upon food exposure; therefore, these tests may result in false-positive tests for food allergy. This is why the gold standard for diagnosis remains the double-blind, placebo-controlled food challenge. In another condition, systemic contact dermatitis, ingestion of a specific food can actually cause dermatitis. Systemic contact dermatitis is a distinct T-cell mediated immunological reaction in which dietary exposure to specific allergens results in dermatitis. Balsam of Peru and nickel are well-known causes of systemic contact dermatitis, and reports have implicated multiple other allergens. This review seeks to increase awareness of important food allergens, elucidate their relationship with atopic dermatitis and systemic contact dermatitis, and review available diagnostic and treatment strategies. PMID:24688624

Identification of ribonucleotide reductase mutation causing temperature-sensitivity of herpes simplex virus isolates from whitlow by deep sequencing.

PubMed

Daikoku, Tohru; Oyama, Yukari; Yajima, Misako; Sekizuka, Tsuyoshi; Kuroda, Makoto; Shimada, Yuka; Takehara, Kazuhiko; Miwa, Naoko; Okuda, Tomoko; Sata, Tetsutaro; Shiraki, Kimiyasu

2015-06-01

Herpes simplex virus 2 caused a genital ulcer, and a secondary herpetic whitlow appeared during acyclovir therapy. The secondary and recurrent whitlow isolates were acyclovir-resistant and temperature-sensitive in contrast to a genital isolate. We identified the ribonucleotide reductase mutation responsible for temperature-sensitivity by deep-sequencing analysis.

The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kulebyakin, Konstantin; Penkov, Dmitry; IFOM – the FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, 20139

Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to searchmore » new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. - Highlights: • A novel model of liver-specific Prep1 knockout is established. • Ablation of Prep1 in hepatocytes increases insulin sensitivity. • Prep1 controls hepatic insulin sensitivity by regulating localization of FOXO1. • Prep1 regulates localization of FOXO1 via Wnt/β-catenin signaling pathway.« less

A review of the thermal sensitivity of the mechanics of vertebrate skeletal muscle.

PubMed

James, Rob S

2013-08-01

Environmental temperature varies spatially and temporally, affecting many aspects of an organism's biology. In ectotherms, variation in environmental temperature can cause parallel changes in skeletal muscle temperature, potentially leading to significant alterations in muscle performance. Endotherms can also undergo meaningful changes in skeletal muscle temperature that can affect muscle performance. Alterations in skeletal muscle temperature can affect contractile performance in both endotherms and ectotherms, changing the rates of force generation and relaxation, shortening velocity, and consequently mechanical power. Such alterations in the mechanical performance of skeletal muscle can in turn affect locomotory performance and behaviour. For instance, as temperature increases, a consequent improvement in limb muscle performance causes some lizard species to be more likely to flee from a potential predator. However, at lower temperatures, they are much more likely to stand their ground, show threatening displays and even bite. There is no consistent pattern in reported effects of temperature on skeletal muscle fatigue resistance. This review focuses on the effects of temperature variation on skeletal muscle performance in vertebrates, and investigates the thermal sensitivity of different mechanical measures of skeletal muscle performance. The plasticity of thermal sensitivity in skeletal muscle performance has been reviewed to investigate the extent to which individuals can acclimate to chronic changes in their thermal environment. The effects of thermal sensitivity of muscle performance are placed in a wider context by relating thermal sensitivity of skeletal muscle performance to aspects of vertebrate species distribution.

Subconjunctival Bevacizumab Injection Impairs Corneal Innervations and Epithelial Wound Healing in Mice.

PubMed

Dong, Muchen; Di, Guohu; Zhang, Xiaoping; Zhou, Qingjun; Shi, Weiyun

2017-03-01

To investigate the effects of subconjunctival bevacizumab injection on the corneal nerve, sensitivity, and epithelial wound healing in mice. Adult C57BL/6 mice were treated with subconjunctival injection of 1, 2, 5, or 25 mg/mL bevacizumab. The corneal nerve was observed with whole-mount anti-β3-tubulin fluorescence staining. Corneal sensitivity was measured with a Cochet-Bonnet esthesiometer. The protein levels of pigment epithelium-derived factor (PEDF), nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were measured by ELISA. The corneal epithelial wound-healing rate was evaluated by fluorescein staining. The recovery of impaired mouse corneal innervations and epithelial wound-healing rate following bevacizumab injection was evaluated with the co-injection of PEDF, NGF, or CNTF. Subconjunctival bevacizumab injection caused apparent corneal nerve degeneration, attenuated corneal sensitivity, and delayed corneal epithelial wound healing and nerve regeneration in normal mice, which was more significant with increased concentration and times of the bevacizumab injection. However, the corneal nerve and sensitivity gradually improved and recovered in mice with a single injection of 1 to 5 mg/mL bevacizumab. Moreover, the bevacizumab injection significantly decreased the corneal PEDF, NGF, and CNTF content, whereas exogenous PEDF, NGF, or CNTF supplement attenuated impairment of the corneal nerve, sensitivity, and epithelial wound healing after subconjunctival bevacizumab injection. Subconjunctival bevacizumab injection impairs corneal innervations, epithelial wound healing, and nerve regeneration in normal mice, which may be caused by the reduction of neurotrophic factor content in the cornea.

Pulse-drought atop press-drought: unexpected plant responses and implications for dryland ecosystems.

PubMed

Hoover, David L; Duniway, Michael C; Belnap, Jayne

2015-12-01

In drylands, climate change is predicted to cause chronic reductions in water availability (press-droughts) through reduced precipitation and increased temperatures as well as increase the frequency and intensity of short-term extreme droughts (pulse-droughts). These changes in precipitation patterns may have profound ecosystem effects, depending on the sensitivities of the dominant plant functional types (PFTs). Here we present the responses of four Colorado Plateau PFTs to an experimentally imposed, 4-year, press-drought during which a natural pulse-drought occurred. Our objectives were to (1) identify the drought sensitivities of the PFTs, (2) assess the additive effects of the press- and pulse-drought, and (3) examine the interactive effects of soils and drought. Our results revealed that the C3 grasses were the most sensitive PFT to drought, the C3 shrubs were the most resistant, and the C4 grasses and shrubs had intermediate drought sensitivities. Although we expected the C3 grasses would have the greatest response to drought, the higher resistance of C3 shrubs relative to the C4 shrubs was contrary to our predictions based on the higher water use efficiency of C4 photosynthesis. Also, the additive effects of press- and pulse-droughts caused high morality in C3 grasses, which has large ecological and economic ramifications for this region. Furthermore, despite predictions based on the inverse texture hypothesis, we observed no interactive effects of soils with the drought treatment on cover or mortality. These results suggest that plant responses to droughts in drylands may differ from expectations and have large ecological effects if press- and pulse-droughts push species beyond physiological and mortality thresholds.

Pulse-drought atop press-drought: unexpected plant responses and implications for dryland ecosystems

USGS Publications Warehouse

Hoover, David L.; Duniway, Michael C.; Belnap, Jayne

2015-01-01

In drylands, climate change is predicted to cause chronic reductions in water availability (press-droughts) through reduced precipitation and increased temperatures as well as increase the frequency and intensity of short-term extreme droughts (pulse-droughts). These changes in precipitation patterns may have profound ecosystem effects, depending on the sensitivities of the dominant plant functional types (PFTs). Here we present the responses of four Colorado Plateau PFTs to an experimentally imposed, 4-year, press-drought during which a natural pulse-drought occurred. Our objectives were to (1) identify the drought sensitivities of the PFTs, (2) assess the additive effects of the press- and pulse-drought, and (3) examine the interactive effects of soils and drought. Our results revealed that the C3 grasses were the most sensitive PFT to drought, the C3shrubs were the most resistant, and the C4 grasses and shrubs had intermediate drought sensitivities. Although we expected the C3 grasses would have the greatest response to drought, the higher resistance of C3 shrubs relative to the C4 shrubs was contrary to our predictions based on the higher water use efficiency of C4 photosynthesis. Also, the additive effects of press- and pulse-droughts caused high morality in C3 grasses, which has large ecological and economic ramifications for this region. Furthermore, despite predictions based on the inverse texture hypothesis, we observed no interactive effects of soils with the drought treatment on cover or mortality. These results suggest that plant responses to droughts in drylands may differ from expectations and have large ecological effects if press- and pulse-droughts push species beyond physiological and mortality thresholds.

IDH1/2 Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1/2-Mutant Inhibitors.

PubMed

Molenaar, Remco J; Radivoyevitch, Tomas; Nagata, Yasunobu; Khurshed, Mohammed; Przychodzen, Bartolomiej; Makishima, Hideki; Xu, Mingjiang; Bleeker, Fonnet E; Wilmink, Johanna W; Carraway, Hetty E; Mukherjee, Sudipto; Sekeres, Mikkael A; van Noorden, Cornelis J F; Maciejewski, Jaroslaw P

2018-04-01

Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2 MUT enzymes produce D -2-hydroxyglutarate ( D 2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2 MUT AML is not known. Experimental Design: Well-characterized primary IDH1 MUT , IDH2 MUT , and IDH1/2 WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors. Results: IDH1/2 MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2 MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2 MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2 MUT cells was caused by D 2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2 MUT cells. Conclusions: IDH1/2 MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent, such as daunorubicin, whereas concomitant administration of IDH1/2 MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2 MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2 MUT AML. Clin Cancer Res; 24(7); 1705-15. ©2018 AACR . ©2018 American Association for Cancer Research.

Three methionine residues located within the regulator of conductance for K+ (RCK) domains confer oxidative sensitivity to large-conductance Ca2+-activated K+ channels.

PubMed

Santarelli, Lindsey Ciali; Wassef, Ramez; Heinemann, Stefan H; Hoshi, Toshinori

2006-03-01

Methionine-directed oxidation of the human Slo1 potassium channel (hSlo1) shifts the half-activation voltage by -30 mV and markedly slows channel deactivation at low concentrations of intracellular Ca2+ ([Ca2+]i). We demonstrate here that the contemporaneous mutation of M536, M712 and M739 to leucine renders the channel functionally insensitive to methionine oxidation caused by the oxidant chloramine-T (Ch-T) without altering other functional characteristics. Coexpression with the auxiliary beta1 subunit fails to restore the full oxidative sensitivity to this triple mutant channel. The Ch-T effect is mediated specifically by M536, M712 and M739 because even small changes in this residue combination interfere with the ability to remove the oxidant sensitivity following mutation. Replacement of M712 or M739, but not M536, with the hydrophilic residue glutamate largely mimics oxidation of the channel and essentially removes the Ch-T sensitivity, suggesting that M712 and M739 may be part of a hydrophobic pocket disrupted by oxidation of non-polar methionine to the more hydrophilic methionine sulfoxide. The increase in wild-type hSlo1 open probability caused by methionine oxidation disappears at high [Ca2+]i and biophysical modelling of the Ch-T effect on steady-state activation implicates a decrease in the allosteric coupling between Ca2+ binding and the pore. The dramatic increase in open probability at low [Ca2+]i especially within the physiological voltage range suggests that oxidation of M536, M712 or M739 may enhance the Slo1 BK activity during conditions of oxidative stress, such as those associated with ischaemia-reperfusion and neurodegenerative disease, or in response to metabolic cues.

Methylglyoxal-bis(guanylhydrazone), a polyamine analogue, sensitized γ-radiation-induced cell death in HL-60 leukemia cells Sensitizing effect of MGBG on γ-radiation-induced cell death.

PubMed

Kim, Jin Sik; Lee, Jin; Chung, Hai Won; Choi, Han; Paik, Sang Gi; Kim, In Gyu

2006-09-01

Methylglyoxal-bis(guanylhydrazone) (MGBG), a polyamine analogue, has been known to inhibit the biosynthesis of polyamines, which are important in cell proliferation. We showed that MGBG treatment significantly affected γ-radiation-induced cell cycle transition (G(1)/G(0)→S→G(2)/M) and thus γ-radiation-induced cell death. As determined by micronuclei and comet assay, we showed that it sensitized the cytotoxic effect induced by γ-radiation. One of the reasons is that polyamine depletion by MGBG treatment did not effectively protect against the chemical (OH) or physical damage to DNA caused by γ-radiation. Through in vitro experiment, we confirmed that DNA strand breaks induced by γ-radiation was prevented more effectively in the presence of polyamines (spermine and spermidine) than in the absence of polyamines. MGBG also blocks the cell cycle transition caused by γ-radiation (G(2) arrest), which helps protect cells by allowing time for DNA repair before entry into mitosis or apoptosis, via the down regulation of cyclin D1, which mediates the transition from G(1) to S phase of cell cycle, and ataxia telangiectasia mutated, which is involved in the DNA sensing, repair and cell cycle check point. Therefore, the abrogation of G(2) arrest sensitizes cells to the effect of γ-radiation. As a result, γ-radiation-induced cell death increased by about 2.5-3.0-fold in cells treated with MGBG. However, exogenous spermidine supplement partially relieved this γ-radiation-induced cytotoxicity and cell death. These findings suggest a potentially therapeutic strategy for increasing the cytotoxic efficacy of γ-radiation.

Sex-dependent differences in the in vivo respiratory phenotype of the TASK-1 potassium channel knockout mouse.

PubMed

Jungbauer, Stefan; Buehler, Philipp Karl; Neubauer, Jacqueline; Haas, Cordula; Heitzmann, Dirk; Tegtmeier, Ines; Sterner, Christina; Barhanin, Jacques; Georgieff, Michael; Warth, Richard; Thomas, Jörg

2017-11-01

TASK-1 potassium channels have been implicated in central and peripheral chemoreception; however, the precise contribution of TASK-1 for the control of respiration is still under debate. Here, we investigated the respiration of unrestrained adult and neonatal TASK-1 knockout mice (TASK-1 -/- ) using a plethysmographic device. Respiration in adult female TASK-1 -/- mice under control (21% O 2 ), hypoxia and hypercapnia was unaffected. Under acute hypoxia male TASK-1 -/- mice exhibited a reduced increase of the respiratory frequency (f R ) compared to wildtypes. However, the tidal volume (V T ) of male TASK-1 -/- mice was strongly enhanced. The volatile anesthetic isoflurane induced in male TASK-1 -/- and male wild type mice (TASK-1 +/+ ) a similar respiratory depression. Neonatal TASK-1 -/- mice demonstrated a 30-40% decrease of the minute volume, caused by a reduction of the f R under control condition (21% O 2 ). Under hypoxia, neonatal TASK-1 -/- mice more frequently stopped breathing (apnea>3s) suggesting an increased hypoxia-sensitivity. As reported before, this increased hypoxia sensitivity had no influence on the survival rate of neonatal TASK-1 -/- mice. In adult and neonatal mice, TASK-1 gene deletion induced a significant prolongation of the relaxation time (R T ), which is a parameter for expiration kinetics. Additionally, screening for mutations in the human TASK-1 gene in 155 cases of sudden infant death syndrome (SIDS) was inconclusive. In conclusion, these data are suggestive for an increased hypoxia-sensitivity of neonatal TASK-1 -/- mice, however, without causing an increase in neonatal lethality. In adult female TASK-1 -/- mice respiration was unaffected, whereas adult male TASK-1 -/- mice showed a modified breathing pattern. These results are suggestive for sex-specific mechanisms for compensating the inactivation of TASK-1 in mice. Copyright © 2016 Elsevier B.V. All rights reserved.

Concomitant behavioral and PFC neuronal activity recorded following dose-response protocol of MPD in adult male rats.

PubMed

Venkataraman, Sidish S; Claussen, Catherine; Joseph, Michael; Dafny, Nachum

2017-04-01

The use of methylphenidate (MPD), a commonly prescribed drug to treat attention-deficit hyperactivity disorder (ADHD), has steadily increased over the past 25 years. This trend has been accompanied by more MPD abuse by ordinary individuals for its cognitive enhancing effects. Therefore, understanding the effects of MPD on the prefrontal cortex (PFC), a brain area involved in higher cortical processing such as executive function, language, planning, and attention regulation, is of particular importance. The goal of this study is to investigate the effects of acute and chronic dose-response characteristics following MPD exposure on both the PFC neuronal population and behavioral activity in freely behaving animals implanted previously with permanent electrodes within the PFC. Four groups of animals were used: saline (control), 0.6, 2.5, and 10.0mg/kg MPD. It was observed that the same dose of either 0.6, 2.5, or 10.0mg/kg repetitive (chronic) MPD exposure elicited behavioral sensitization in some animals and behavioral tolerance in others, and that the majority of PFC units recorded from animals expressing behavioral sensitization to chronic MPD exposure responded to MPD by increasing their neuronal firing rate, whereas the majority of PFC neurons recorded from animals expressing behavioral tolerance in response to chronic MPD responded by decreasing their neuronal firing rate. This data suggests that in animals that display behavioral sensitization, chronic MPD exposure causes an increase in the number of post-synaptic D1 dopamine receptors leading to an increase in behavioral and neuronal firing rate, while in animals that display behavioral tolerance, chronic MPD exposure causes an increase in the number of post-synaptic D2 dopamine receptors leading to a decrease in behavioral and neuronal firing rate. This dichotomy needs to be further investigated. Copyright © 2017 Elsevier Inc. All rights reserved.

Induction of human airway hyperresponsiveness by tumour necrosis factor-alpha.

PubMed

Anticevich, S Z; Hughes, J M; Black, J L; Armour, C L

1995-09-15

Tumour necrosis factor-alpha (TNF alpha) is implicated in the pathogenesis of asthma; however, little is known of its direct effect on smooth muscle reactivity. We investigated the effect of TNF alpha on the responsiveness of human bronchial tissue to electrical field stimulation in vitro. Incubation of non-sensitized tissue with 1 nM, 3 nM and 10 nM TNF alpha significantly increased responsiveness to electrical field stimulation (113 +/- 8, 110 +/- 4 and 112 +/- 2% respectively) compared to control (99 +/- 2%) (P < 0.05, n = 6). Responses were not increased in sensitized tissue (101 +/- 3% versus 105 +/- 5%, n = 3, P > 0.05) nor were responses to exogenous acetylcholine (93 +/- 4% versus 73 +/- 7%, n = 3, P = 0.38). These results show that TNF alpha causes an increase in responsiveness of human bronchial tissue and that this occurs prejunctionally on the parasympathetic nerve pathway. This is the first report of a cytokine increasing human airway tissue responsiveness.

Potential impacts of climate change on infectious diseases in the Arctic.

PubMed

Parkinson, Alan J; Butler, Jay C

2005-12-01

Climate change could cause changes in the incidence of infectious diseases in Arctic regions. Higher ambient temperatures in the Arctic may result in an increase in some temperature sensitive foodborne diseases such as gastroenteritis, paralytic shellfish poisoning and botulism. An increase in mean temperature may also influence the incidence of infectious diseases of animals that are spread to humans (zoonoses) by changing the population and range of animal hosts and insect vectors. An increase in flooding events may result in outbreaks of waterborne infection, such as Giardia lamblia or Cryptospordium parvum. A change in rodent and fox populations may result in an increase in rabies or echinococcosis. Temperature and humidity influence the distribution and density of many arthropod vectors which in turn may influence the incidence and northern range of vectorborne diseases such as West Nile virus. Recommendations include: the strenghtening of public health systems, disease surveillance coordinated with climate monitoring, and research into the detection, prevention, control and treatment of temperature-sensitive infectious diseases.

Occupational skin hazards from synthetic plastics.

PubMed

Tosti, A; Guerra, L; Vincenzi, C; Peluso, A M

1993-01-01

Epoxy and acrylic resins have numerous industrial applications but are also widely used in the household environment. These compounds are presently one of the most important sources of occupational contact dermatitis. Contact sensitization to epoxy resins is usually caused by the resin itself but hardeners or other additives, such as reactive diluents, plasticizers, fillers and pigments, can occasionally be responsible. Since completely cured epoxy resins are not sensitizers, epoxy resin sensitization is always due to the presence, in the final polymer, of uncured allergenic low molecular weight oligomers. Acrylates are now considered the fourth most common cause of contact sensitization due to resins. Unpolymerized monomers of acrylic compounds are known to be responsible for the contact allergy. Accelerators, inhibitors and catalysts, which are usually added to the acrylates to promote the polymerization process, can also sensitize. Both allergic and irritant contact dermatitis may be caused by exposure to epoxy or acrylic resins and their additives. Contact urticaria, allergic or irritant airborne contact dermatitis caused by volatile compounds, onychia and paronychia can also occur. From January of 1984 to May of 1992 we detected 39 cases of occupational allergic contact dermatitis to epoxy resin system substances and 11 cases of occupational contact sensitization to acrylic compounds. In our experience, the electronics industry as well as paint and glue related activities were the most important sources of epoxy sensitization. Dental materials and anaerobic sealants were found to be the most frequent acrylate sensitizers.

Regulation of Ca(2+)-dependent protein turnover in skeletal muscle by thyroxine

NASA Technical Reports Server (NTRS)

Zeman, Richard J.; Bernstein, Paul L.; Ludemann, Robert; Etlinger, Joseph D.

1986-01-01

Dantrolene, an agent that inhibits Ca(2+) mobilization, improved protein balance in skeletal muscle, as thyroid status was increased, by altering rates of protein synthesis and degradation. Thyroxine (T4) caused increases in protein degradation that were blocked by leupeptin, a proteinase inhibitor previously shown to inhibit Ca(2+)-dependent nonlysosomal proteolysis in these muscles. In addition, T4 abolished sensitivity to the lysosomotropic agent methylamine and the autophagy inhibitor 3-methyladenine, suggesting that T4 inhibits autophagic/lysosomal proteolysis.

21 CFR 524.1044b - Gentamicin sulfate, betamethasone valerate otic solution.

Code of Federal Regulations, 2011 CFR

2011-04-01

... use—(i) For the treatment of acute and chronic otitis externa caused by bacteria sensitive to.... (ii) For the treatment of infected superficial lesions caused by bacteria sensitive to gentamicin in...

21 CFR 524.1044b - Gentamicin sulfate, betamethasone valerate otic solution.

Code of Federal Regulations, 2010 CFR

2010-04-01

... use—(i) For the treatment of acute and chronic otitis externa caused by bacteria sensitive to.... (ii) For the treatment of infected superficial lesions caused by bacteria sensitive to gentamicin in...

21 CFR 524.1044b - Gentamicin and betamethasone otic solution.

Code of Federal Regulations, 2014 CFR

2014-04-01

... treatment of acute and chronic otitis externa caused by bacteria sensitive to gentamicin in dogs, instill... of infected superficial lesions caused by bacteria sensitive to gentamicin in dogs and cats, apply a...

Influence of Mn concentration on magnetic topological insulator Mn xBi 2−xTe 3 thin-film Hall-effect sensor

DOE PAGES

Ni, Y.; Zhang, Z.; Nlebedim, I. C.; ...

2015-06-11

Hall-effect (HE) sensors based on high-quality Mn-doped Bi 2Te 3 topological insulator (TI) thin films have been systematically studied in this paper. Improvement of Hall sensitivity is found after doping the magnetic element Mn into Bi 2Te 3. The sensors with low Mn concentrations, Mn xBi 2-xTe 3, x = 0.01 and 0.08 show the linear behavior of Hall resistance with sensitivity about 5 Ω/T. And their Hall sensitivity shows weak dependence on temperature. For sensors with high Mn concentration (x = 0.23), the Hall resistance with respect to magnetic field shows a hysteretic behavior. Moreover, its sensitivity shows almostmore » eight times as high as that of the HE sensors with low Mn concentration. The highest sensitivity can reach 43 Ω/T at very low magnetic field. This increase of Hall sensitivity is caused by the occurrence of anomalous HE (AHE) after ferromagnetic phase transition. Our work indicates that the magnetic-element-doped TIs with AHE are good candidates for HE sensors.« less

Analytical and numerical simulation of the steady-state hydrologic effects of mining aggregate in hypothetical sand-and-gravel and fractured crystalline-rock aquifers

USGS Publications Warehouse

Arnold, L.R.; Langer, William H.; Paschke, Suzanne Smith

2003-01-01

Analytical solutions and numerical models were used to predict the extent of steady-state drawdown caused by mining of aggregate below the water table in hypothetical sand-and-gravel and fractured crystalline-rock aquifers representative of hydrogeologic settings in the Front Range area of Colorado. Analytical solutions were used to predict the extent of drawdown under a wide range of hydrologic and mining conditions that assume aquifer homogeneity, isotropy, and infinite extent. Numerical ground-water flow models were used to estimate the extent of drawdown under conditions that consider heterogeneity, anisotropy, and hydrologic boundaries and to simulate complex or unusual conditions not readily simulated using analytical solutions. Analytical simulations indicated that the drawdown radius (or distance) of influence increased as horizontal hydraulic conductivity of the aquifer, mine penetration of the water table, and mine radius increased; radius of influence decreased as aquifer recharge increased. Sensitivity analysis of analytical simulations under intermediate conditions in sand-and-gravel and fractured crystalline-rock aquifers indicated that the drawdown radius of influence was most sensitive to mine penetration of the water table and least sensitive to mine radius. Radius of influence was equally sensitive to changes in horizontal hydraulic conductivity and recharge. Numerical simulations of pits in sand-and- gravel aquifers indicated that the area of influence in a vertically anisotropic sand-and-gravel aquifer of medium size was nearly identical to that in an isotropic aquifer of the same size. Simulated area of influence increased as aquifer size increased and aquifer boundaries were farther away from the pit, and simulated drawdown was greater near the pit when aquifer boundaries were close to the pit. Pits simulated as lined with slurry walls caused mounding to occur upgradient from the pits and drawdown to occur downgradient from the pits. Pits simulated as refilled with water and undergoing evaporative losses had little hydro- logic effect on the aquifer. Numerical sensitivity analyses for simulations of pits in sand-and-gravel aquifers indicated that simulated head was most sensitive to horizontal hydraulic conductivity and the hydraulic conductance of general-head boundaries in the models. Simulated head was less sensitive to riverbed conductance and recharge and relatively insensitive to vertical hydraulic conductivity. Numerical simulations of quarries in fractured crystalline-rock aquifers indicated that the area of influence in a horizontally anisotropic aquifer was elongated in the direction of higher horizontal hydraulic conductivity and shortened in the direction of lower horizontal hydraulic conductivity compared to area of influence in a homogeneous, isotropic aquifer. Area of influence was larger in an aquifer with ground-water flow in deep, low-permeability fractures than in a homogeneous, isotropic aquifer. Area of influence was larger for a quarry intersected by a hydraulically conductive fault zone and smaller for a quarry intersected by a low-conductivity fault zone. Numerical sensitivity analyses for simulations of quarries in fractured crystalline-rock aquifers indicated simulated head was most sensitive to variations in recharge and horizontal hydraulic conductivity, had little sensitivity to vertical hydraulic conductivity and drain cells used to simulate valleys, and was relatively insensitive to drain cells used to simulate the quarry.

Defect Generation for a Hydrated Layer and Thermal Stability Based on Ba0.7Sr0.3TiO3/SiO2 as H+ Sensitive Layer in Ion-Sensitive Field-Effect Transistor Devices

NASA Astrophysics Data System (ADS)

Chen, Chun-Yuan; Chou, Jung-Chuan; Chou, Hsueh-Tao

2009-04-01

In this paper, we present a novel sensitive ion-sensitive field-effect transistor (ISFET) membrane based on Ba0.7Sr0.3TiO3 (BST)/SiO2 fabricated by sputtering deposition. The proposed device exhibits a linear shift in acidic solutions in the pH range from 1 to 10. The device sensitivity was about 50-55 mV/pH for different deposition times. We also examined the trapping behavior of the surface hydrated layer using the metal-insulator-semiconductor (MIS) structure. Results show that the hydration layer gives rise to stress polarity dependence of electron injection when immersed in pH buffer solutions. Injection from the gate electrode produces larger positive charges and interface state densities in contrast to the substrate injection, which causes simultaneous positive and negative charge trapping. A physical model that quantitatively describes the asymmetry associated with the hydrated diffusion layer is presented, and the temperature effects of BST/SiO2 ISFET devices in the range from 25 to 65 °C were examined. We observed that pH sensitivity increases with increasing temperature. The temperature coefficient of sensitivity (TCS) can be divided into two different ranges: 0.08 mV/pH °C between 25 and 45 °C, and 0.57 mV/pH °C between 45 and 65 °C. A better thermal stability is produced in the 25 and 45 °C range in comparison with other sensitive layers.

Review. The incentive sensitization theory of addiction: some current issues.

PubMed

Robinson, Terry E; Berridge, Kent C

2008-10-12

We present a brief overview of the incentive sensitization theory of addiction. This posits that addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems that attribute incentive salience to reward-associated stimuli. If rendered hypersensitive, these systems cause pathological incentive motivation ('wanting') for drugs. We address some current questions including: what is the role of learning in incentive sensitization and addiction? Does incentive sensitization occur in human addicts? Is the development of addiction-like behaviour in animals associated with sensitization? What is the best way to model addiction symptoms using animal models? And, finally, what are the roles of affective pleasure or withdrawal in addiction?

Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice.

PubMed

Yu, Q; Teixeira, C M; Mahadevia, D; Huang, Y; Balsam, D; Mann, J J; Gingrich, J A; Ansorge, M S

2014-06-01

Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypoactivity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (>P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.

The Sympathetic Release Test: A Test Used to Assess Thermoregulation and Autonomic Control of Blood Flow

ERIC Educational Resources Information Center

Tansey, E. A.; Roe, S. M.; Johnson, C. J.

2014-01-01

When a subject is heated, the stimulation of temperature-sensitive nerve endings in the skin, and the raising of the central body temperature, results in the reflex release of sympathetic vasoconstrictor tone in the skin of the extremities, causing a measurable temperature increase at the site of release. In the sympathetic release test, the…

Auditory evoked potential could reflect emotional sensitivity and impulsivity

PubMed Central

Kim, Ji Sun; Kim, Sungkean; Jung, Wookyoung; Im, Chang-Hwan; Lee, Seung-Hwan

2016-01-01

Emotional sensitivity and impulsivity could cause interpersonal conflicts and neuropsychiatric problems. Serotonin is correlated with behavioral inhibition and impulsivity. This study evaluated whether the loudness dependence of auditory evoked potential (LDAEP), a potential biological marker of central serotonergic activity, could reflect emotional sensitivity and impulsivity. A total of 157 healthy individuals were recruited, who performed LDAEP and Go/Nogo paradigms during electroencephalogram measurement. Barratt impulsivity scale (BIS), Conners’ Adult ADHD rating scale (CAARS), and affective lability scale (ALS) were evaluated. Comparison between low and high LDAEP groups was conducted for behavioural, psychological, and event-related potential (ERP) measures. The high LDAEP group showed significantly increased BIS, a subscale of the CAARS, ALS, and false alarm rate of Nogo stimuli compared to the low LDAEP group. LDAEP showed significant positive correlations with the depression scale, ALS scores, subscale of the CAARS and Nogo-P3 amplitude. In the source activity of Nogo-P3, the cuneus, lingual gyrus, and precentral gyrus activities were significantly increased in the high LDAEP group. Our study revealed that LDAEP could reflect emotional sensitivity and impulsivity. LDAEP, an auditory evoked potential could be a useful tool to evaluate emotional regulation. PMID:27910865

Photon Shot Noise Limited Radio Frequency Electric Field Sensing Using Rydberg Atoms in Vapor Cells

NASA Astrophysics Data System (ADS)

Kumar, Santosh; Jahangiri, Akbar J.; Fan, Haoquan; Kuebler, Harald; Shaffer, James P.

2017-04-01

We report Rydberg atom-based radio frequency (RF) electrometry measurements at a sensitivity limited by probe laser photon shot noise. By utilizing the phenomena of electromagnetically induced transparency (EIT) in room temperature atomic vapor cells, Rydberg atoms can be used for absolute electric field measurements that significantly surpass conventional methods in utility, sensitivity and accuracy. We show that by using a Mach-Zehnder interferometer with homodyne detection or using frequency modulation spectroscopy with active control of residual amplitude modulation we can achieve a RF electric field detection sensitivity of 3 μVcm-1Hz/2. The sensitivity is limited by photon shot noise on the detector used to readout the probe laser of the EIT scheme. We suggest a new multi-photon scheme that can mitigate the effect of photon shot noise. The multi-photon approach allows an increase in probe laser power without decreasing atomic coherence times that result from collisions caused by an increase in Rydberg atom excitation. The multi-photon scheme also reduces Residual Doppler broadening enabling more accurate measurements to be carried out. This work is supported by DARPA, and NRO.

Uncomplicated malaria in children: The place of rapid diagnostic test.

PubMed

Elechi, Hassan Abdullahi; Rabasa, Adamu Ibrahim; Bashir, Muhammad Faruk; Gofama, Mustapha Modu; Ibrahim, Halima Abubakar; Askira, Umoru Muhammed

2015-01-01

Malaria has remained a major cause of morbidity and mortality among the under-five children in Nigeria. Prompt and accurate diagnosis of malaria is necessary in controlling this high burden and preventing unnecessary use of anti-malarial drugs. Malaria rapid diagnostic test (MRDT) offers the hope of achieving this goal. However, the performance of these kits among the most vulnerable age group to malaria is inadequate. In this cross-sectional study, 433 out-patients, aged <5 years with fever or history of fever were enrolled. Each candidate was tested for malaria parasitaemia using ACON; malaria pf. Thick and thin films were also prepared from the same finger prick blood for each candidate. Malaria rapid diagnostic test had sensitivity of 8.3%, specificity of 100%, positive predictive value (PPV) of 100% and negative predictive value (NPV) of 74%. The sensitivity of MRDT increased with increasing age. This effect of age on sensitivity was statistically significant (P = 0.007). Similarly parasite density had significant effect on the sensitivity of MRDT (P = <0.001). Histidine-rich protein-2 based MRDT is not a reliable mean of diagnosing malaria in the under-five age children with acute uncomplicated malaria.

A demonstration of athermal effects of continuous microwave irradiation on the growth and antibiotic sensitivity of Pseudomonas aeruginosa PAO1.

PubMed

Nakouti, Ismini; Hobbs, Glyn; Teethaisong, Yothin; Phipps, David

2017-01-01

Stress, caused by exposure to microwaves (2.45 GHz) at constant temperature (37 ± 0.5°C), alters the growth profile of Pseudomonas aeruginosa PAO1. In the absence of microwave treatment a simple, highly reproducible growth curve was observed over 24 h or more. Microwave treatment caused no reduction in growth during the first 6 h, but at a later stage (>12 h) the growth was markedly different to the controls. Secondary growth, typical of the presence of persisters clearly became apparent, as judged by both the dissolved oxygen and the cell density profiles. These treated cells showed distinct morphological changes, but on regrowth these cells reverted to normal. The microwave induced persisters were subject to antibiotic challenge (tobramycin) and showed increased sensitivity when compared to the unstressed planktonic cells. This is in marked contrast to antibiotic induced persisters which show increased resistance. This provides evidence for both a nonthermal effect of microwaves and a previously undescribed route to a novel form of antibiotic susceptible persister cells. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:37-44, 2017. © 2016 American Institute of Chemical Engineers.

Delamination of Composite Cylinders

NASA Astrophysics Data System (ADS)

Davies, Peter; Carlsson, Leif A.

The delamination resistance of filament wound glass/epoxy cylinders has been characterized for a range of winding angles and fracture mode ratios using beam fracture specimens. The results reveal that the delamination fracture resistance increases with increasing winding angle and mode II (shear) fraction (GΠ/G). It was also found that interlaced fiber bundles in the filament wound cylinder wall acted as effective crack arresters in mode I loading. To examine the sensitivity of delamina-tion damage on the strength of the cylinders, external pressure tests were performed on filament-wound glass/epoxy composite cylinders with artificial defects and impact damage. The results revealed that the cylinder strength was insensitive to the presence of single delaminations but impact damage caused reductions in failure pressure. The insensitivity of the failure pressure to a single delamination is attributed to the absence of buckling of the delaminated sublaminates before the cylinder wall collapsed. The impacted cylinders contained multiple delaminations, which caused local reduction in the compressive load capability and reduction in failure pressure. The response of glass/epoxy cylinders was compared to impacted carbon reinforced cylinders. Carbon/epoxy is more sensitive to damage but retains higher implosion resistance while carbon/PEEK shows the opposite trend.

Interferon Gamma potentiates the injury caused by MPP(+) on SH-SY5Y cells, which is attenuated by the nitric oxide synthases inhibition.

PubMed

Titze-de-Almeida, Simoneide S; Lustosa, Cátia Faria; Horst, Camila Hillesheim; Bel, Elaine Del; Titze-de-Almeida, Ricardo

2014-12-01

This study examined whether the cytokine interferon (IFN) gamma plays a role in the injury of SH-SY5Y cells caused by MPP(+) (1-methyl-4-phenylpyridinium). First of all, IFN-gamma sensitized cells to the neurotoxin MPP(+), as determined by MTT (3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide) assay. MPP(+)-injured cells showed higher reactive oxygen species (ROS) levels, which was reinforced by IFN-gamma. The injury triggered a marked expression of the neuronal NOS (nNOS) enzyme. L-NAME [N(ω)-nitro-L-arginine methyl ester, a non-specific NOS inhibitor] reestablished the cell viability after IFN-gamma challenging, and recovered cells from MPP(+) injury (95.0 vs. 84.7 %; P < 0.05). Seven-NI (7-nitroindazole, a nNOS inhibitor) protected cells against the injury by MPP(+) co-administered with IFN-gamma. Both inhibitors restrained the apoptosis of SH-SY5Y cells caused by MPP(+)/IFN-gamma. Regarding oxidative stress, L-NAME and 7-NI attenuated the increase in ROS levels caused by MPP(+) (45.3 or 48.4 vs. 87.9 %, P < 0.05). Indeed, L-NAME was more effective than 7-NI for reducing oxidative stress caused by MPP(+) under IFN-gamma exposition. The nNOS gene silencing by small-interfering RNAs recovered cells challenged by IFN-gamma (24 h), or MPP(+) (8 h). In conclusion, IFN-gamma sensitizes cells to MPP(+)-induced injury, also causing an increase in ROS levels. Pretreating cells with L-NAME or 7-NI reverts both the oxidative stress and apoptosis triggered by the neurotoxin MPP(+). Taking together, our data reinforce that IFN-gamma and NOS enzymes play a role in oxidative stress and dopaminergic cell death triggered by MPP(+).

Obesity, diabetes, and associated costs of exposure to endocrine-disrupting chemicals in the European Union.

PubMed

Legler, Juliette; Fletcher, Tony; Govarts, Eva; Porta, Miquel; Blumberg, Bruce; Heindel, Jerrold J; Trasande, Leonardo

2015-04-01

Obesity and diabetes are epidemic in the European Union (EU). Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a contributor, independent of diet and physical activity. The objective was to estimate obesity, diabetes, and associated costs that can be reasonably attributed to EDC exposures in the EU. An expert panel evaluated evidence for probability of causation using weight-of-evidence characterization adapted from that applied by the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and burden of disease. Cost estimation as of 2010 utilized published cost estimates for childhood obesity, adult obesity, and adult diabetes. Setting, Patients and Participants, and Intervention: Cost estimation was performed from the societal perspective. The panel identified a 40% to 69% probability of dichlorodiphenyldichloroethylene causing 1555 cases of overweight at age 10 (sensitivity analysis: 1555-5463) in 2010 with associated costs of €24.6 million (sensitivity analysis: €24.6-86.4 million). A 20% to 39% probability was identified for dichlorodiphenyldichloroethylene causing 28 200 cases of adult diabetes (sensitivity analysis: 28 200-56 400) with associated costs of €835 million (sensitivity analysis: €835 million-16.6 billion). The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and €15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with €607 million in associated costs. Prenatal bisphenol A exposure was identified to have a 20% to 69% probability of causing 42 400 cases of childhood obesity, with associated lifetime costs of €1.54 billion. EDC exposures in the EU contribute substantially to obesity and diabetes, with a moderate probability of >€18 billion costs per year. This is a conservative estimate; the results emphasize the need to control EDC exposures.

Obesity, Diabetes, and Associated Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union

PubMed Central

Legler, Juliette; Fletcher, Tony; Govarts, Eva; Porta, Miquel; Blumberg, Bruce; Heindel, Jerrold J.

2015-01-01

Context: Obesity and diabetes are epidemic in the European Union (EU). Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a contributor, independent of diet and physical activity. Objective: The objective was to estimate obesity, diabetes, and associated costs that can be reasonably attributed to EDC exposures in the EU. Design: An expert panel evaluated evidence for probability of causation using weight-of-evidence characterization adapted from that applied by the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and burden of disease. Cost estimation as of 2010 utilized published cost estimates for childhood obesity, adult obesity, and adult diabetes. Setting, Patients and Participants, and Intervention: Cost estimation was performed from the societal perspective. Results: The panel identified a 40% to 69% probability of dichlorodiphenyldichloroethylene causing 1555 cases of overweight at age 10 (sensitivity analysis: 1555–5463) in 2010 with associated costs of €24.6 million (sensitivity analysis: €24.6–86.4 million). A 20% to 39% probability was identified for dichlorodiphenyldichloroethylene causing 28 200 cases of adult diabetes (sensitivity analysis: 28 200–56 400) with associated costs of €835 million (sensitivity analysis: €835 million–16.6 billion). The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and €15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with €607 million in associated costs. Prenatal bisphenol A exposure was identified to have a 20% to 69% probability of causing 42 400 cases of childhood obesity, with associated lifetime costs of €1.54 billion. Conclusions: EDC exposures in the EU contribute substantially to obesity and diabetes, with a moderate probability of >€18 billion costs per year. This is a conservative estimate; the results emphasize the need to control EDC exposures. PMID:25742518

Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.

PubMed

Ridker, Paul M; Danielson, Eleanor; Fonseca, Francisco A H; Genest, Jacques; Gotto, Antonio M; Kastelein, John J P; Koenig, Wolfgang; Libby, Peter; Lorenzatti, Alberto J; MacFadyen, Jean G; Nordestgaard, Børge G; Shepherd, James; Willerson, James T; Glynn, Robert J

2008-11-20

Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.) 2008 Massachusetts Medical Society

Effect of experimental hyperthyroidism on protein turnover in skeletal and cardiac muscle.

PubMed

Carter, W J; Van Der Weijden Benjamin, W S; Faas, F H

1980-10-01

Since experimental hyperthyroidism reduces skeletal muscle mass while simultaneously increasing cardiac muscle mass, the effect of hyperthyroidism on muscle protein degradation was compared in skeletal and cardiac muscle. Pulse-labeling studies using (3H) leucine and (14C) carboxyl labeled aspartate and glutamate were carried out. Hyperthyroidism caused a 25%-29% increase in protein breakdown in both sarcoplasmic and myofibrillar fractions of skeletal muscle. Increased muscle protein degradation may be a major factor in the development of skeletal muscle wasting and weakness in hyperthyroidism. In contrast, protein breakdown appeared to be reduced 22% in the sarcoplasmic fraction of hyperthyroid heart muscle and was unchanged in the myofibrillar fraction. Possible reasons for the contrasting effects of hyperthyroidism on skeletal and cardiac muscle include increased sensitivity of the hyperthyroid heart to catecholamines, increased cardiac work caused by the hemodynamic effects of hyperthyroidism, and a different direct effect of thyroid hormone at the nuclear level in cardiac as opposed to skeletal muscle.

Inhibition of the RhoA GTPase Activity Increases Sensitivity of Melanoma Cells to UV Radiation Effects

PubMed Central

Espinha, Gisele; Osaki, Juliana Harumi; Costa, Erico Tosoni; Forti, Fabio Luis

2016-01-01

Ultraviolet radiation is the main cause of DNA damage to melanocytes and development of melanoma, one of the most lethal human cancers, which leads to metastasis due to uncontrolled cell proliferation and migration. These phenotypes are mediated by RhoA, a GTPase overexpressed or overactivated in highly aggressive metastatic tumors that plays regulatory roles in cell cycle progression and cytoskeleton remodeling. This work explores whether the effects of UV on DNA damage, motility, proliferation, and survival of human metastatic melanoma cells are mediated by the RhoA pathway. Mutant cells expressing dominant-negative (MeWo-RhoA-N19) or constitutively active RhoA (MeWo-RhoA-V14) were generated and subjected to UV radiation. A slight reduction in migration and invasion was observed in MeWo and MeWo-RhoA-V14 cells but not in MeWo-RhoA-N19 cells, which presented inefficient motility and invasiveness associated with stress fibers fragmentation. Proliferation and survival of RhoA-deficient cells were drastically reduced by UV compared to cells displaying normal or high RhoA activity, suggesting increased sensitivity to UV. Loss of RhoA activity also caused less efficient DNA repair, with elevated levels of DNA lesions such as strand breaks and cyclobutane pyrimidine dimers (CPDs). Thus, RhoA mediates genomic stability and represents a potential target for sensitizing metastatic tumors to genotoxic agents. PMID:26823948

Alternative translation initiation of Caveolin-2 desensitizes insulin signaling through dephosphorylation of insulin receptor by PTP1B and causes insulin resistance.

PubMed

Kwon, Hayeong; Jang, Donghwan; Choi, Moonjeong; Lee, Jaewoong; Jeong, Kyuho; Pak, Yunbae

2018-06-01

Insulin resistance, defined as attenuated sensitivity responding to insulin, impairs insulin action. Direct causes and molecular mechanisms of insulin resistance have thus far remained elusive. Here we show that alternative translation initiation (ATI) of Caveolin-2 (Cav-2) regulates insulin sensitivity. Cav-2β isoform yielded by ATI desensitizes insulin receptor (IR) via dephosphorylation by protein-tyrosine phosphatase 1B (PTP1B), and subsequent endocytosis and lysosomal degradation of IR, causing insulin resistance. Blockage of Cav-2 ATI protects against insulin resistance by preventing Cav-2β-PTP1B-directed IR desensitization, thereby normalizing insulin sensitivity and glucose uptake. Our findings show that Cav-2β is a negative regulator of IR signaling, and identify a mechanism causing insulin resistance through control of insulin sensitivity via Cav-2 ATI. Copyright © 2018 Elsevier B.V. All rights reserved.

CatB is Critical for Total Catalase Activity and Reduces Bactericidal Effects of Phenazine-1-Carboxylic Acid on Xanthomonas oryzae pv. oryzae and X. oryzae pv. oryzicola.

PubMed

Pan, Xiayan; Wu, Jian; Xu, Shu; Duan, Yabing; Zhou, Mingguo

2017-02-01

Rice bacterial leaf blight, caused by Xanthomonas oryzae pv. oryzae, and rice bacterial leaf streak, caused by X. oryzae pv. oryzicola, are major diseases of rice. Phenazine-1-carboxylic acid (PCA) is a natural product that is isolated from Pseudomonas spp. and is used to control many important rice diseases in China. We previously reported that PCA disturbs the redox balance, which results in the accumulation of reactive oxygen species in X. oryzae pv. oryzae. In this study, we found that PCA significantly upregulated the transcript levels of catB and katE, which encode catalases, and that PCA sensitivity was reduced when X. oryzae pvs. oryzae and oryzicola were cultured with exogenous catalase. Furthermore, catB deletion mutants of X. oryzae pvs. oryzae and oryzicola showed dramatically decreased total catalase activity, increased sensitivity to PCA, and reduced virulence in rice. In contrast, deletion mutants of srpA and katG, which also encode catalases, exhibited little change in PCA sensitivity. The results indicate that catB in both X. oryzae pvs. oryzae and oryzicola encodes a catalase that helps protect the bacteria against PCA-induced stress.

GABAa and GABAc receptor-mediated modulation of responses to color stimuli: electroretinographic study in the turtle Emys orbicularis.

PubMed

Kupenova, Petia; Vitanova, Lily; Popova, Elka

2010-04-01

GABAergic transmission is involved in color coding in the retina. The specific contribution of different GABA receptors to spectral sensitivity of the retinal responses is not well characterized. We studied GABAa and GABAc receptor-mediated effects on the intensity-response functions of the electroretinographic ON (b-wave) and OFF (d-wave) responses to color stimuli. For this purpose, we compared the effects of GABAa receptor blockade by bicuculline with the effects of GABAa + GABAc receptor blockade by picrotoxin. The blockade of both GABAa and GABAc receptors caused an amplitude increase of the electroretinographic responses, but the effects of the two blockades depended in a specific manner on stimulus intensity and wavelength. The effects of GABAa receptor blockade showed distinct color ON/OFF asymmetry. The absolute and relative sensitivities of the ON responses to blue stimuli and OFF responses to red stimuli were increased to the greatest degree while the sensitivity of the ON responses to red stimuli and OFF responses to blue stimuli was least increased. In contrast, color ON/OFF asymmetry was not typical of the effects of GABAc receptor blockade. The most prominent GABAc effect was the sensitivity increase of the ON and OFF responses to blue stimuli and, to some lesser extent, to green stimuli. The results of this study indicate a specific role of GABAa and GABAc receptor-mediated influences in processing of chromatic information in the distal retina.

Machine learning for classifying tuberculosis drug-resistance from DNA sequencing data.

PubMed

Yang, Yang; Niehaus, Katherine E; Walker, Timothy M; Iqbal, Zamin; Walker, A Sarah; Wilson, Daniel J; Peto, Tim E A; Crook, Derrick W; Smith, E Grace; Zhu, Tingting; Clifton, David A

2018-05-15

Correct and rapid determination of Mycobacterium tuberculosis (MTB) resistance against available tuberculosis (TB) drugs is essential for the control and management of TB. Conventional molecular diagnostic test assumes that the presence of any well-studied single nucleotide polymorphisms is sufficient to cause resistance, which yields low sensitivity for resistance classification. Given the availability of DNA sequencing data from MTB, we developed machine learning models for a cohort of 1839 UK bacterial isolates to classify MTB resistance against eight anti-TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, ciprofloxacin, moxifloxacin, ofloxacin, streptomycin) and to classify multi-drug resistance. Compared to previous rules-based approach, the sensitivities from the best-performing models increased by 2-4% for isoniazid, rifampicin and ethambutol to 97% (P < 0.01), respectively; for ciprofloxacin and multi-drug resistant TB, they increased to 96%. For moxifloxacin and ofloxacin, sensitivities increased by 12 and 15% from 83 and 81% based on existing known resistance alleles to 95% and 96% (P < 0.01), respectively. Particularly, our models improved sensitivities compared to the previous rules-based approach by 15 and 24% to 84 and 87% for pyrazinamide and streptomycin (P < 0.01), respectively. The best-performing models increase the area-under-the-ROC curve by 10% for pyrazinamide and streptomycin (P < 0.01), and 4-8% for other drugs (P < 0.01). The details of source code are provided at http://www.robots.ox.ac.uk/~davidc/code.php. david.clifton@eng.ox.ac.uk. Supplementary data are available at Bioinformatics online.

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

PubMed Central

Huseinovic, Angelina; van Leeuwen, Jolanda S.; van Welsem, Tibor; Stulemeijer, Iris; van Leeuwen, Fred; Vermeulen, Nico P. E.; Kooter, Jan M.; Vos, J. Chris

2017-01-01

Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity. PMID:28291796

Multi-Drug Resistance Transporters and a Mechanism-Based Strategy for Assessing Risks of Pesticide Combinations to Honey Bees

PubMed Central

Guseman, Alex J.; Miller, Kaliah; Kunkle, Grace; Dively, Galen P.; Pettis, Jeffrey S.; Evans, Jay D.; vanEngelsdorp, Dennis; Hawthorne, David J.

2016-01-01

Annual losses of honey bee colonies remain high and pesticide exposure is one possible cause. Dangerous combinations of pesticides, plant-produced compounds and antibiotics added to hives may cause or contribute to losses, but it is very difficult to test the many combinations of those compounds that bees encounter. We propose a mechanism-based strategy for simplifying the assessment of combinations of compounds, focusing here on compounds that interact with xenobiotic handling ABC transporters. We evaluate the use of ivermectin as a model substrate for these transporters. Compounds that increase sensitivity of bees to ivermectin may be inhibiting key transporters. We show that several compounds commonly encountered by honey bees (fumagillin, Pristine, quercetin) significantly increased honey bee mortality due to ivermectin and significantly reduced the LC50 of ivermectin suggesting that they may interfere with transporter function. These inhibitors also significantly increased honey bees sensitivity to the neonicotinoid insecticide acetamiprid. This mechanism-based strategy may dramatically reduce the number of tests needed to assess the possibility of adverse combinations among pesticides. We also demonstrate an in vivo transporter assay that provides physical evidence of transporter inhibition by tracking the dynamics of a fluorescent substrate of these transporters (Rhodamine B) in bee tissues. Significantly more Rhodamine B remains in the head and hemolymph of bees pretreated with higher concentrations of the transporter inhibitor verapamil. Mechanism-based strategies for simplifying the assessment of adverse chemical interactions such as described here could improve our ability to identify those combinations that pose significantly greater risk to bees and perhaps improve the risk assessment protocols for honey bees and similar sensitive species. PMID:26840460

Multi-Drug Resistance Transporters and a Mechanism-Based Strategy for Assessing Risks of Pesticide Combinations to Honey Bees.

PubMed

Guseman, Alex J; Miller, Kaliah; Kunkle, Grace; Dively, Galen P; Pettis, Jeffrey S; Evans, Jay D; vanEngelsdorp, Dennis; Hawthorne, David J

2016-01-01

Annual losses of honey bee colonies remain high and pesticide exposure is one possible cause. Dangerous combinations of pesticides, plant-produced compounds and antibiotics added to hives may cause or contribute to losses, but it is very difficult to test the many combinations of those compounds that bees encounter. We propose a mechanism-based strategy for simplifying the assessment of combinations of compounds, focusing here on compounds that interact with xenobiotic handling ABC transporters. We evaluate the use of ivermectin as a model substrate for these transporters. Compounds that increase sensitivity of bees to ivermectin may be inhibiting key transporters. We show that several compounds commonly encountered by honey bees (fumagillin, Pristine, quercetin) significantly increased honey bee mortality due to ivermectin and significantly reduced the LC50 of ivermectin suggesting that they may interfere with transporter function. These inhibitors also significantly increased honey bees sensitivity to the neonicotinoid insecticide acetamiprid. This mechanism-based strategy may dramatically reduce the number of tests needed to assess the possibility of adverse combinations among pesticides. We also demonstrate an in vivo transporter assay that provides physical evidence of transporter inhibition by tracking the dynamics of a fluorescent substrate of these transporters (Rhodamine B) in bee tissues. Significantly more Rhodamine B remains in the head and hemolymph of bees pretreated with higher concentrations of the transporter inhibitor verapamil. Mechanism-based strategies for simplifying the assessment of adverse chemical interactions such as described here could improve our ability to identify those combinations that pose significantly greater risk to bees and perhaps improve the risk assessment protocols for honey bees and similar sensitive species.

The novel thymidylate synthase inhibitor trifluorothymidine (TFT) and TRAIL synergistically eradicate non-small cell lung cancer cells.

PubMed

Azijli, Kaamar; van Roosmalen, Ingrid A M; Smit, Jorn; Pillai, Saravanan; Fukushima, Masakazu; de Jong, Steven; Peters, Godefridus J; Bijnsdorp, Irene V; Kruyt, Frank A E

2014-06-01

TRAIL, a tumor selective anticancer agent, may be used for the treatment of non-small cell lung cancer (NSCLC). However, TRAIL resistance is frequently encountered. Here, the combined use of TRAIL with trifluorothymidine (TFT), a thymidylate synthase inhibitor, was examined for sensitizing NSCLC cells to TRAIL. Interactions between TRAIL and TFT were studied in NSCLC cells using growth inhibition and apoptosis assays. Western blotting and flow cytometry were used to investigate underlying mechanisms. The combined treatment of TFT and TRAIL showed synergistic cytotoxicity in A549, H292, H322 and H460 cells. For synergistic activity, the sequence of administration was important; TFT treatment followed by TRAIL exposure did not show sensitization. Combined TFT and TRAIL treatment for 24 h followed by 48 h of TFT alone was synergistic in all cell lines, with combination index values below 0.9. The treatments affected cell cycle progression, with TRAIL inducing a G1 arrest and TFT, a G2/M arrest. TFT activated Chk2 and reduced Cdc25c levels known to cause G2/M arrest. TRAIL-induced caspase-dependent apoptosis was enhanced by TFT, whereas TFT alone mainly induced caspase-independent death. TFT increased the expression of p53 and p21/WAF1, and p53 was involved in the increase of TRAIL-R2 surface expression. TFT also caused downregulation of cFLIP and XIAP and increased Bax expression. TFT enhances TRAIL-induced apoptosis in NSCLC cells by sensitizing the apoptotic machinery at different levels in the TRAIL pathway. Our findings suggest a possible therapeutic benefit of the combined use of TFT and TRAIL in NSCLC.

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae.

PubMed

Huseinovic, Angelina; van Leeuwen, Jolanda S; van Welsem, Tibor; Stulemeijer, Iris; van Leeuwen, Fred; Vermeulen, Nico P E; Kooter, Jan M; Vos, J Chris

2017-01-01

Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity.

Different sensitivities of rat skeletal muscles and brain to novel anti-cholinesterase agents, alkylammonium derivatives of 6-methyluracil (ADEMS)

PubMed Central

Petrov, Konstantin A; Yagodina, Lilia O; Valeeva, Guzel R; Lannik, Natalya I; Nikitashina, Alexandra D; Rizvanov, Albert A; Zobov, Vladimir V; Bukharaeva, Ellya A; Reznik, Vladimir S; Nikolsky, Eugeny E; Vyskočil, František

2011-01-01

BACKGROUND AND PURPOSE The rat respiratory muscle diaphragm has markedly lower sensitivity than the locomotor muscle extensor digitorum longus (EDL) to the new acetylcholinesterase (AChE) inhibitors, alkylammonium derivatives of 6-methyluracil (ADEMS). This study evaluated several possible reasons for differing sensitivity between the diaphragm and limb muscles and between the muscles and the brain. EXPERIMENTAL APPROACH Increased amplitude and prolonged decay time of miniature endplate currents were used to assess anti-cholinesterase activity in muscles. In hippocampal slices, induction of synchronous network activity was used to follow cholinesterase inhibition. The inhibitor sensitivities of purified AChE from the EDL and brain were also estimated. KEY RESULTS The intermuscular difference in sensitivity to ADEMS is partly explained caused by a higher level of mRNA and activity of 1,3-bis[5(diethyl-o-nitrobenzylammonium)pentyl]-6-methyluracildibromide (C-547)-resistant BuChE in the diaphragm. Moreover, diaphragm AChE was more than 20 times less sensitive to C-547 than that from the EDL. Sensitivity of the EDL to C-547 dramatically decreased after treadmill exercises that increased the amount of PRiMA AChE(G4), but not ColQ AChE(A12) molecular forms. The A12 form present in muscles appeared more sensitive to C-547. The main form of AChE in brain, PRiMA AChE(G4), was apparently less sensitive because brain cholinesterase activity was almost three orders of magnitude more resistant to C-547 than that of the EDL. CONCLUSIONS AND IMPLICATIONS Our findings suggest that ADEMS compounds could be used for the selective inhibition of AChEs and as potential therapeutic tools. PMID:21232040

Cough and expiration reflexes elicited by inhaled irritant gases are intensified in ovalbumin-sensitized mice.

PubMed

Zhang, Cheng; Lin, Ruei-Lung; Hong, Jeff; Khosravi, Mehdi; Lee, Lu-Yuan

2017-05-01

This study was designed to determine the effect of active sensitization with ovalbumin (Ova) on cough responses to inhaled irritant gases in mice. Conscious mice moved freely in a recording chamber, while the pressure change in the chamber and audio and video signals of the mouse movements were recorded simultaneously to measure the frequencies of cough reflex (CR) and expiration reflex (ER). To further verify the accuracy of cough analysis, the intrapleural pressure was also recorded by a telemetry sensor surgically implanted in the intrapleural space in a subgroup of mice. During the irritant gas inhalation challenge, sulfur dioxide (SO 2 ; 200 and 400 ppm) or ammonia (NH 3 ; 0.1% and 0.2%) was drawn into the chamber at a constant flow rate for 8 min. Ova sensitization and sham sensitization with vehicle (Veh) were performed over a 25-day period in separate groups of mice. Our results showed that 1 ) both SO 2 and NH 3 inhalation challenges increased CR and ER frequencies in a concentration-dependent manner before Ova sensitization; 2 ) the baseline CR frequency was significantly elevated after Ova sensitization, accompanied by pronounced airway inflammation; and 3 ) Ova sensitization also markedly augmented the responses of CR and ER to both SO 2 and NH 3 inhalation challenges; in sharp contrast, the cough responses did not change after sham sensitization in the Veh group. In conclusion, Ova sensitization caused distinct and lingering increases in baseline cough frequency, and also intensified both CR and ER responses to inhaled irritant gases, which probably resulted from an allergic inflammation-induced hypersensitivity of airway sensory nerves. Copyright © 2017 the American Physiological Society.

Sensitivity and specificity of dosing alerts for dosing errors among hospitalized pediatric patients

PubMed Central

Stultz, Jeremy S; Porter, Kyle; Nahata, Milap C

2014-01-01

Objectives To determine the sensitivity and specificity of a dosing alert system for dosing errors and to compare the sensitivity of a proprietary system with and without institutional customization at a pediatric hospital. Methods A retrospective analysis of medication orders, orders causing dosing alerts, reported adverse drug events, and dosing errors during July, 2011 was conducted. Dosing errors with and without alerts were identified and the sensitivity of the system with and without customization was compared. Results There were 47 181 inpatient pediatric orders during the studied period; 257 dosing errors were identified (0.54%). The sensitivity of the system for identifying dosing errors was 54.1% (95% CI 47.8% to 60.3%) if customization had not occurred and increased to 60.3% (CI 54.0% to 66.3%) with customization (p=0.02). The sensitivity of the system for underdoses was 49.6% without customization and 60.3% with customization (p=0.01). Specificity of the customized system for dosing errors was 96.2% (CI 96.0% to 96.3%) with a positive predictive value of 8.0% (CI 6.8% to 9.3). All dosing errors had an alert over-ridden by the prescriber and 40.6% of dosing errors with alerts were administered to the patient. The lack of indication-specific dose ranges was the most common reason why an alert did not occur for a dosing error. Discussion Advances in dosing alert systems should aim to improve the sensitivity and positive predictive value of the system for dosing errors. Conclusions The dosing alert system had a low sensitivity and positive predictive value for dosing errors, but might have prevented dosing errors from reaching patients. Customization increased the sensitivity of the system for dosing errors. PMID:24496386

The Genetic and Molecular Bases for Hypertrophic Cardiomyopathy: The Role for Calcium Sensitization.

PubMed

Ren, Xianfeng; Hensley, Nadia; Brady, Mary Beth; Gao, Wei Dong

2018-02-01

Hypertrophic cardiomyopathy (HCM) affects millions of people around the world as one of the most common genetic heart disorders and leads to cardiac ischemia, heart failure, dysfunction of other organ systems, and increased risk for sudden unexpected cardiac deaths. HCM can be caused by single-point mutations, insertion or deletion mutations, or truncation of cardiac myofilament proteins. The molecular mechanism that leads to disease progression and presentation is still poorly understood, despite decades of investigations. However, recent research has made dramatic advances in the understanding of HCM disease development. Studies have shown that increased calcium sensitivity is a universal feature in HCM. At the molecular level, increased crossbridge force (or power) generation resulting in hypercontractility is the prominent feature. Thus, calcium sensitization/hypercontractility is emerging as the primary stimulus for HCM disease development and phenotypic expression. Cross-bridge inhibition has been shown to halt HCM presentation, and myofilament desensitization appears to reduce lethal arrhythmias in animal models of HCM. These advances in basic research will continue to deepen the knowledge of HCM pathogenesis and are beginning to revolutionize the management of HCM. Copyright © 2018 Elsevier Inc. All rights reserved.

Granulocyte phagocytosis and killing virulent and avirulent serotypes of Streptococcus pneumoniae.

PubMed

Braconier, J H; Odeberg, H

1982-08-01

Five commonly isolated Streptococcus pneumoniae serotypes (3, 6, 14, 19, and 23) and five rarely found serotypes (31, 35, 36, 42, and 43) were compared to elucidate whether increased resistance against granulocyte phagocytosis and killing could explain the restricted number of pneumococcal serotypes found in infections. There was a great variation in sensitivity among the serotypes to granulocyte killing. No consistent pattern was found when pathogenicity and resistance to granulocytes were compared. The results do not indicate that the increased tendency of pathogenic pneumococcal serotypes to cause infections is due to increased resistance to granulocytes. Monocyte killing of some pneumococal serotypes (6, 19, 23, 35, and 43) was also studied and found very similar to granulocyte killing. Defective granulocyte kiling of encapsulated pneumococci was due to impaired phagocytosis. Moreover, no correlation was found between the sensitivity of the serotypes to isolated intragranulocytic microbial systems (i.e., MPO, hydrogen peroxide, or CCP) and the sensitivity to killing by intact granulocytes or pathogenicity. The significance of both the classical and alternative complement pathways for pneumococcal opsonization was indicated by reduced, the residual phagocytosis in C2-deficient and MgEGTA-chelated serum.

Postnatal Day 2 to 11 Constitutes a 5-HT-Sensitive Period Impacting Adult mPFC Function

PubMed Central

Rebello, Tahilia J.; Yu, Qinghui; Goodfellow, Nathalie M.; Caffrey Cagliostro, Martha K.; Teissier, Anne; Morelli, Emanuela; Demireva, Elena Y.; Chemiakine, Alexei; Rosoklija, Gorazd B.; Dwork, Andrew J.; Lambe, Evelyn K.; Ansorge, Mark S.

2014-01-01

Early-life serotonin [5-hydroxytryptamine (5-HT)] signaling modulates brain development, which impacts adult behavior, but 5-HT-sensitive periods, neural substrates, and behavioral consequences remain poorly understood. Here we identify the period ranging from postnatal day 2 (P2) to P11 as 5-HT sensitive, with 5-HT transporter (5-HTT) blockade increasing anxiety- and depression-like behavior, and impairing fear extinction learning and memory in adult mice. Concomitantly, P2–P11 5-HTT blockade causes dendritic hypotrophy and reduced excitability of infralimbic (IL) cortex pyramidal neurons that normally promote fear extinction. By contrast, the neighboring prelimbic (PL) pyramidal neurons, which normally inhibit fear extinction, become more excitable. Excitotoxic IL but not PL lesions in adult control mice reproduce the anxiety-related phenotypes. These findings suggest that increased 5-HT signaling during P2–P11 alters adult mPFC function to increase anxiety and impair fear extinction, and imply a differential role for IL and PL neurons in regulating affective behaviors. Together, our results support a developmental mechanism for the etiology and pathophysiology of affective disorders and fear-related behaviors. PMID:25209278

Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels

PubMed Central

Liu, Jinfeng; Dong, Huansheng; Zhang, Yong; Cao, Mingjun; Song, Lili; Pan, Qingjie; Bulmer, Andrew; Adams, David B.; Dong, Xiao; Wang, Hongjun

2015-01-01

Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice. PMID:26017184

Warmer winters modulate life history and energy storage but do not affect sensitivity to a widespread pesticide in an aquatic insect.

PubMed

Arambourou, Hélène; Stoks, Robby

2015-10-01

Despite the increased attention for the effects of pesticides under global warming no studies tested how winter warming affects subsequent sensitivity to pesticides. Winter warming is expected to cause delayed negative effects when it increases metabolic rates and thereby depletes energy reserves. Using a common-garden experiment, we investigated the combined effect of a 4 °C increase in winter temperature and subsequent exposure to chlorpyrifos in the aquatic larvae of replicated low- and high-latitude European populations of the damselfly Ischnura elegans. The warmer winter (8 °C) resulted in a higher winter survival and higher growth rates compared to the cold winter (4 °C) commonly experienced by European high-latitude populations. Low-latitude populations were better at coping with the warmer winter, indicating thermal adaptation to the local winter temperatures. Subsequent chlorpyrifos exposure at 20 °C induced strong negative effects on survival, growth rate, lipid content and acetylcholinesterase activity while phenoloxidase activity increased. These pesticide effects were not affected by winter warming. Our results suggest that for species where winter warming has positive effects on life history, no delayed effects on the sensitivity to subsequent pesticide exposure should be expected. Copyright © 2015 Elsevier B.V. All rights reserved.

Developmental plasticity in vision and behavior may help guppies overcome increased turbidity.

PubMed

Ehlman, Sean M; Sandkam, Benjamin A; Breden, Felix; Sih, Andrew

2015-12-01

Increasing turbidity in streams and rivers near human activity is cause for environmental concern, as the ability of aquatic organisms to use visual information declines. To investigate how some organisms might be able to developmentally compensate for increasing turbidity, we reared guppies (Poecilia reticulata) in either clear or turbid water. We assessed the effects of developmental treatments on adult behavior and aspects of the visual system by testing fish from both developmental treatments in turbid and clear water. We found a strong interactive effect of rearing and assay conditions: fish reared in clear water tended to decrease activity in turbid water, whereas fish reared in turbid water tended to increase activity in turbid water. Guppies from all treatments decreased activity when exposed to a predator. To measure plasticity in the visual system, we quantified treatment differences in opsin gene expression of individuals. We detected a shift from mid-wave-sensitive opsins to long wave-sensitive opsins for guppies reared in turbid water. Since long-wavelength sensitivity is important in motion detection, this shift likely allows guppies to salvage motion-detecting abilities when visual information is obscured in turbid water. Our results demonstrate the importance of developmental plasticity in responses of organisms to rapidly changing environments.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vallis, Geoffrey K.

The project had two main components. The first concerns estimating the climate sensitivity in the presence of forcing uncertainty and natural variability. Climate sensitivity is the increase in the average surface temperature for a given increase in greenhouse gases, for example a doubling of carbon dioxide. We have provided new, probabilistic estimates of climate sensitivity using a simple climate model an the observed warming in the 20th century, in conjunction with ideas in data assimilation and parameter estimation developed in the engineering community. The estimates combine the uncertainty in the anthropogenic aerosols with the uncertainty arising because of natural variability.more » The second component concerns how the atmospheric circulation itself might change with anthropogenic global warming. We have shown that GCMs robustly predict an increase in the length scale of eddies, and we have also explored the dynamical mechanisms whereby there might be a shift in the latitude of the jet stream associated with anthropogenic warming. Such shifts in the jet might cause large changes in regional climate, potentially larger than the globally-averaged signal itself. We have also shown that the tropopause robustly increases in height with global warming, and that the Hadley Cell expands, and that the expansion of the Hadley Cell is correlated with the polewards movement of the mid-latitude jet.« less

Canine model of nasal congestion and allergic rhinitis.

PubMed

Tiniakov, Ruslan L; Tiniakova, Olga P; McLeod, Robbie L; Hey, John A; Yeates, Donovan B

2003-05-01

The ragweed- and histamine-induced decreases in nasal patency in cohorts of ragweed-sensitized and nonsensitized dogs were assessed. The volume of nasal airways (V(NA)) was assessed by acoustic rhinometry and resistance to airflow (R(NA)) by anterior rhinomanometry. Histamine delivered to the nasal passages of five dogs caused a rapid and prolonged increase in R(NA) (0.75 +/- 0.26 to 3.56 +/- 0.50 cmH(2)O. l(-1). min), an effect that was reversed by intranasal delivery of aerosolized phenylephrine. Ragweed challenge in five ragweed-sensitized dogs increased R(NA) from 0.16 +/- 0.02 to 0.53 +/- 0.07 cmH(2)O. l(-1). min and decreased V(NA) from 12.5 +/- 1.9 to 3.9 +/- 0.3 cm(3), whereas administration of saline aerosol neither increased R(NA) nor decreased V(NA). Prior administration of d-pseudoephedrine (30 mg po) attenuated the ragweed-induced increase in R(NA) and decrease in V(NA). Ragweed challenge changed neither R(NA) nor V(NA) in four nonsensitized dogs. Mediator-induced nasal congestion and allergen-induced allergic rhinitis in ragweed-sensitized dogs, which exhibit symptoms similar to human disease, can be used in the evaluation of safety and efficacy of antiallergic activity of potential drugs.

Analysis of thermal performance of penetrated multi-layer insulation

NASA Technical Reports Server (NTRS)

Foster, Winfred A., Jr.; Jenkins, Rhonald M.; Yoo, Chai H.; Barrett, William E.

1988-01-01

Results of research performed for the purpose of studying the sensitivity of multi-layer insulation blanket performance caused by penetrations through the blanket are presented. The work described in this paper presents the experimental data obtained from thermal vacuum tests of various penetration geometries similar to those present on the Hubble Space Telescope. The data obtained from these tests is presented in terms of electrical power required sensitivity factors referenced to a multi-layer blanket without a penetration. The results of these experiments indicate that a significant increase in electrical power is required to overcome the radiation heat losses in the vicinity of the penetrations.

Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans.

PubMed

Gouspillou, Gilles; Sgarioto, Nicolas; Kapchinsky, Sophia; Purves-Smith, Fennigje; Norris, Brandon; Pion, Charlotte H; Barbat-Artigas, Sébastien; Lemieux, Francois; Taivassalo, Tanja; Morais, José A; Aubertin-Leheudre, Mylène; Hepple, Russell T

2014-04-01

Mitochondrial dysfunction is implicated in skeletal muscle atrophy and dysfunction with aging, with strong support for an increased mitochondrial-mediated apoptosis in sedentary rodent models. Whether this applies to aged human muscle is unknown, nor is it clear whether these changes are caused by sedentary behavior. Thus, we examined mitochondrial function [respiration, reactive oxygen species (ROS) emission, and calcium retention capacity (CRC)] in permeabilized myofibers obtained from vastus lateralis muscle biopsies of healthy physically active young (23.7±2.7 yr; mean±SD) and older (71.2±4.9 yr) men. Although mitochondrial ROS and maximal respiratory capacity were unaffected, the acceptor control ratio was reduced by 18% with aging, suggesting mild uncoupling of oxidative phosphorylation. CRC was reduced by 50% with aging, indicating sensitization of the mitochondrial permeability transition pore (mPTP) to apoptosis. Consistent with the mPTP sensitization, older muscles showed a 3-fold greater fraction of endonuclease G (a mitochondrial proapoptotic factor)-positive myonuclei. Aged muscles also had lower mitophagic potential, based on a 43% reduction in Parkin to the voltage-dependent anion channel (VDAC) protein ratio. Collectively, these results show that mitochondrial-mediated apoptotic signaling is increased in older human muscle and suggest that accumulation of dysfunctional mitochondria with exaggerated apoptotic sensitivity is due to impaired mitophagy.

Equine grass sickness, but not botulism, causes autonomic and enteric neurodegeneration and increases soluble N-ethylmaleimide-sensitive factor attachment receptor protein expression within neuronal perikarya.

PubMed

McGorum, B C; Scholes, S; Milne, E M; Eaton, S L; Wishart, T M; Poxton, I R; Moss, S; Wernery, U; Davey, T; Harris, J B; Pirie, R S

2016-11-01

Equine grass sickness (EGS) is of unknown aetiology. Despite some evidence suggesting that it represents a toxico-infection with Clostridium botulinum types C and/or D, the effect of EGS on the functional targets of botulinum neurotoxins, namely the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins, is unknown. Further, while it is commonly stated that, unlike EGS, equine botulism is not associated with autonomic and enteric neurodegeneration, this has not been definitively assessed. To determine: 1) whether botulism causes autonomic and enteric neurodegeneration; and 2) the effect of EGS on the expression of SNARE proteins within cranial cervical ganglion (CCG) and enteric neuronal perikarya. Descriptive study. Light microscopy was used to compare the morphology of neurons in haematoxylin-eosin stained sections of CCG and ileum from 6 EGS horses, 5 botulism horses and 6 control horses. Immunohistochemistry was used to compare the expression of synaptosomal-associated protein-25, synaptobrevin (Syb) and syntaxin within CCG neurons, and of Syb in enteric neurons, from horses with EGS, horses with botulism and control horses. The concentrations of these SNARE proteins in extracts of CCG from EGS and control horses were compared using quantitative fluorescent western blotting. EGS, but not botulism, was associated with autonomic and enteric neurodegeneration and with increased immunoreactivity for SNARE proteins within neuronal perikarya. Quantitative fluorescent western blotting confirmed increased concentrations of synaptosomal-associated protein-25, Syb and syntaxin within CCG extracts from EGS vs. control horses, with the increases in the latter 2 proteins being statistically significant. The occurrence of autonomic and enteric neurodegeneration, and increased expression of SNARE proteins within neuronal perikarya, in EGS but not botulism, suggests that EGS may not be caused by botulinum neurotoxins. Further investigation of the aetiology of EGS is therefore warranted. © 2015 EVJ Ltd.

Sensitization to Rubber Accelerators in Northeastern Italy: The Triveneto Patch Test Database.

PubMed

Buttazzo, Silvia; Prodi, Andrea; Fortina, Anna Belloni; Corradin, Maria Teresa; Larese Filon, Francesca

2016-01-01

Natural and synthetic rubbers containing rubber accelerators are well-known causes of occupational skin disease. Allergic contact dermatitis caused by rubber gloves is frequent and has almost exclusively been attributed to contact sensitization to accelerators. This study aimed to evaluate the frequency of rubber accelerators sensitization in the population living in northeastern Italy, to find time trend and a correlation with occupations, and to investigate co-sensitization between rubber accelerators. A population of 23,774 subjects was patch tested in 6 cities in northeastern Italy in the years 1996 to 2012 using carba mix 3%, thiuram mix 1%, benzothiazole (MBT) mix 1%, and isopropyl phenyl paraphenylamine diamine (IPPD) mix 0.6%. The overall frequency of carbamates, MBT, thiurams, and IPPD mix sensitization was 3.4%, 0.65%, 1.75%, and 0.83%, respectively. On a logistic regression analysis (control group: white-collar workers), we found a statistically significant association to carbamates (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.03-1.7) and thiurams (OR, 1.6; 95% CI, 1.1-2.3) for health care workers. Thiuram sensitivity was also significantly associated with dermatitis in maids and restaurant workers (OR, 2.2; 95% CI, 1.4-3.6), hairdressers (OR, 3.6; 95% CI, 1.8-7.1), shop assistants (OR, 2.9; 95% CI, 1.2-6.8), construction workers (OR, 2.7; 95% CI, 1.7-4.1), mechanics (OR, 2.1; 95% CI, 1.3-3.4), and professional drivers (OR, 2.6; 95% CI, 1.2-5.9). In conclusion, our results demonstrated that rubber accelerators have an important role in allergic contact dermatitis in the northeast of Italy and their sensitization is associated significantly with occupations that wear gloves or use chemical substances. Between rubber accelerators tested, carbamates sensitization is prevalent and increasing during considered years.

Bilirubin Increases Insulin Sensitivity in Leptin-Receptor Deficient and Diet-Induced Obese Mice Through Suppression of ER Stress and Chronic Inflammation

PubMed Central

Dong, Huansheng; Huang, Hu; Yun, Xinxu; Kim, Do-sung; Yue, Yinan; Wu, Hongju; Sutter, Alton; Chavin, Kenneth D.; Otterbein, Leo E.; Adams, David B.; Kim, Young-Bum

2014-01-01

Obesity-induced endoplasmic reticulum (ER) stress causes chronic inflammation in adipose tissue and steatosis in the liver, and eventually leads to insulin resistance and type 2 diabetes (T2D). The goal of this study was to understand the mechanisms by which administration of bilirubin, a powerful antioxidant, reduces hyperglycemia and ameliorates obesity in leptin-receptor-deficient (db/db) and diet-induced obese (DIO) mouse models. db/db or DIO mice were injected with bilirubin or vehicle ip. Blood glucose and body weight were measured. Activation of insulin-signaling pathways, expression of inflammatory cytokines, and ER stress markers were measured in skeletal muscle, adipose tissue, and liver of mice. Bilirubin administration significantly reduced hyperglycemia and increased insulin sensitivity in db/db mice. Bilirubin treatment increased protein kinase B (PKB/Akt) phosphorylation in skeletal muscle and suppressed expression of ER stress markers, including the 78-kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein, X box binding protein (XBP-1), and activating transcription factor 4 in db/db mice. In DIO mice, bilirubin treatment significantly reduced body weight and increased insulin sensitivity. Moreover, bilirubin suppressed macrophage infiltration and proinflammatory cytokine expression, including TNF-α, IL-1β, and monocyte chemoattractant protein-1, in adipose tissue. In liver and adipose tissue of DIO mice, bilirubin ameliorated hepatic steatosis and reduced expression of GRP78 and C/EBP homologous protein. These results demonstrate that bilirubin administration improves hyperglycemia and obesity by increasing insulin sensitivity in both genetically engineered and DIO mice models. Bilirubin or bilirubin-increasing drugs might be useful as an insulin sensitizer for the treatment of obesity-induced insulin resistance and type 2 diabetes based on its profound anti-ER stress and antiinflammatory properties. PMID:24424052

A two-fold increase of carbon cycle sensitivity to tropical temperature variations.

PubMed

Wang, Xuhui; Piao, Shilong; Ciais, Philippe; Friedlingstein, Pierre; Myneni, Ranga B; Cox, Peter; Heimann, Martin; Miller, John; Peng, Shushi; Wang, Tao; Yang, Hui; Chen, Anping

2014-02-13

Earth system models project that the tropical land carbon sink will decrease in size in response to an increase in warming and drought during this century, probably causing a positive climate feedback. But available data are too limited at present to test the predicted changes in the tropical carbon balance in response to climate change. Long-term atmospheric carbon dioxide data provide a global record that integrates the interannual variability of the global carbon balance. Multiple lines of evidence demonstrate that most of this variability originates in the terrestrial biosphere. In particular, the year-to-year variations in the atmospheric carbon dioxide growth rate (CGR) are thought to be the result of fluctuations in the carbon fluxes of tropical land areas. Recently, the response of CGR to tropical climate interannual variability was used to put a constraint on the sensitivity of tropical land carbon to climate change. Here we use the long-term CGR record from Mauna Loa and the South Pole to show that the sensitivity of CGR to tropical temperature interannual variability has increased by a factor of 1.9 ± 0.3 in the past five decades. We find that this sensitivity was greater when tropical land regions experienced drier conditions. This suggests that the sensitivity of CGR to interannual temperature variations is regulated by moisture conditions, even though the direct correlation between CGR and tropical precipitation is weak. We also find that present terrestrial carbon cycle models do not capture the observed enhancement in CGR sensitivity in the past five decades. More realistic model predictions of future carbon cycle and climate feedbacks require a better understanding of the processes driving the response of tropical ecosystems to drought and warming.

O(6)-methylguanine DNA-methyltransferase (MGMT) overexpression in melanoma cells induces resistance to nitrosoureas and temozolomide but sensitizes to mitomycin C.

PubMed

Passagne, Isabelle; Evrard, Alexandre; Depeille, Philippe; Cuq, Pierre; Cupissol, Didier; Vian, Laurence

2006-03-01

Alkylating agents play an important role in the chemotherapy of malignant melanomas. The activity of alkylating agents depends on their capacity to form alkyl adducts with DNA, in some cases causing cross-linking of DNA strands. However, the use of these agents is limited by cellular resistance induced by the DNA repair enzyme O(6)-methylguanine DNA-methyltransferase (MGMT) which removes alkyl groups from alkylated DNA strands. To determine to what extent the expression of MGMT in melanoma cells induces resistance to alkylating agents, the human cell line CAL77 Mer- (i.e., MGMT deficient) were transfected with pcMGMT vector containing human MGMT cDNA. Several clones expressing MGMT at a high level were selected to determine their sensitivity to chemotherapeutic drugs. Melanoma-transfected cells were found to be significantly less sensitive to nitrosoureas (carmustine, fotemustine, streptozotocin) and temozolomide with an increase of IC(50) values between 3 and 14 when compared to parent cells. No difference in cell survival rates between MGMT-proficient and -deficient cells was observed for melphalan, chlorambucil, busulphan, thiotepa and cisplatin which preferentially induce N(7) guanine lesions. Surprisingly, MGMT overexpression increased the sensitivity of CAL77 cells to mitomycin C by approximately 10-fold. Treatment of clonal cell lines with buthionine-[S,R]-sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase which depletes cellular glutathione, completely reversed this unexpected increase in sensitivity to mitomycin C. This observation suggests that glutathione is involved in the sensitivity of MGMT-transfected cells to mitomycin C and may act synergistically with MGMT via an unknown mechanism.

Assessing the mandatory bovine abortion notification system in France using unilist capture-recapture approach.

PubMed

Bronner, Anne; Hénaux, Viviane; Vergne, Timothée; Vinard, Jean-Luc; Morignat, Eric; Hendrikx, Pascal; Calavas, Didier; Gay, Emilie

2013-01-01

The mandatory bovine abortion notification system in France aims to detect as soon as possible any resurgence of bovine brucellosis. However, under-reporting seems to be a major limitation of this system. We used a unilist capture-recapture approach to assess the sensitivity, i.e. the proportion of farmers who reported at least one abortion among those who detected such events, and representativeness of the system during 2006-2011. We implemented a zero-inflated Poisson model to estimate the proportion of farmers who detected at least one abortion, and among them, the proportion of farmers not reporting. We also applied a hurdle model to evaluate the effect of factors influencing the notification process. We found that the overall surveillance sensitivity was about 34%, and was higher in beef than dairy cattle farms. The observed increase in the proportion of notifying farmers from 2007 to 2009 resulted from an increase in the surveillance sensitivity in 2007/2008 and an increase in the proportion of farmers who detected at least one abortion in 2008/2009. These patterns suggest a raise in farmers' awareness in 2007/2008 when the Bluetongue Virus (BTV) was detected in France, followed by an increase in the number of abortions in 2008/2009 as BTV spread across the country. Our study indicated a lack of sensitivity of the mandatory bovine abortion notification system, raising concerns about the ability to detect brucellosis outbreaks early. With the increasing need to survey the zoonotic Rift Valley Fever and Q fever diseases that may also cause bovine abortions, our approach is of primary interest for animal health stakeholders to develop information programs to increase abortion notifications. Our framework combining hurdle and ZIP models may also be applied to estimate the completeness of other clinical surveillance systems.

Assessing the Mandatory Bovine Abortion Notification System in France Using Unilist Capture-Recapture Approach

PubMed Central

Bronner, Anne; Hénaux, Viviane; Vergne, Timothée; Vinard, Jean-Luc; Morignat, Eric; Hendrikx, Pascal; Calavas, Didier; Gay, Emilie

2013-01-01

The mandatory bovine abortion notification system in France aims to detect as soon as possible any resurgence of bovine brucellosis. However, under-reporting seems to be a major limitation of this system. We used a unilist capture-recapture approach to assess the sensitivity, i.e. the proportion of farmers who reported at least one abortion among those who detected such events, and representativeness of the system during 2006–2011. We implemented a zero-inflated Poisson model to estimate the proportion of farmers who detected at least one abortion, and among them, the proportion of farmers not reporting. We also applied a hurdle model to evaluate the effect of factors influencing the notification process. We found that the overall surveillance sensitivity was about 34%, and was higher in beef than dairy cattle farms. The observed increase in the proportion of notifying farmers from 2007 to 2009 resulted from an increase in the surveillance sensitivity in 2007/2008 and an increase in the proportion of farmers who detected at least one abortion in 2008/2009. These patterns suggest a raise in farmers’ awareness in 2007/2008 when the Bluetongue Virus (BTV) was detected in France, followed by an increase in the number of abortions in 2008/2009 as BTV spread across the country. Our study indicated a lack of sensitivity of the mandatory bovine abortion notification system, raising concerns about the ability to detect brucellosis outbreaks early. With the increasing need to survey the zoonotic Rift Valley Fever and Q fever diseases that may also cause bovine abortions, our approach is of primary interest for animal health stakeholders to develop information programs to increase abortion notifications. Our framework combining hurdle and ZIP models may also be applied to estimate the completeness of other clinical surveillance systems. PMID:23691004

The resolution sensitivity of the South Asian monsoon and Indo-Pacific in a global 0.35° AGCM

NASA Astrophysics Data System (ADS)

Johnson, Stephanie J.; Levine, Richard C.; Turner, Andrew G.; Martin, Gill M.; Woolnough, Steven J.; Schiemann, Reinhard; Mizielinski, Matthew S.; Roberts, Malcolm J.; Vidale, Pier Luigi; Demory, Marie-Estelle; Strachan, Jane

2016-02-01

The South Asian monsoon is one of the most significant manifestations of the seasonal cycle. It directly impacts nearly one third of the world's population and also has substantial global influence. Using 27-year integrations of a high-resolution atmospheric general circulation model (Met Office Unified Model), we study changes in South Asian monsoon precipitation and circulation when horizontal resolution is increased from approximately 200-40 km at the equator (N96-N512, 1.9°-0.35°). The high resolution, integration length and ensemble size of the dataset make this the most extensive dataset used to evaluate the resolution sensitivity of the South Asian monsoon to date. We find a consistent pattern of JJAS precipitation and circulation changes as resolution increases, which include a slight increase in precipitation over peninsular India, changes in Indian and Indochinese orographic rain bands, increasing wind speeds in the Somali Jet, increasing precipitation over the Maritime Continent islands and decreasing precipitation over the northern Maritime Continent seas. To diagnose which resolution-related processes cause these changes, we compare them to published sensitivity experiments that change regional orography and coastlines. Our analysis indicates that improved resolution of the East African Highlands results in the improved representation of the Somali Jet and further suggests that improved resolution of orography over Indochina and the Maritime Continent results in more precipitation over the Maritime Continent islands at the expense of reduced precipitation further north. We also evaluate the resolution sensitivity of monsoon depressions and lows, which contribute more precipitation over northeast India at higher resolution. We conclude that while increasing resolution at these scales does not solve the many monsoon biases that exist in GCMs, it has a number of small, beneficial impacts.

Calcium sensitization in human esophageal muscle: role for RhoA kinase in maintenance of lower esophageal sphincter tone.

PubMed

Sims, Stephen M; Chrones, Tom; Preiksaitis, Harold G

2008-10-01

A rise in intracellular-free calcium ([Ca(2+)](i)) concentration is important for initiating contraction of smooth muscles, and Ca(2+) sensitization involving RhoA kinase can sustain tension. We previously found that [Ca(2+)](i) was comparable in cells from the esophageal body (EB) and lower esophageal sphincter (LES) muscles, despite the fact that the LES maintains resting tone. We hypothesized that Ca(2+) sensitization contributes to contraction in human esophageal muscle. Tension and [Ca(2+)](i) were measured simultaneously in intact human EB and LES muscles using the ratiometric Ca(2+)-sensitive dye fura-2. Spontaneous oscillations in EB muscle tension were associated with transient elevations of [Ca(2+)](i). Carbachol caused a large increase in tension, compared with spontaneous oscillations, although the rise of [Ca(2+)](i) was similar, suggesting Ca(2+) sensitization. The RhoA-kinase blockers (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632) and 1-(5-isoquinolinesulfonyl)-homopiperazine hydrochloride (HA-1077) reduced carbachol- and nerve-evoked contraction of the EB, accompanied by smaller reduction in the rise of [Ca(2+)](i). Protein kinase C inhibitors reduced force to a lesser extent. RhoA-kinase blockers caused concentration-dependent reduction of tension in spontaneously contracted LES muscles. Moreover, RhoA-kinase blockers reduced intrinsic nerve-evoked and carbachol-evoked contraction. However, there was no effect on nerve- or nitric oxide-mediated relaxation of LES. Ca(2+) sensitization mediated by the RhoA-kinase pathway has an important role in contraction of human EB muscles and LES tonic contraction, a feature not previously recognized.

Treatment of PCOS in adolescence.

PubMed

Warren-Ulanch, Julia; Arslanian, Silva

2006-06-01

Polycystic ovary syndrome (PCOS) is increasingly being recognized in adolescent girls seeking treatment for signs and symptoms of hyperandrogenism. It is difficult to diagnose PCOS in adolescents, therefore a high index of suspicion is necessary. Timely screening and treatment are crucial because another important component of the syndrome is insulin resistance/hyperinsulinemia increasing the risk for type 2 diabetes, dyslipidemia, and cardiovascular sequelae. Diagnosis of PCOS in adolescents should include a thorough family history, exclusion of other causes of hyperandrogenism, and appropriate laboratory evaluation. The scarcity of controlled clinical trials makes treatment controversial. Therapeutic options include lifestyle intervention, oral contraceptive pills, and insulin sensitizers. Long-term follow-up is needed to determine the effectiveness of these approaches in changing the natural history of the reproductive and metabolic outcomes without causing undue harm.

Genetic Ablation of the Aryl Hydrocarbon Receptor Causes Cigarette Smoke-induced Mitochondrial Dysfunction and Apoptosis*

PubMed Central

Rico de Souza, Angela; Zago, Michela; Pollock, Stephen J.; Sime, Patricia J.; Phipps, Richard P.; Baglole, Carolyn J.

2011-01-01

Cigarette smoke is the primary risk factor for chronic obstructive pulmonary disease (COPD). Alterations in the balance between apoptosis and proliferation are involved in the etiology of COPD. Fibroblasts and epithelial cells are sensitive to the oxidative properties of cigarette smoke, and whose loss may precipitate the development of COPD. Fibroblasts express the aryl hydrocarbon receptor (AhR), a transcription factor that attenuates pulmonary inflammation and may also regulate apoptosis. We hypothesized the AhR would prevent apoptosis caused by cigarette smoke. Using genetically deleted in vitro AhR expression models and an established method of cigarette smoke exposure, we report that AhR expression regulates fibroblasts proliferation and prevents morphological features of apoptosis, including membrane blebbing and chromatin condensation caused by cigarette smoke extract (CSE). Absence of AhR expression results in cleavage of PARP, lamin, and caspase-3. Mitochondrial dysfunction, including cytochrome c release, was associated with loss of AhR expression, indicating activation of the intrinsic apoptotic cascade. Heightened sensitivity of AhR-deficient fibroblasts was not the result of alterations in GSH, Nrf2, or HO-1 expression. Instead, AhR−/− cells had significantly less MnSOD and CuZn-SOD expression, enzymes that protects against oxidative stress. The ability of the AhR to suppress apoptosis was not restricted to fibroblasts, as siRNA-mediated knockdown of the AhR in lung epithelial cells also increased sensitivity to smoke-induced apoptosis. Collectively, these results suggest that cigarette smoke induced loss of lung structural support (i.e. fibroblasts, epithelial cells) caused by aberrations in AhR expression may explain why some smokers develop lung diseases such as COPD. PMID:21984831

Sensitivity of Climate to Changes in NDVI

NASA Technical Reports Server (NTRS)

Bounoua, L.; Collatz, G. J.; Los, S. O.; Sellers, P. J.; Dazlich, D. A.; Tucker, C. J.; Randall, D. A.

1999-01-01

The sensitivity of global and regional climate to changes in vegetation density is investigated using a coupled biosphere-atmosphere model. The magnitude of the vegetation changes and their spatial distribution are based on natural decadal variability of the normalized difference vegetation index (ndvi). Different scenarios using maximum and minimum vegetation cover were derived from satellite records spanning the period 1982-1990. Albedo decreased in the northern latitudes and increased in the tropics with increased ndvi. The increase in vegetation density revealed that the vegetation's physiological response was constrained by the limits of the available water resources. The difference between the maximum and minimum vegetation scenarios resulted in a 46% increase in absorbed visible solar radiation and a similar increase in gross photosynthetic C02 uptake on a global annual basis. This caused the canopy transpiration and interception fluxes to increase, and reduced those from the soil. The redistribution of the surface energy fluxes substantially reduced the Bowen ratio during the growing season, resulting in cooler and moister near-surface climate, except when soil moisture was limiting. Important effects of increased vegetation on climate are : (1) A cooling of about 1.8 K in the northern latitudes during the growing season and a slight warming during the winter, which is primarily due to the masking of high albedo of snow by a denser canopy. and (2) A year round cooling of 0.8 K in the tropics. These results suggest that increases in vegetation density could partially compensate for parallel increases in greenhouse warming . Increasing vegetation density globally caused both evapotranspiration and precipitation to increase. Evapotranspiration, however increased more than precipitation resulting in a global soil-water deficit of about 15 %. A spectral analysis on the simulated results showed that changes in the state of vegetation could affect the low-frequency modes of the precipitation distribution and might reduce its low frequency variability in the tropics while increasing it in northern latitudes.

Lack of desensitization of the cough reflex in ovalbumin-sensitized rabbits during exercise.

PubMed

Tiotiu, Angelica; Chenuel, Bruno; Foucaud, Laurent; Demoulin, Bruno; Demoulin-Alexikova, Silvia; Christov, Christo; Poussel, Mathias

2017-01-01

Cough is a major symptom of asthma frequently experienced during exercise but little is known about interactions between cough and exercise. The goal of our study was to clarify the potential modulation of the cough reflex (CR) by exercise in a spontaneously breathing anaesthetized animal model of airway eosinophilic inflammation. Ten ovalbumin (OVA) sensitized adult rabbits and 8 controls were studied. The ventilatory response to direct tracheal stimulation, performed both at rest and during exercise was determined to quantify the incidence and the sensitivity of the CR. Broncho-alveolar lavages (BAL) and cell counts were performed to assess the level of the airway inflammation following OVA-induced sensitization. Exercise was mimicked by Electrically induced hindlimb Muscular Contractions (EMC). Among 494 tracheal stimulations, 261 were performed at rest and 233 at exercise. OVA challenges in sensitized rabbits caused a significant increase in the percentage of eosinophils (p = 0.008) in BAL. EMC increased minute ventilation by 36% and 35% in OVA and control rabbits respectively, compared to rest values. The sensitivity of the CR decreased during exercise compared to baseline in control rabbits (p = 0.0313) while it remained unchanged in OVA rabbits. The desensitization of the CR during exercise in control rabbits was abolished in OVA rabbits. The precise role of airway inflammation in this lack of CR desensitization needs to be further investigated but it might contribute to the exercise-induced cough in asthmatics.

Hospitalizations for ambulatory care-sensitive conditions, Minas Gerais, Southeastern Brazil, 2000 and 2010

PubMed Central

Rodrigues-Bastos, Rita Maria; Campos, Estela Márcia Saraiva; Ribeiro, Luiz Cláudio; Bastos, Mauro Gomes; Bustamante-Teixeira, Maria Teresa

2014-01-01

OBJECTIVE To analyze hospitalization rates and the proportion of deaths due to ambulatory care-sensitive hospitalizations and to characterize them according to coverage by the Family Health Strategy, a primary health care guidance program. METHODS An ecological study comprising 853 municipalities in the state of Minas Gerais, under the purview of 28 regional health care units, was conducted. We used data from the Hospital Information System of the Brazilian Unified Health System. Ambulatory care-sensitive hospitalizations in 2000 and 2010 were compared. Population data were obtained from the demographic censuses. RESULTS The number of ambulatory care-sensitive hospitalizations declined from 20.75/1,000 inhabitants [standard deviation (SD) = 10.42) in 2000 to 14.92/thousand inhabitants (SD = 10.04) in 2010 Heart failure was the most frequent cause in both years. Hospitalizations rates for hypertension, asthma, and diabetes mellitus, decreased, whereas those for angina pectoris, prenatal and birth disorders, kidney and urinary tract infections, and other acute infections increased. Hospitalization durations and the proportion of deaths due to ambulatory care-sensitive hospitalizations increased significantly. CONCLUSIONS Mean hospitalization rates for sensitive conditions were significantly lower in 2010 than in 2000, but no correlation was found with regard to the expansion of the population coverage of the Family Health Strategy. Hospitalization rates and proportion of deaths were different between the various health care regions in the years evaluated, indicating a need to prioritize the primary health care with high efficiency and quality. PMID:26039399

Radiation damage and sensitization effects on thermoluminescence of LiF:Mg,Ti (TLD-700)

NASA Astrophysics Data System (ADS)

Farag, M. A.; Sadek, A. M.; Shousha, Hany. A.; El-Hagg, A. A.; Atta, M. R.; Kitis, G.

2017-09-01

The radiation damage effects and enhancement the thermoluminescence (TL) efficiency of LiF:Mg,Ti (TLD-700)dosimeters via sensitization method were discussed. Attempts to eliminate the effects of damage and sensitization were made using different types of annealing processes. The results showed that after irradiating the dosimeters with dose > 250 Gy of 60Co gamma source, damage effects were observed. The sensitivity of the total area under the curve was decreased by a factor of ∼0.5 after irradiation at a pre-test dose of 2 kGy. However, the effects of radiation damage on each glow-peak are different. The glow-peak 2 was the only peak that was not affected by the high-dose irradiation. It has been shown that the degree of the radiation damage effect is related to the maximum dose-response function, f(D)max of the glow-peak. In general, significant radiation damage effects were observed for the glow-peaks of high f(D)max . Post-irradiation anneal at 280 °C for 30 min causes dramatic effects on the shape of the glow-curve and as well as on the sensitivity of the dosimeters. An increasing by a factor of ∼35 in the sensitivity of the total area under the curve was observed at a pre-test dose of 2 kGy. Improving the sensitivity of peak 7 by a factor of∼22 was the dominant factor in increasing the sensitivity of the dosimeters. On the other hand, an increasing by factors of ∼2.5 and ∼4 was found for peaks 2 and 5 respectively. On the other hand, a decreasing by a factor ∼0.5 was observed for peaks 3 and 4. At pre-test dose levels >250 Gy, a very strange and high intensity tail was observed in the high-temperature region of the glow-curves. The readout anneal was not enough to remove this tail. While, the furnace anneal could eliminate the sensitization effects but not the radiation damage effects on the sensitivity of the dosimeters.

Viability, biofilm formation, and MazEF expression in drug-sensitive and drug-resistant Mycobacterium tuberculosis strains circulating in Xinjiang, China.

PubMed

Zhao, Ji-Li; Liu, Wei; Xie, Wan-Ying; Cao, Xu-Dong; Yuan, Li

2018-01-01

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is one of the most common chronic infectious amphixenotic diseases worldwide. Prevention and control of TB are greatly difficult, due to the increase in drug-resistant TB, particularly multidrug-resistant TB. We speculated that there were some differences between drug-sensitive and drug-resistant MTB strains and that mazEF 3,6,9 toxin-antitoxin systems (TASs) were involved in MTB viability. This study aimed to investigate differences in viability, biofilm formation, and MazEF expression between drug-sensitive and drug-resistant MTB strains circulating in Xinjiang, China, and whether mazEF 3,6,9 TASs contribute to MTB viability under stress conditions. Growth profiles and biofilm-formation abilities of drug-sensitive, drug-resistant MTB strains and the control strain H37Rv were monitored. Using molecular biology experiments, the mRNA expression of the mazF 3, 6, and 9 toxin genes, the mazE 3, 6, and 9 antitoxin genes, and expression of the MazF9 protein were detected in the different MTB strains, H37RvΔ mazEF 3,6,9 mutants from the H37Rv parent strain were generated, and mutant viability was tested. Ex vivo culture analyses demonstrated that drug-resistant MTB strains exhibit higher survival rates than drug-sensitive strains and the control strain H37Rv. However, there was no statistical difference in biofilm-formation ability in the drug-sensitive, drug-resistant, and H37Rv strains. mazE 3,6 mRNA-expression levels were relatively reduced in the drug-sensitive and drug-resistant strains compared to H37Rv. Conversely, mazE 3,9 expression was increased in drug-sensitive strains compared to drug-resistant strains. Furthermore, compared with the H37Rv strain, mazF 3,6 expression was increased in drug-resistant strains, mazF 9 expression was increased in drug-sensitive strains, and mazF 9 exhibited reduced expression in drug-resistant strains compared with drug-sensitive strains. Protein expression of mazF9 was increased in drug-sensitive and drug-resistant strains compared to H37Rv, while drug-resistant strains exhibited reduced mazF9 expression compared to drug-sensitive strains. Compared to H37Rv, H37RvΔ mazEF 3,6,9-deletion mutants grew more slowly under both stress conditions, and their ability to survive in host macrophages was also weaker. Furthermore, the host macrophage-apoptosis rate was higher after infection with any of the H37RvΔ mazE F3,6,9 mutants than with the H37Rv strain. The increased viability of MTB drug-resistant strains compared with drug-sensitive strains is likely to be related to differential MazEF mRNA and protein expression. mazEF 3,6,9 TASs contribute to MTB viability under stress conditions.

Analysis of cyanide in whole blood of dosed cathartids

USGS Publications Warehouse

Krynitsky, A.J.; Wiemeyer, Stanley N.; Hill, E.F.; Carpenter, J.W.

1986-01-01

A gas-liquid chromatographic method was modified to quantify both unmetabolized ('free') and metabolized ('bound', i.e., thiocyanates) cyanides. The methods for both are efficient and sensitive to 0.05 ppm. Repeated freezing and thawing of whole blood from treated cathartids caused an initial increase in free cyanide concentrations, followed by a gradual decline to a plateau. Bound cyanide concentrations declined after repeated freezing and thawing.

Clouds Versus Carbon: Predicting Vegetation Roughness by Maximizing Productivity

NASA Technical Reports Server (NTRS)

Olsen, Lola M.

2004-01-01

Surface roughness is one of the dominant vegetation properties that affects land surface exchange of energy, water, carbon, and momentum with the overlying atmosphere. We hypothesize that the canopy structure of terrestrial vegetation adapts optimally to climate by maximizing productivity, leading to an optimum surface roughness. An optimum should exist because increasing values of surface roughness cause increased surface exchange, leading to increased supply of carbon dioxide for photosynthesis. At the same time, increased roughness enhances evapotranspiration and cloud cover, thereby reducing the supply of photosynthetically active radiation. We demonstrate the optimum through sensitivity simulations using a coupled dynamic vegetation-climate model for present day conditions, in which we vary the value of surface roughness for vegetated surfaces. We find that the maximum in productivity occurs at a roughness length of 2 meters, a value commonly used to describe the roughness of today's forested surfaces. The sensitivity simulations also illustrate the strong climatic impacts of vegetation roughness on the energy and water balances over land: with increasing vegetation roughness, solar radiation is reduced by up to 20 W/sq m in the global land mean, causing shifts in the energy partitioning and leading to general cooling of the surface by 1.5 K. We conclude that the roughness of vegetated surfaces can be understood as a reflection of optimum adaptation, and it is associated with substantial changes in the surface energy and water balances over land. The role of the cloud feedback in shaping the optimum underlines the importance of an integrated perspective that views vegetation and its adaptive nature as an integrated component of the Earth system.

Developmental programming: insulin sensitizer treatment improves reproductive function in prenatal testosterone-treated female sheep.

PubMed

Veiga-Lopez, Almudena; Lee, James S; Padmanabhan, Vasantha

2010-08-01

Prenatal testosterone (T) excess causes reproductive and metabolic disruptions including insulin resistance, attributes of women with polycystic ovary syndrome. This study tested the hypothesis that insulin resistance contributes toward severity of reproductive disruptions in prenatally T-treated females. Pregnant sheep were injected im with 100 mg of T-propionate semiweekly from d 30-90 of gestation. Immediately after the first breeding season, a subset of controls and prenatal T-treated (TR) sheep were administered an insulin sensitizer (rosiglitazone; 8 mg/d) orally for 8 months. Untreated control and prenatal T-treated females (T group) were studied in parallel. Biochemical analyses revealed rosiglitazone to be safe for use in sheep. Glucose tolerance tests performed before and after the insulin sensitizer treatment found that insulin sensitizer decreased cumulative insulin, cumulative insulin/glucose ratio, and insulin area under the curve by about 50% and increased the insulin sensitivity index by about 70% in the TR compared with the T group. Twenty percent of TR females showed a reduced number of cycles in the second relative to first breeding season as opposed to 80% of T group females showing such deterioration. Insulin sensitizer treatment also decreased the number of aberrant cycles (>/=18 d) during the second breeding season in the TR group relative to the first as opposed to the T group females showing an increase in the second breeding season relative to the first. These findings provide evidence that insulin sensitizer treatment prevents further deterioration of the reproductive axis in prenatal T-treated sheep, a finding of translational relevance to women with polycystic ovary syndrome.

High-sensitivity pressure sensor based on fiber Mach-Zehnder interferometer

NASA Astrophysics Data System (ADS)

Wu, Yue; Xu, Yao; Yang, Yuguang; Jin, Wenxing; Jiang, Youchao; Shen, Ya; Jian, Shuisheng

2017-10-01

In this paper we propose and experimentally demonstrate an optical fiber structure sensor based on a Mach-Zehnder interferometer for pressure measurement. The fiber sensor is composed of a single-mode-no-core-single-mode structure, a section of capillary pure silica tube and refractive index matching fluid (RIMF). As the pressure decreases, the sealed air in the tube expands and the liquid level of the RIMF increases, which causes a wavelength shift of the interferometer. The measurement of the pressure variation can thus be achieved by monitoring the wavelength shift. The experimental results agree well with the numerical simulation, and a maximum pressure sensitivity of 266.6 nm Mpa-1 is achieved experimentally. Furthermore, the proposed fiber sensor has the potential to obtain higher sensitivity by enlarging the length of the air cavity.

Species-Specific Antimonial Sensitivity in Leishmania Is Driven by Post-Transcriptional Regulation of AQP1

PubMed Central

Mandal, Goutam; Mandal, Srotoswati; Sharma, Mansi; Charret, Karen Santos; Papadopoulou, Barbara; Bhattacharjee, Hiranmoy; Mukhopadhyay, Rita

2015-01-01

Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3’-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species. PMID:25714343

Ageing sensitized by iPLA2β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids.

PubMed

Jiao, Li; Gan-Schreier, Hongying; Zhu, Xingya; Wei, Wang; Tuma-Kellner, Sabine; Liebisch, Gerhard; Stremmel, Wolfgang; Chamulitrat, Walee

2017-12-01

Ageing is a major risk factor for various forms of liver and gastrointestinal (GI) disease and genetic background may contribute to the pathogenesis of these diseases. Group VIA phospholipase A2 or iPLA 2 β is a homeostatic PLA 2 by playing a role in phospholipid metabolism and remodeling. Global iPLA 2 β -/- mice exhibit aged-dependent phenotypes with body weight loss and abnormalities in the bone and brain. We have previously reported the abnormalities in these mutant mice showing susceptibility for chemical-induced liver injury and colitis. We hypothesize that iPLA 2 β deficiency may sensitize with ageing for an induction of GI injury. Male wild-type and iPLA 2 β -/- mice at 4 and 20-22months of age were studied. Aged, but not young, iPLA 2 β -/- mice showed increased hepatic fibrosis and biliary ductular expansion as well as severe intestinal atrophy associated with increased apoptosis, pro-inflammation, disrupted tight junction, and reduced number of mucin-containing globlet cells. This damage was associated with decreased expression of intestinal endoplasmic stress XBP1 and its regulator HNF1α, FATP4, ACSL5, bile-acid transport genes as well as nuclear receptors LXRα and FXR. By LC/MS-MS profiling, iPLA 2 β deficiency in aged mice caused an increase of intestinal arachidonate-containing phospholipids concomitant with a decrease in ceramides. By the suppression of intestinal FXR/FGF-15 signaling, hepatic bile-acid synthesis gene expression was increased leading to an elevation of secondary and hydrophobic bile acids in liver, bile, and intestine. In conclusions, ageing sensitized by iPLA 2 β deficiency caused a decline of key intestinal homeostatic genes resulting in the development of GI disease in a gut-to-liver manner. Copyright © 2017 Elsevier B.V. All rights reserved.

Stress Sensitivity Is Associated with Differential Accumulation of Reactive Oxygen and Nitrogen Species in Maize Genotypes with Contrasting Levels of Drought Tolerance

PubMed Central

Yang, Liming; Fountain, Jake C.; Wang, Hui; Ni, Xinzhi; Ji, Pingsheng; Lee, Robert D.; Kemerait, Robert C.; Scully, Brian T.; Guo, Baozhu

2015-01-01

Drought stress decreases crop growth, yield, and can further exacerbate pre-harvest aflatoxin contamination. Tolerance and adaptation to drought stress is an important trait of agricultural crops like maize. However, maize genotypes with contrasting drought tolerances have been shown to possess both common and genotype-specific adaptations to cope with drought stress. In this research, the physiological and metabolic response patterns in the leaves of maize seedlings subjected to drought stress were investigated using six maize genotypes including: A638, B73, Grace-E5, Lo964, Lo1016, and Va35. During drought treatments, drought-sensitive maize seedlings displayed more severe symptoms such as chlorosis and wilting, exhibited significant decreases in photosynthetic parameters, and accumulated significantly more reactive oxygen species (ROS) and reactive nitrogen species (RNS) than tolerant genotypes. Sensitive genotypes also showed rapid increases in enzyme activities involved in ROS and RNS metabolism. However, the measured antioxidant enzyme activities were higher in the tolerant genotypes than in the sensitive genotypes in which increased rapidly following drought stress. The results suggest that drought stress causes differential responses to oxidative and nitrosative stress in maize genotypes with tolerant genotypes with slower reaction and less ROS and RNS production than sensitive ones. These differential patterns may be utilized as potential biological markers for use in marker assisted breeding. PMID:26492235

A role for tyrosinase-related protein 1 in 4-tert-butylphenol-induced toxicity in melanocytes: Implications for vitiligo.

PubMed

Manga, Prashiela; Sheyn, David; Yang, Fan; Sarangarajan, Rangaprasad; Boissy, Raymond E

2006-11-01

Vitiligo presents with depigmented cutaneous lesions following localized melanocyte death. Multiple factors contribute to cell death, including genetically determined susceptibility to trauma, and environmental factors, such as exposure to 4-tert-butylphenol (4-TBP). We demonstrate that 4-TBP induces oxidative stress that is more readily overcome by melanocytes from normally pigmented individuals than from two individuals with vitiligo. The antioxidant catalase selectively and significantly reduced death of melanocytes derived from two individuals with vitiligo, indicating a role for oxidative stress in vitiligo pathogenesis. In normal melanocytes, oxidative stress results in reduced expression of microphthalmia-associated transcription factor (MITF). Melanocyte-stimulating hormone-induced expression of MITF protein caused increased sensitivity to 4-TBP, whereas sensitivity of melanomas correlated with MITF expression. MITF stimulates melanin synthesis by up-regulating expression of melanogenic enzymes such as tyrosinase-related protein-1 (Tyrp1). Although melanin content per se did not affect sensitivity to 4-TBP, expression of Tyrp1 significantly increased sensitivity. Melanocytes and melanomas that express functional Tyrp1 were significantly more sensitive to 4-TBP than Tyrp1-null cells. Thus, normal melanocytes respond to 4-TBP by reducing expression of MITF and Tyrp1. We hypothesize that melanocytes in vitiligo demonstrate reduced ability to withstand oxidative stress due, partly, to a disruption in MITF regulation of Tyrp1.

The Role of Aldosterone in Obesity-Related Hypertension

PubMed Central

Kawarazaki, Wakako

2016-01-01

Obese subjects often have hypertension and related cardiovascular and renal diseases, and this has become a serious worldwide health problem. In obese subjects, impaired renal-pressure natriuresis causes sodium retention, leading to the development of salt-sensitive hypertension. Physical compression of the kidneys by visceral fat and activation of the sympathetic nervous system, renin–angiotensin systems (RAS), and aldosterone/mineralocorticoid receptor (MR) system are involved in this mechanism. Obese subjects often exhibit hyperaldosteronism, with increased salt sensitivity of blood pressure (BP). Adipose tissue excretes aldosterone-releasing factors, thereby stimulating aldosterone secretion independently of the systemic RAS, and aldosterone/MR activation plays a key role in the development of hypertension and organ damage in obesity. In obese subjects, both salt sensitivity of BP, enhanced by obesity-related metabolic disorders including aldosterone excess, and increased dietary sodium intake are closely related to the incidence of hypertension. Some salt sensitivity-related gene variants affect the risk of obesity, and together with salt intake, its combination is possibly associated with the development of hypertension in obese subjects. With high salt levels common in modern diets, salt restriction and weight control are undoubtedly important. However, not only MR blockade but also new diagnostic modalities and therapies targeting and modifying genes that are related to salt sensitivity, obesity, or RAS regulation are expected to prevent obesity and obesity-related hypertension. PMID:26927805

Extreme sensitivity to ultraviolet light in the fungal pathogen causing white-nose syndrome of bats.

PubMed

Palmer, Jonathan M; Drees, Kevin P; Foster, Jeffrey T; Lindner, Daniel L

2018-01-02

Bat white-nose syndrome (WNS), caused by the fungal pathogen Pseudogymnoascus destructans, has decimated North American hibernating bats since its emergence in 2006. Here, we utilize comparative genomics to examine the evolutionary history of this pathogen in comparison to six closely related nonpathogenic species. P. destructans displays a large reduction in carbohydrate-utilizing enzymes (CAZymes) and in the predicted secretome (~50%), and an increase in lineage-specific genes. The pathogen has lost a key enzyme, UVE1, in the alternate excision repair (AER) pathway, which is known to contribute to repair of DNA lesions induced by ultraviolet (UV) light. Consistent with a nonfunctional AER pathway, P. destructans is extremely sensitive to UV light, as well as the DNA alkylating agent methyl methanesulfonate (MMS). The differential susceptibility of P. destructans to UV light in comparison to other hibernacula-inhabiting fungi represents a potential "Achilles' heel" of P. destructans that might be exploited for treatment of bats with WNS.

Weather sensitivity for zoo visitation in Toronto, Canada: a quantitative analysis of historical data.

PubMed

Hewer, Micah J; Gough, William A

2016-11-01

Based on a case study of the Toronto Zoo (Canada), multivariate regression analysis, involving both climatic and social variables, was employed to assess the relationship between daily weather and visitation. Zoo visitation was most sensitive to weather variability during the shoulder season, followed by the off-season and, then, the peak season. Temperature was the most influential weather variable in relation to zoo visitation, followed by precipitation and, then, wind speed. The intensity and direction of the social and climatic variables varied between seasons. Temperatures exceeding 26 °C during the shoulder season and 28 °C during the peak season suggested a behavioural threshold associated with zoo visitation, with conditions becoming too warm for certain segments of the zoo visitor market, causing visitor numbers to decline. Even light amounts of precipitation caused average visitor numbers to decline by nearly 50 %. Increasing wind speeds also demonstrated a negative influence on zoo visitation.

Increased thermal pain sensitivity in animals exposed to chronic high dose Vicodin but not pure hydrocodone.

PubMed

O'Connell, Thomas F; Carpenter, Patrick S; Caballero, Nadia; Putnam, Andrew J; Steere, Joshua T; Matz, Gregory J; Foecking, Eileen M

2014-01-01

Vicodin, the combination drug of acetaminophen and the opioid hydrocodone, is one of the most prescribed drugs on the market today. Opioids have demonstrated the ability to paradoxically cause increased pain sensitivity to users in a phenomena called opioid-induced hyperalgesia (OIH). While selected opioids have been shown to produce OIH symptoms in an animal model, hydrocodone and the combination drug Vicodin have yet to be studied. The purpose of this study was to explore the effect of exposure to chronic high dose Vicodin or its components on the sensitivity to both thermal and mechanical pain. Animals were randomly divided into 4 groups, Vicodin, acetaminophen, hydrocodone, or vehicle control, and administered the drug daily for 120 days. Rats were subsequently tested for thermal and mechanical sensitivity. The rats in the Vicodin group displayed a significant decrease in withdrawal time to thermal pain. The rats receiving acetaminophen, hydrocodone, and vehicle showed no statistically significant hypersensitivity in thermal testing. None of the groups demonstrated statistically significant hypersensitivity to mechanical testing. The data suggests Vicodin produces signs of OIH in a rodent model. However, increased pain sensitivity was only noted in the thermal pathway and the hypersensitivity was only seen with the opioid combination drug, not the opioid alone. The results of this study both support the results of previous rodent opioid studies while generating further questions about the specific properties of Vicodin that contribute to pain hypersensitivity. The growing use of Vicodin to treat chronic pain necessitates further research looking into this paradoxical pain response.

Extinction of Zika virus and Usutu virus by lethal mutagenesis reveals different patterns of sensitivity to three mutagenic drugs.

PubMed

Bassi, Maria Rosaria; Sempere, Raquel Navarro; Meyn, Prashansa; Polacek, Charlotta; Arias, Armando

2018-06-18

Flaviviruses constitute an increasing source of public health concern with growing numbers of pathogens causing disease, and a geographic spread to temperate climates. Despite a large body of evidence supporting mutagenesis as a conceivable antiviral strategy, there is currently no data on the sensitivity to increased mutagenesis for Zika virus (ZIKV) and Usutu virus (USUV), two emerging flaviviral threats. In this study, we demonstrate that both viruses are sensitive to three ribonucleosides that have shown mutagenic activity against other RNA viruses - favipiravir, ribavirin and 5-fluorouracil - while they remain unaffected by a mutagenic deoxyribonucleoside. Serial cell culture passages of ZIKV in the presence of these compounds resulted in the rapid extinction of infectivity, suggesting elevated sensitivity to mutagenesis. USUV extinction was achieved when a 10-fold dilution was applied between every passage, but not in experiments involving undiluted virus, indicating an overall lower susceptibility than ZIKV. Although both viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin) while USUV replication is suppressed more efficiently by 5-fluorouracil. These differences in sensitivity typically correlate with the increases in the mutation frequencies observed in each nucleoside treatment. These results are relevant to the development of efficient therapies based on lethal mutagenesis, and support the rational selection of different mutagenic nucleosides for each pathogen. We will discuss the implications of these results to the fidelity of flavivirus replication, and the design of antiviral therapies based on lethal mutagenesis. Copyright © 2018 Bassi et al.

Calcium homeostasis in the outer segments of retinal rods from the tiger salamander.

PubMed Central

Lagnado, L; Cervetto, L; McNaughton, P A

1992-01-01

1. The processes regulating intracellular calcium in the outer segments of salamander rods have been investigated. The main preparation used was the isolated rod loaded with the Ca(2+)-sensitive photoprotein aequorin, from which outer segment membrane current and free [Ca2+]i could be recorded simultaneously. Two other preparations were also used: outer segment membrane current was recorded from intact, isolated rods using a suction pipette, and from detached outer segments using a whole-cell pipette. 2. Measurements of free intracellular [Ca2+] in Ringer solution were obtained from two aequorin-loaded rods. Mean [Ca2+]i in darkness was 0.41 microM, and after a bright flash [Ca2+]i fell to below detectable levels ( < 0.3 microM). No release of intracellular Ca2+ by a bright flash of light could be detected ( < 0.2 microM). 3. Application of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) caused an increase in the size of the light-sensitive current and a rise in [Ca2+]i, but application of IBMX either when the light-sensitive channels had been closed by a bright light or in the absence of external Ca2+ caused no detectable rise in [Ca2+]i. It is concluded that IBMX increases [Ca2+]i by opening light-sensitive channels, and does not release Ca2+ from stores within the outer segment. 4. Removal of external Na+ caused a rise in [Ca2+]i to around 2 microM and completely suppressed the light-sensitive current. 5. The Na(+)-Ca2+, K+ exchange current in aequorin-loaded rods was activated in first-order manner by internal free calcium, with a mean Michaelis constant, KCa, of 1.6 microM. 6. The KCa of the Na(+)-Ca2+, K+ exchange was increased by elevating internal [Na+]. 7. The Michaelis relation between [Ca2+]i and the activity of the Na(+)-Ca2+, K+ exchange was used to calculate the change in [Ca2+]i occurring during the response to a bright light. In aequorin-loaded rods in Ringer solution the mean change in free [Ca2+]i after a bright flash was 0.34 microM. In these rods 10% of the dark current was carried by Ca2+. 8. Most of the calcium entering the outer segment was taken up rapidly and reversibly by buffer systems. The time constant of equilibration between free and rapidly bound Ca2+ was less than 20 ms. No slow component of calcium uptake was detected. 9. Two components of calcium buffering could be distinguished in the outer segments of aequorin-loaded rods.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1282928

Cutaneous exposure to clinically-relevant pigeon pea (Cajanus cajan) proteins promote TH2-dependent sensitization and IgE-mediated anaphylaxis in Balb/c mice.

PubMed

Kumar Gupta, Rinkesh; Kumar, Sandeep; Gupta, Kriti; Sharma, Akanksha; Roy, Ruchi; Kumar Verma, Alok; Chaudhari, Bhushan P; Das, Mukul; Ahmad Ansari, Irfan; Dwivedi, Premendra D

2016-11-01

Epicutaneous (EC) sensitization to food allergens may occur when the skin has been lightly damaged. The study here tested whether cutaneous exposure to pigeon pea protein(s) may cause allergic sensitization. BALB/c mice were either orally gavaged or epicutaneously sensitized by repeated application of pigeon pea crude protein extract (CPE) on undamaged areas of skin without any adjuvant; afterwards, both groups were orally challenged with the pigeon pea CPE. Anaphylactic symptoms along with measures of body temperature, MCPT-1, TSLP, pigeon pea-specific IgE and IgG 1 , myeloperoxidase (MPO) activity, T H 2 cytokines, T H 2 transcription factors (TFs) and filaggrin expression were determined. Mast cell staining, eosinophil levels and histopathological analysis of the skin and intestines were also performed. In the epicutaneously-sensitized mice, elevated levels of specific IgE and IgG 1 , as well as of MCPT-1, TSLP, T H 2 cytokines and TFs, higher anaphylactic scores and histological changes in the skin and intestine were indicative of sensitization ability via both routes in the pigeon pea CPE-treated hosts. Elevated levels of mast cells were observed in both the skin and intestine; increased levels of eosinophils and MPO activity were noted only in the skin. Decreased levels of filaggrin in skin may have played a key role in the skin barrier dysfunction, increasing the chances of sensitization. Therefore, the experimental data support the hypothesis that in addition to oral exposure, skin exposure to food allergens can promote T H 2-dependent sensitization, IgE-mediated anaphylaxis and intestinal changes after oral challenge. Based on this, an avoidance of cutaneous exposures to allergens might prevent development of food anaphylaxis.

Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors.

PubMed

Sutton, Gregory M; Trevaskis, James L; Hulver, Matthew W; McMillan, Ryan P; Markward, Nathan J; Babin, M Josephine; Meyer, Emily A; Butler, Andrew A

2006-05-01

Loss of brain melanocortin receptors (Mc3rKO and Mc4rKO) causes increased adiposity and exacerbates diet-induced obesity (DIO). Little is known about how Mc3r or Mc4r genotype, diet, and obesity affect insulin sensitivity. Insulin resistance, assessed by insulin and glucose tolerance tests, Ser(307) phosphorylation of insulin receptor substrate 1, and activation of protein kinase B, was examined in control and DIO wild-type (WT), Mc3rKO and Mc4rKO C57BL/6J mice. Mc4rKO mice were hyperphagic and had increased metabolic efficiency (weight gain per kilojoule consumed) relative to WT; both parameters increased further on high-fat diet. Obesity of Mc3rKO was more dependent on fat intake, involving increased metabolic efficiency. Fat mass of DIO Mc3rKO and Mc4rKO was similar, although Mc4rKO gained weight more rapidly. Mc4rKO develop hepatic insulin resistance and severe hepatic steatosis with obesity, independent of diet. DIO caused further deterioration of insulin action in Mc4rKO of either sex and, in male Mc3rKO, compared with controls, associated with increased fasting insulin, severe glucose intolerance, and reduced insulin signaling in muscle and adipose tissue. DIO female Mc3rKO exhibited very modest perturbations in glucose metabolism and insulin sensitivity. Consistent with previous data suggesting impaired fat oxidation, both Mc3rKO and Mc4rKO had reduced muscle oxidative metabolism, a risk factor for weight gain and insulin resistance. Energy expenditure was, however, increased in Mc4rKO compared with Mc3rKO and controls, perhaps due to hyperphagia and metabolic costs associated with rapid growth. In summary, DIO affects insulin sensitivity more severely in Mc4rKO compared with Mc3rKO, perhaps due to a more positive energy balance.

Of the milk sugars, galactose, but not prebiotic galacto-oligosaccharide, improves insulin sensitivity in male Sprague-Dawley rats.

PubMed

Stahel, Priska; Kim, Julie J; Xiao, Changting; Cant, John P

2017-01-01

Consumption of dairy products reduces risk of type 2 diabetes. Milk proteins and fats exhibit anti-diabetic properties but milk sugars have been studied little in this context. Galactose from milk lactose is readily converted to glycogen in the liver but its effects on insulin sensitivity have not been assessed. Prebiotic oligosaccharides from milk alter gut microbiota and can thereby influence host metabolism. Our objective was to assess the effect on insulin sensitivity of dietary galactose compared to glucose and fructose, and fermentable galacto-oligosaccharides compared to non-fermentable methylcellulose. Diets containing 15% of dry matter from glucose, fructose, galactose, galacto-oligosaccharides, or methylcellulose were fed to 36 rats per diet for 9 weeks. Hyperinsulinemic-euglycemic clamps with [3-3H]glucose infusion and a steady-state 2-[1-14C]deoxyglucose bolus injection were used to assess insulin sensitivity and glucose uptake indices. Tissue was collected in fed, fasted and fasted, insulin-stimulated states. Galactose increased glucose infusion rate during the clamp by 53% and decreased endogenous glucose production by 57% compared to glucose and fructose. Fed-state hepatic glycogen content was greater with galactose compared to glucose and fructose, consistent with a potentiation of the insulin effect on glycogen synthase by dephosphorylation. Galactose decreased the fecal Firmicutes:Bacteroidetes ratio while galacto-oligosaccharides increased abundance of fecal Bifidobacterium spp. 481-fold compared to methylcellulose, and also increased abundance of Lactobacillus spp. and Bacteroidetes. Galacto-oligosaccharides did not affect glucose infusion rate or endogenous glucose production during basal or clamp periods compared to methylcellulose. Galactose at 15% of daily intake improved hepatic insulin sensitivity in rats compared to glucose and fructose. Galactose caused an increase in fed-state hepatic glycogen content and a favourable shift in gut microbial populations. Intake of galacto-oligosaccharides improved the gut microbial profile but did not improve insulin sensitivity.

EWS-FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma.

PubMed

Gorthi, Aparna; Romero, July Carolina; Loranc, Eva; Cao, Lin; Lawrence, Liesl A; Goodale, Elicia; Iniguez, Amanda Balboni; Bernard, Xavier; Masamsetti, V Pragathi; Roston, Sydney; Lawlor, Elizabeth R; Toretsky, Jeffrey A; Stegmaier, Kimberly; Lessnick, Stephen L; Chen, Yidong; Bishop, Alexander J R

2018-03-15

Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress. In addition, homologous recombination is impaired in Ewing sarcoma owing to an enriched interaction between BRCA1 and the elongating transcription machinery. Finally, we uncover a role for EWSR1 in the transcriptional response to damage, suppressing R-loops and promoting homologous recombination. Our findings improve the current understanding of EWSR1 function, elucidate the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 inhibitors) and highlight a class of BRCA-deficient-like tumours.

Alcohols enhance caerulein-induced zymogen activation in pancreatic acinar cells

PubMed Central

LU, ZHAO; KARNE, SURESH; KOLODECIK, THOMAS; GORELICK, FRED S.

2010-01-01

Activation of zymogens within the pancreatic acinar cell is an early feature of acute pancreatitis. Supraphysiological concentrations of cholecystokinin (CCK) cause zymogen activation and pancreatitis. The effects of the CCK analog, caerulein, and alcohol on trypsin and chymotrypsin activation in isolated pancreatic acini were examined. Caerulein increased markers of zymogen activation in a time- and concentration-dependent manner. Notably, trypsin activity reached a peak value within 30 min, then diminished with time, whereas chymotrypsin activity increased with time. Ethanol (35 mM) sensitized the acinar cells to the effects of caerulein (10−10 to 10−7 M) on zymogen activation but had no effect alone. The effects of ethanol were concentration dependent. Alcohols with a chain length of ≥2 also sensitized the acinar cell to caerulein; the most potent was butanol. Branched alcohols (2-propanol and 2-butanol) were less potent than aliphatic alcohols (1-propanol and 1-butanol). The structure of an alcohol is related to its ability to sensitize acinar cells to the effects of caerulein on zymogen activation. PMID:11842000

Sensitivity of salad greens (Lactuca sativa L. and Eruca sativa Mill.) exposed to crude extracts of toxic and non-toxic cyanobacteria.

PubMed

Bittencourt-Oliveira, M C; Hereman, T C; Macedo-Silva, I; Cordeiro-Araújo, M K; Sasaki, F F C; Dias, C T S

2015-05-01

We evaluated the effect of crude extracts of the microcystin-producing (MC+) cyanobacteria Microcystis aeruginosa on seed germination and initial development of lettuce and arugula, at concentrations between 0.5 μg.L(-1) and 100 μg.L(-1) of MC-LR equivalent, and compared it to crude extracts of the same species without the toxin (MC-). Crude extracts of the cyanobacteria with MC (+) and without MC (-) caused different effects on seed germination and initial development of the salad green seedlings, lettuce being more sensitive to both extracts when compared to arugula. Crude extracts of M. aeruginosa (MC+) caused more evident effects on seed germination and initial development of both species of salad greens than MC-. Concentrations of 75 μg.L(-1) and 100 μg.L(-1) of MC-LR equivalent induced a greater occurrence of abnormal seedlings in lettuce, due to necrosis of the radicle and shortening of this organ in normal seedlings, as well as the reduction in total chlorophyll content and increase in the activity of the antioxidant enzyme peroxidase (POD). The MC- extract caused no harmful effects to seed germination and initial development of seedlings of arugula. However, in lettuce, it caused elevation of POD enzyme activity, decrease in seed germination at concentrations of 75 μg.L(-1) (MC-75) and 100 μg.L(-1) (MC-100), and shortening of the radicle length, suggesting that other compounds present in the cyanobacteria extracts contributed to this result. Crude extracts of M. aeruginosa (MC-) may contain other compounds, besides the cyanotoxins, capable of causing inhibitory or stimulatory effects on seed germination and initial development of salad green seedlings. Arugula was more sensitive to the crude extracts of M. aeruginosa (MC+) and (MC-) and to other possible compounds produced by the cyanobacteria.

The consequences of human actions on risks for infectious diseases: a review

PubMed Central

Lindahl, Johanna F.; Grace, Delia

2015-01-01

The human population is growing, requiring more space for food production, and needing more animals to feed it. Emerging infectious diseases are increasing, causing losses in both human and animal lives, as well as large costs to society. Many factors are contributing to disease emergence, including climate change, globalization and urbanization, and most of these factors are to some extent caused by humans. Pathogens may be more or less prone to emergence in themselves, and rapidly mutating viruses are more common among the emerging pathogens. The climate-sensitive vector-borne diseases are likely to be emerging due to climate changes and environmental changes, such as increased irrigation. This review lists the factors within pathogens that make them prone to emergence, and the modes of transmission that are affected. The anthropogenic changes contributing to disease emergence are described, as well as how they directly and indirectly cause either increased numbers of susceptible or exposed individuals, or cause increased infectivity. Many actions may have multiple direct or indirect effects, and it may be difficult to assess what the consequences may be. In addition, most anthropogenic drivers are related to desired activities, such as logging, irrigation, trade, and travelling, which the society is requiring. It is important to research more about the indirect and direct effects of the different actions to understand both the benefits and the risks. PMID:26615822

In vivo substitution of choline for sodium evokes a selective osmoinsensitive increase of extracellular taurine in the rat hippocampus.

PubMed

Lehmann, A; Sandberg, M

1990-01-01

Recent investigations have demonstrated that taurine and phosphoethanolamine (PEA) are the amino acids most sensitive to microdialysis-perfusion with reduced concentrations of NaCl. The aim of the present work was to assess the importance of Na+ deficiency in evoking this response. Further, the previously described selectivity of replacement of Cl- with acetate with respect to amino acid release was reinvestigated. The hippocampus of urethane-anesthetized rats was dialyzed with Krebs-Ringer bicarbonate buffer, and amino acid concentrations of the perfusate were determined. Choline chloride was then stepwise substituted for NaCl, and, in some cases, mannitol (122 mM) was included in low sodium-containing media. In other experiments, NaCl was replaced with sodium acetate. The dialysate levels of taurine increased selectively in response to Na+ substitution. The elevation of taurine was linearly related to the increase in choline chloride, and maximal levels amounted to 335% of basal levels. The increase in extracellular taurine was not inhibited by perfusion with medium made hyperosmotic with mannitol. Replacement of Cl- with acetate stimulated the release of taurine to 652% of resting levels. In addition, PEA levels increased to 250% of control concentration. Other amino acids were unaffected by Cl- substitution. The results show that taurine transport is considerably more sensitive to Na+ depletion than glutamate transport, which also is known to be Na+ dependent. The taurine increase evoked by low Na+ is not caused by cellular swelling as it was unaffected by hyperosmolar medium. Finally, substitution of acetate for Cl- causes a specific elevation of extracellular taurine and PEA, possibly as a result of cytotoxic edema.

Quantitative mass spectrometry methods for pharmaceutical analysis

PubMed Central

Loos, Glenn; Van Schepdael, Ann

2016-01-01

Quantitative pharmaceutical analysis is nowadays frequently executed using mass spectrometry. Electrospray ionization coupled to a (hybrid) triple quadrupole mass spectrometer is generally used in combination with solid-phase extraction and liquid chromatography. Furthermore, isotopically labelled standards are often used to correct for ion suppression. The challenges in producing sensitive but reliable quantitative data depend on the instrumentation, sample preparation and hyphenated techniques. In this contribution, different approaches to enhance the ionization efficiencies using modified source geometries and improved ion guidance are provided. Furthermore, possibilities to minimize, assess and correct for matrix interferences caused by co-eluting substances are described. With the focus on pharmaceuticals in the environment and bioanalysis, different separation techniques, trends in liquid chromatography and sample preparation methods to minimize matrix effects and increase sensitivity are discussed. Although highly sensitive methods are generally aimed for to provide automated multi-residue analysis, (less sensitive) miniaturized set-ups have a great potential due to their ability for in-field usage. This article is part of the themed issue ‘Quantitative mass spectrometry’. PMID:27644982

Performance analysis of higher mode spoof surface plasmon polariton for terahertz sensing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yao, Haizi; Tu, Wanli; Zhong, Shuncong, E-mail: zhongshuncong@hotmail.com

2015-04-07

We investigated the spoof surface plasmon polaritons (SSPPs) on 1D grooved metal surface for terahertz sensing of refractive index of the filling analyte through a prism-coupling attenuated total reflection setup. From the dispersion relation analysis and the finite element method-based simulation, we revealed that the dispersion curve of SSPP got suppressed as the filling refractive index increased, which cause the coupling resonance frequency redshifting in the reflection spectrum. The simulated results for testing various refractive indexes demonstrated that the incident angle of terahertz radiation has a great effect on the performance of sensing. Smaller incident angle will result in amore » higher sensitive sensing with a narrower detection range. In the meanwhile, the higher order mode SSPP-based sensing has a higher sensitivity with a narrower detection range. The maximum sensitivity is 2.57 THz/RIU for the second-order mode sensing at 45° internal incident angle. The proposed SSPP-based method has great potential for high sensitive terahertz sensing.« less

Hazards of geomagnetic storms

USGS Publications Warehouse

Herzog, D.C.

1992-01-01

Geomagnetic storms are large and sometimes rapid fluctuations in the Earth's magnetic field that are related to disturbances on the Sun's surface. Although it is not widely recognized, these transient magnetic disturbances can be a significant hazard to people and property. Many of us know that the intensity of the auroral lights increases during magnetic storms, but few people realize that these storms can also cause massive power outages, interrupt radio communications and satellite operations, increase corrosion in oil and gas pipelines, and lead to spuriously high rejection rates in the manufacture of sensitive electronic equipment. 

Restraint training for awake functional brain scanning of rodents can cause long-lasting changes in pain and stress responses

PubMed Central

Low, Lucie A.; Bauer, Lucy C.; Pitcher, Mark H.; Bushnell, M. Catherine

2016-01-01

Abstract With the increased interest in longitudinal brain imaging of awake rodents, it is important to understand both the short-term and long-term effects of restraint on sensory and emotional processing in the brain. To understand the effects of repeated restraint on pain behaviors and stress responses, we modeled a restraint protocol similar to those used to habituate rodents for magnetic resonance imaging scanning, and studied sensory sensitivity and stress hormone responses over 5 days. To uncover lasting effects of training, we also looked at responses to the formalin pain test 2 weeks later. We found that while restraint causes acute increases in the stress hormone corticosterone, it can also cause lasting reductions in nociceptive behavior in the formalin test, coupled with heightened corticosterone levels and increased activation of the “nociceptive” central nucleus of the amygdala, as seen by Fos protein expression. These results suggest that short-term repeated restraint, similar to that used to habituate rats for awake functional brain scanning, could potentially cause long-lasting changes in physiological and brain responses to pain stimuli that are stress-related, and therefore could potentially confound the functional activation patterns seen in awake rodents in response to pain stimuli. PMID:27058679

Restraint training for awake functional brain scanning of rodents can cause long-lasting changes in pain and stress responses.

PubMed

Low, Lucie A; Bauer, Lucy C; Pitcher, Mark H; Bushnell, M Catherine

2016-08-01

With the increased interest in longitudinal brain imaging of awake rodents, it is important to understand both the short-term and long-term effects of restraint on sensory and emotional processing in the brain. To understand the effects of repeated restraint on pain behaviors and stress responses, we modeled a restraint protocol similar to those used to habituate rodents for magnetic resonance imaging scanning, and studied sensory sensitivity and stress hormone responses over 5 days. To uncover lasting effects of training, we also looked at responses to the formalin pain test 2 weeks later. We found that while restraint causes acute increases in the stress hormone corticosterone, it can also cause lasting reductions in nociceptive behavior in the formalin test, coupled with heightened corticosterone levels and increased activation of the "nociceptive" central nucleus of the amygdala, as seen by Fos protein expression. These results suggest that short-term repeated restraint, similar to that used to habituate rats for awake functional brain scanning, could potentially cause long-lasting changes in physiological and brain responses to pain stimuli that are stress-related, and therefore could potentially confound the functional activation patterns seen in awake rodents in response to pain stimuli.

Allergic contact dermatitis in preservatives: current standing and future options.

PubMed

Deza, Gustavo; Giménez-Arnau, Ana M

2017-08-01

Preservatives are well known skin sensitizers and represent one of the main causes of contact allergy. The purpose of this article is to review the current state of contact sensitization induced by preservatives and point future alternatives for products' preservation. Isothiazolinones currently are the most common preservatives responsible of contact allergy in Europe and in the United States, and although some regulatory interventions have been taken place, the current contact allergy outbreak is not yet under control. Despite the ban of methyldibromo glutaronitrile from cosmetics in Europe, sensitized patients are still diagnosed, suggesting other nonregulated sources of exposure. Sensitization rates to formaldehyde and formaldehyde-releasers are lower in Europe in comparison with the United States due to stricter regulations regarding their use. Prevalence of contact allergy to parabens has remained stable over the last decades, whereas iodopropynyl butylcarbamate is an emerging allergen with an increasing prevalence. Future alternatives for products' preservation look for a broad antimicrobial spectrum, but with a better safety profile (in terms of sensitization) than the currently available compounds. Given the high rates of sensitization reported over the last years, timely regulatory actions are urgently required for some preservatives that currently represent a concern for public health.

Cell Electrosensitization Exists Only in Certain Electroporation Buffers.

PubMed

Dermol, Janja; Pakhomova, Olga N; Pakhomov, Andrei G; Miklavčič, Damijan

2016-01-01

Electroporation-induced cell sensitization was described as the occurrence of a delayed hypersensitivity to electric pulses caused by pretreating cells with electric pulses. It was achieved by increasing the duration of the electroporation treatment at the same cumulative energy input. It could be exploited in electroporation-based treatments such as electrochemotherapy and tissue ablation with irreversible electroporation. The mechanisms responsible for cell sensitization, however, have not yet been identified. We investigated cell sensitization dynamics in five different electroporation buffers. We split a pulse train into two trains varying the delay between them and measured the propidium uptake by fluorescence microscopy. By fitting the first-order model to the experimental results, we determined the uptake due to each train (i.e. the first and the second) and the corresponding resealing constant. Cell sensitization was observed in the growth medium but not in other tested buffers. The effect of pulse repetition frequency, cell size change, cytoskeleton disruption and calcium influx do not adequately explain cell sensitization. Based on our results, we can conclude that cell sensitization is a sum of several processes and is buffer dependent. Further research is needed to determine its generality and to identify underlying mechanisms.

Cell Electrosensitization Exists Only in Certain Electroporation Buffers

PubMed Central

Dermol, Janja; Pakhomova, Olga N.; Pakhomov, Andrei G.; Miklavčič, Damijan

2016-01-01

Electroporation-induced cell sensitization was described as the occurrence of a delayed hypersensitivity to electric pulses caused by pretreating cells with electric pulses. It was achieved by increasing the duration of the electroporation treatment at the same cumulative energy input. It could be exploited in electroporation-based treatments such as electrochemotherapy and tissue ablation with irreversible electroporation. The mechanisms responsible for cell sensitization, however, have not yet been identified. We investigated cell sensitization dynamics in five different electroporation buffers. We split a pulse train into two trains varying the delay between them and measured the propidium uptake by fluorescence microscopy. By fitting the first-order model to the experimental results, we determined the uptake due to each train (i.e. the first and the second) and the corresponding resealing constant. Cell sensitization was observed in the growth medium but not in other tested buffers. The effect of pulse repetition frequency, cell size change, cytoskeleton disruption and calcium influx do not adequately explain cell sensitization. Based on our results, we can conclude that cell sensitization is a sum of several processes and is buffer dependent. Further research is needed to determine its generality and to identify underlying mechanisms. PMID:27454174

Machine learning for classifying tuberculosis drug-resistance from DNA sequencing data

PubMed Central

Yang, Yang; Niehaus, Katherine E; Walker, Timothy M; Iqbal, Zamin; Walker, A Sarah; Wilson, Daniel J; Peto, Tim E A; Crook, Derrick W; Smith, E Grace; Zhu, Tingting; Clifton, David A

2018-01-01

Abstract Motivation Correct and rapid determination of Mycobacterium tuberculosis (MTB) resistance against available tuberculosis (TB) drugs is essential for the control and management of TB. Conventional molecular diagnostic test assumes that the presence of any well-studied single nucleotide polymorphisms is sufficient to cause resistance, which yields low sensitivity for resistance classification. Summary Given the availability of DNA sequencing data from MTB, we developed machine learning models for a cohort of 1839 UK bacterial isolates to classify MTB resistance against eight anti-TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, ciprofloxacin, moxifloxacin, ofloxacin, streptomycin) and to classify multi-drug resistance. Results Compared to previous rules-based approach, the sensitivities from the best-performing models increased by 2-4% for isoniazid, rifampicin and ethambutol to 97% (P < 0.01), respectively; for ciprofloxacin and multi-drug resistant TB, they increased to 96%. For moxifloxacin and ofloxacin, sensitivities increased by 12 and 15% from 83 and 81% based on existing known resistance alleles to 95% and 96% (P < 0.01), respectively. Particularly, our models improved sensitivities compared to the previous rules-based approach by 15 and 24% to 84 and 87% for pyrazinamide and streptomycin (P < 0.01), respectively. The best-performing models increase the area-under-the-ROC curve by 10% for pyrazinamide and streptomycin (P < 0.01), and 4–8% for other drugs (P < 0.01). Availability and implementation The details of source code are provided at http://www.robots.ox.ac.uk/~davidc/code.php. Contact david.clifton@eng.ox.ac.uk Supplementary information Supplementary data are available at Bioinformatics online. PMID:29240876

Sensitivity of nocturnal boundary layer temperature to tropospheric aerosol surface radiative forcing under clear-sky conditions

NASA Astrophysics Data System (ADS)

Nair, Udaysankar S.; McNider, Richard; Patadia, Falguni; Christopher, Sundar A.; Fuller, Kirk

2011-01-01

Since the middle of the last century, global surface air temperature exhibits an increasing trend, with nocturnal temperatures increasing at a much higher rate. Proposed causative mechanisms include the radiative impact of atmospheric aerosols on the nocturnal boundary layer (NBL) where the temperature response is amplified due to shallow depth and its sensitivity to potential destabilization. A 1-D version of the Regional Atmospheric Modeling System is used to examine the sensitivity of the nocturnal boundary layer temperature to the surface longwave radiative forcing (SLWRF) from urban aerosol loading and doubled atmospheric carbon dioxide concentrations. The analysis is conducted for typical midlatitude nocturnal boundary layer case days from the CASES-99 field experiment and is further extended to urban sites in Pune and New Delhi, India. For the cases studied, locally, the nocturnal SLWRF from urban atmospheric aerosols (2.7-47 W m-2) is comparable or exceeds that caused by doubled atmospheric carbon dioxide (3 W m-2), with the surface temperature response ranging from a compensation for daytime cooling to an increase in the nocturnal minimum temperature. The sensitivity of the NBL to radiative forcing is approximately 4 times higher compared to the daytime boundary layer. Nighttime warming or cooling may occur depending on the nature of diurnal variations in aerosol optical depth. Soil moisture also modulates the magnitude of SLWRF, decreasing from 3 to 1 W m-2 when soil saturation increases from 37% to 70%. These results show the importance of aerosols on the radiative balance of the climate system.

Baroreflex sensitivity in acute hypoxia and carbohydrate loading.

PubMed

Klemenc, Matjaž; Golja, Petra

2011-10-01

Hypoxia decreases baroreflex sensitivity (BRS) and can be a sufficient cause for syncope in healthy individuals. Carbohydrate loading enhances efferent sympathetic activity, which affects cardiac contractility, heart rate and vascular resistance, the main determinants of blood pressure. Thus, in both normoxia and hypoxia, carbohydrate loading may be more than simply metabolically beneficial, as it may affect blood pressure regulation. We hypothesised that carbohydrate loading will, in both normoxia and hypoxia, alter the regulation of blood pressure, as reflected in a change in baroreflex sensitivity. Fourteen subjects participated in two experiments, composed of a 15-min normoxic period, after which the subjects ingested water or an equal amount of water with carbohydrates. A 30-min rest period was then followed by a 10-min second normoxic and a 30-min hypoxic period. Blood pressure and heart rate were monitored continuously during the experiment to determine BRS. Despite an increased sympathetic activation, reflected in increased heart rate (P < 0.001) BRS was lower (P < 0.01) after carbohydrate loading, as compared to the water experiment, in both normoxic [23.7 (12.4) versus 28.8 (13.8) ms/mmHg] and hypoxic [16.8 (11.0) versus 24.3 (12.3) ms/mmHg] phases of the present study. As BRS was decreased in acute hypoxic exposure, the results confirm that hypoxia interferes with blood pressure regulation. However, although oral carbohydrate loading induced sympathoexcitation, it did not improve blood pressure regulation in hypoxia, as evident from the BRS data. Baroreflex effects of other forms of carbohydrate loading, not causing postprandial blood shifts to digestive system, should therefore be investigated.

Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma.

PubMed

Crommentuijn, Matheus H W; Maguire, Casey A; Niers, Johanna M; Vandertop, W Peter; Badr, Christian E; Würdinger, Thomas; Tannous, Bakhos A

2016-04-01

Glioblastoma (GBM) is the most common malignant brain tumor in adults. We designed an adeno-associated virus (AAV) vector for intracranial delivery of secreted, soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) to GBM tumors in mice and combined it with the TRAIL-sensitizing cardiac glycoside, lanatoside C (lan C). We applied this combined therapy to two different GBM models using human U87 glioma cells and primary patient-derived GBM neural spheres in culture and in orthotopic GBM xenograft models in mice. In U87 cells, conditioned medium from AAV2-sTRAIL expressing cells combined with lan C induced 80% cell death. Similarly, lan C sensitized primary GBM spheres to sTRAIL causing over 90% cell death. In mice bearing intracranial U87 tumors treated with AAVrh.8-sTRAIL, administration of lan C caused a decrease in tumor-associated Fluc signal, while tumor size increased within days of stopping the treatment. Another round of lan C treatment re-sensitized GBM tumor to sTRAIL-induced cell death. AAVrh.8-sTRAIL treatment alone and combined with lanatoside C resulted in a significant decrease in tumor growth and longer survival of mice bearing orthotopic invasive GBM brain tumors. In summary, AAV-sTRAIL combined with lanatoside C induced cell death in U87 glioma cells and patient-derived GBM neural spheres in culture and in vivo leading to an increased in overall mice survival. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR.

PubMed

Veiga, Sonia Rosa; Ge, Xuemei; Mercer, Carol A; Hernández-Alvarez, María Isabel; Thomas, Hala Elnakat; Hernández-Losa, Javier; Ramón Y Cajal, Santiago; Zorzano, Antonio; Thomas, George; Kozma, Sara C

2018-04-24

Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mammalian target of rapamycin (mTOR) for the treatment of HCC. However, such inhibitors induce glycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor Phenformin could reverse both side effects, impose an energetic-stress on cancer cells and suppress the growth of HCC. Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and Phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated pre-clinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival. We found Phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with Phenformin, was highly efficacious in controlling tumor burden. However, more striking, pretreatment with Phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival. Treatment of HCC cells in vitro with the biguanide Phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC. Copyright ©2018, American Association for Cancer Research.

Central sensitization as the mechanism underlying pain in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

PubMed

Di Stefano, G; Celletti, C; Baron, R; Castori, M; Di Franco, M; La Cesa, S; Leone, C; Pepe, A; Cruccu, G; Truini, A; Camerota, F

2016-09-01

Patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT) commonly suffer from pain. How this hereditary connective tissue disorder causes pain remains unclear although previous studies suggested it shares similar mechanisms with neuropathic pain and fibromyalgia. In this prospective study seeking information on the mechanisms underlying pain in patients with JHS/EDS-HT, we enrolled 27 consecutive patients with this connective tissue disorder. Patients underwent a detailed clinical examination, including the neuropathic pain questionnaire DN4 and the fibromyalgia rapid screening tool. As quantitative sensory testing methods, we included thermal-pain perceptive thresholds and the wind-up ratio and recorded a standard nerve conduction study to assess non-nociceptive fibres and laser-evoked potentials, assessing nociceptive fibres. Clinical examination and diagnostic tests disclosed no somatosensory nervous system damage. Conversely, most patients suffered from widespread pain, the fibromyalgia rapid screening tool elicited positive findings, and quantitative sensory testing showed lowered cold and heat pain thresholds and an increased wind-up ratio. While the lack of somatosensory nervous system damage is incompatible with neuropathic pain as the mechanism underlying pain in JHS/EDS-HT, the lowered cold and heat pain thresholds and increased wind-up ratio imply that pain in JHS/EDS-HT might arise through central sensitization. Hence, this connective tissue disorder and fibromyalgia share similar pain mechanisms. WHAT DOES THIS STUDY ADD?: In patients with JHS/EDS-HT, the persistent nociceptive input due to joint abnormalities probably triggers central sensitization in the dorsal horn neurons and causes widespread pain. © 2016 European Pain Federation - EFIC®

Voltage dependent potassium channel remodeling in murine intestinal smooth muscle hypertrophy induced by partial obstruction.

PubMed

Liu, Dong-Hai; Huang, Xu; Guo, Xin; Meng, Xiang-Min; Wu, Yi-Song; Lu, Hong-Li; Zhang, Chun-Mei; Kim, Young-chul; Xu, Wen-Xie

2014-01-01

Partial obstruction of the small intestine causes obvious hypertrophy of smooth muscle cells and motility disorder in the bowel proximate to the obstruction. To identify electric remodeling of hypertrophic smooth muscles in partially obstructed murine small intestine, the patch-clamp and intracellular microelectrode recording methods were used to identify the possible electric remodeling and Western blot, immunofluorescence and immunoprecipitation were utilized to examine the channel protein expression and phosphorylation level changes in this research. After 14 days of obstruction, partial obstruction caused obvious smooth muscle hypertrophy in the proximally located intestine. The slow waves of intestinal smooth muscles in the dilated region were significantly suppressed, their amplitude and frequency were reduced, whilst the resting membrane potentials were depolarized compared with normal and sham animals. The current density of voltage dependent potassium channel (KV) was significantly decreased in the hypertrophic smooth muscle cells and the voltage sensitivity of KV activation was altered. The sensitivity of KV currents (IKV) to TEA, a nonselective potassium channel blocker, increased significantly, but the sensitivity of IKv to 4-AP, a KV blocker, stays the same. The protein levels of KV4.3 and KV2.2 were up-regulated in the hypertrophic smooth muscle cell membrane. The serine and threonine phosphorylation levels of KV4.3 and KV2.2 were significantly increased in the hypertrophic smooth muscle cells. Thus this study represents the first identification of KV channel remodeling in murine small intestinal smooth muscle hypertrophy induced by partial obstruction. The enhanced phosphorylations of KV4.3 and KV2.2 may be involved in this process.

Snowmelt response to simulated warming across a large elevation gradient, southern Sierra Nevada, California

NASA Astrophysics Data System (ADS)

Musselman, Keith N.; Molotch, Noah P.; Margulis, Steven A.

2017-12-01

In a warmer climate, the fraction of annual meltwater produced at high melt rates in mountainous areas is projected to decline due to a contraction of the snow-cover season, causing melt to occur earlier and under lower energy conditions. How snowmelt rates, including extreme events relevant to flood risk, may respond to a range of warming over a mountain front is poorly known. We present a model sensitivity study of snowmelt response to warming across a 3600 m elevation gradient in the southern Sierra Nevada, USA. A snow model was run for three distinct years and verified against extensive ground observations. To simulate the impact of climate warming on meltwater production, measured meteorological conditions were modified by +1 to +6 °C. The total annual snow water volume exhibited linear reductions (-10 % °C-1) consistent with previous studies. However, the sensitivity of snowmelt rates to successive degrees of warming varied nonlinearly with elevation. Middle elevations and years with more snowfall were prone to the largest reductions in snowmelt rates, with lesser changes simulated at higher elevations. Importantly, simulated warming causes extreme daily snowmelt (99th percentiles) to increase in spatial extent and intensity, and shift from spring to winter. The results offer insight into the sensitivity of mountain snow water resources and how the rate and timing of water availability may change in a warmer climate. The identification of future climate conditions that may increase extreme melt events is needed to address the climate resilience of regional flood control systems.

Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes

PubMed Central

Mathison, Angela; Escande, Carlos; Calvo, Ezequiel; Seo, Seungmae; White, Thomas; Salmonson, Ann; Faubion, William A.; Buttar, Navtej; Iovanna, Juan; Lomberk, Gwen; Chini, Eduardo N.

2015-01-01

We have previously shown that amino acid changes in the human Kruppel-Like Factor (KLF) 11 protein is associated with the development of maturity onset diabetes of the young VII, whereas complete inactivation of this pathway by the −331 human insulin mutation causes neonatal diabetes mellitus. Here, we report that Klf11−/− mice have decreased circulating insulin levels, alterations in the control of blood glucose and body weight, as well as serum dyslipidemia, but do not develop diabetes. Functional assays using ex vivo liver tissue sections demonstrate that Klf11−/− mice display increased insulin sensitivity. Genome-wide experiments validated by pathway-specific quantitative PCR arrays reveal that the Klf11−/− phenotype associates to alterations in the regulation of gene networks involved in lipid metabolism, in particular those regulated by peroxisome proliferator-activated receptor-γ. Combined, these results demonstrate that the major phenotype given by the whole-body deletion of Klf11 in mouse is not diabetes but increased insulin sensitivity, likely due to altered transcriptional regulation in target tissues. The absence of diabetes in the Klf11−/− mouse either indicates an interspecies difference for the role of this transcription factor in metabolic homeostasis between mouse and humans, or potentially highlights the fact that other molecular factors can compensate for its absence. Nevertheless, the data of this study, gathered at the whole-organism level, further support a role for KLF11 in metabolic processes like insulin sensitivity, which regulation is critical in several forms of diabetes. PMID:26248217

Ventilatory responses to hypercapnia and hypoxia after 6 h passive hyperventilation in humans

PubMed Central

Ren, Xiaohui; Robbins, Peter A

1999-01-01

Acute exposure to hypoxia stimulates ventilation and induces hypocapnia. Long-term exposure to hypoxia generates changes in respiratory control known as ventilatory acclimatization to hypoxia. The object of this study was to investigate the degree to which the hyperventilation and hypocapnia can induce the changes known as ventilatory acclimatization to hypoxia, in the absence of the primary hypoxic stimulus itself.Three 6 h protocols were each performed on twelve healthy volunteers: (1) passive hypocapnic hyperventilation, with end-tidal CO2 pressure (PET,CO2) held 10 Torr below the eupnoeic value; (2) passive eucapnic hyperventilation, with PET,CO2 maintained eucapnic; (3) control.Ventilatory responses to acute hypercapnia and hypoxia were assessed before and half an hour after each protocol.The presence of prior hypocapnia, but not prior hyperventilation, caused a reduction in air-breathing PET,CO2 (P < 0·05, ANOVA), and a leftwards shift of the ventilatory response to hypercapnia (P < 0·05). The presence of prior hyperventilation, but not prior hypocapnia, caused an increase in the ventilatory sensitivity to CO2 (P < 0·05). No significant effects of any protocol were detected on the ventilatory sensitivity to hypoxia.We conclude that following 6 h of passive hyperventilation: (i) the left shift of the VE-PET,CO2 relationship is due to alkalosis and not to hyperventilation; (ii) the increase in slope of the VE-PET,CO2 relationship is due to the hyperventilation and not the alkalosis; and (iii) ventilatory sensitivity to hypoxia is unaltered. PMID:9882758

Unique Behavioral and Neurochemical Effects Induced by Repeated Adolescent Consumption of Caffeine-Mixed Alcohol in C57BL/6 Mice

PubMed Central

Robins, Meridith T.; Lu, Julie

2016-01-01

The number of highly caffeinated products has increased dramatically in the past few years. Among these products, highly caffeinated energy drinks are the most heavily advertised and purchased, which has resulted in increased incidences of co-consumption of energy drinks with alcohol. Despite the growing number of adolescents and young adults reporting caffeine-mixed alcohol use, knowledge of the potential consequences associated with co-consumption has been limited to survey-based results and in-laboratory human behavioral testing. Here, we investigate the effect of repeated adolescent (post-natal days P35-61) exposure to caffeine-mixed alcohol in C57BL/6 mice on common drug-related behaviors such as locomotor sensitivity, drug reward and cross-sensitivity, and natural reward. To determine changes in neurological activity resulting from adolescent exposure, we monitored changes in expression of the transcription factor ΔFosB in the dopaminergic reward pathway as a sign of long-term increases in neuronal activity. Repeated adolescent exposure to caffeine-mixed alcohol exposure induced significant locomotor sensitization, desensitized cocaine conditioned place preference, decreased cocaine locomotor cross-sensitivity, and increased natural reward consumption. We also observed increased accumulation of ΔFosB in the nucleus accumbens following repeated adolescent caffeine-mixed alcohol exposure compared to alcohol or caffeine alone. Using our exposure model, we found that repeated exposure to caffeine-mixed alcohol during adolescence causes unique behavioral and neurochemical effects not observed in mice exposed to caffeine or alcohol alone. Based on similar findings for different substances of abuse, it is possible that repeated exposure to caffeine-mixed alcohol during adolescence could potentially alter or escalate future substance abuse as means to compensate for these behavioral and neurochemical alterations. PMID:27380261

Antacids and dietary supplements with an influence on the gastric pH increase the risk for food sensitization

PubMed Central

Pali-Schöll, I.; Herzog, R.; Wallmann, J.; Szalai, K.; Brunner, R.; Lukschal, A.; Karagiannis, P.; Diesner, S. C.; Jensen-Jarolim, E.

2010-01-01

Summary Background Elevation of the gastric pH increases the risk for sensitization against food allergens by hindering protein breakdown. This can be caused by acid-suppressing medication like sucralphate, H2-receptor blockers and proton pump inhibitors, as shown in recent murine experimental and human observational studies. Objective The aim of the present study was to assess the sensitization capacity of the dietary supplement base powder and of over-the-counter antacids. Methods Changes of the pH as well as of protein digestion due to base powder or antacids were measured in vitro. To examine the in vivo influence, BALB/c mice were fed codfish extract with one of the acid-suppressing substances. Read-out of antibody levels in the sera, of cytokine levels of stimulated splenocytes and of intradermal skin tests was performed. Results The pH of hydrochloric acid was substantially increased in vitro by base powder as well as antacids in a time- and dose-dependent manner. This elevation hindered the digestion of codfish proteins in vitro. A significant increase in codfish-specific IgE antibodies was found in the groups fed codfish combined with Rennie® Antacidum or with base powder; the latter also showed significantly elevated IgG1 and IgG2a levels. The induction of an anaphylactic immune response was proven by positive results in intradermal skin tests. Conclusions Antacids and dietary supplements influencing the gastric pH increase the risk for sensitization against allergenic food proteins. As these substances are commonly used in the general population without consulting a physician, our data may have a major practical and clinical impact. PMID:20214670

Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity.

PubMed

Guo, Tingqing; Jou, William; Chanturiya, Tatyana; Portas, Jennifer; Gavrilova, Oksana; McPherron, Alexandra C

2009-01-01

Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn(-/-) mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn(-/-) mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn(-/-) mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn(-/-) mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn(-/-) mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn(-/-) mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.

Asymmetry identification in rigid rotating bodies—Theory and experiment

NASA Astrophysics Data System (ADS)

Bucher, Izhak; Shomer, Ofer

2013-12-01

Asymmetry and anisotropy are important parameters in rotating devices that can cause instability; indicate a manufacturing defect or a developing fault. The present paper discusses an identification method capable of detecting minute levels of asymmetry by exploiting the unique dynamics of parametric excitation caused by asymmetry and rotation. The detection relies on rigid body dynamics without resorting to nonlinear vibration analysis, and the natural dynamics of elastically supported systems is exploited in order to increase the sensitivity to asymmetry. It is possible to isolate asymmetry from other rotation-induced phenomena like unbalance. An asymmetry detection machine which was built in the laboratory demonstrates the method alongside theoretical analysis.

[Development of lipids and carbohydrates metabolism disorders caused by drinkable water with high content of chlorine organic compounds].

PubMed

Luzhetsky, K P; Ustinova, O Yu; Shur, P Z; Kiryanov, D A; Dolgikh, O V; Chigvintsev, v M; Perevalov, A Ya

2015-01-01

Evaluation of effects caused by environmental peroral exposure to chlorine organic compounds revealed that individuals with AG variation of HTR2A gene are a community with increased sensitivity to chloroform and a risk group for lipid and carbohydrates metabolism disorders. Individual risk of endocrine disorders (ICD: E67.8 excessive nutrition and E66.0 obesity) in these individuals is higher than in general population exposed to chloroform at residence (HQ1.72). Serum serotonin level, that is functionally connected with HTR2A gene, is 1.3 times lower vs. the reference group value.

Pick-and-place process for sensitivity improvement of the capacitive type CMOS MEMS 2-axis tilt sensor

NASA Astrophysics Data System (ADS)

Chang, Chun-I.; Tsai, Ming-Han; Liu, Yu-Chia; Sun, Chih-Ming; Fang, Weileun

2013-09-01

This study exploits the foundry available complimentary metal-oxide-semiconductor (CMOS) process and the packaging house available pick-and-place technology to implement a capacitive type micromachined 2-axis tilt sensor. The suspended micro mechanical structures such as the spring, stage and sensing electrodes are fabricated using the CMOS microelectromechanical systems (MEMS) processes. A bulk block is assembled onto the suspended stage by pick-and-place technology to increase the proof-mass of the tilt sensor. The low temperature UV-glue dispensing and curing processes are employed to bond the block onto the stage. Thus, the sensitivity of the CMOS MEMS capacitive type 2-axis tilt sensor is significantly improved. In application, this study successfully demonstrates the bonding of a bulk solder ball of 100 µm in diameter with a 2-axis tilt sensor fabricated using the standard TSMC 0.35 µm 2P4M CMOS process. Measurements show the sensitivities of the 2-axis tilt sensor are increased for 2.06-fold (x-axis) and 1.78-fold (y-axis) after adding the solder ball. Note that the sensitivity can be further improved by reducing the parasitic capacitance and the mismatch of sensing electrodes caused by the solder ball.

Complement C5a-C5aR interaction enhances MAPK signaling pathway activities to mediate renal injury in trichloroethylene sensitized BALB/c mice.

PubMed

Zhang, Jia-xiang; Zha, Wan-sheng; Ye, Liang-ping; Wang, Feng; Wang, Hui; Shen, Tong; Wu, Chang-hao; Zhu, Qi-xing

2016-02-01

We have previously shown complement activation as a possible mechanism for trichloroethylene (TCE) sensitization, leading to multi-organ damage including the kidneys. In particular, excessive deposition of C5 and C5b-9-the membrane attack complex, which can generate significant tissue damage, was observed in the kidney tissue after TCE sensitization. The present study tested the hypothesis that anaphylatoxin C5a binding to its receptor C5aR mediates renal injury in TCE-sensitized BALB/c mice. BALB/c mice were sensitized through skin challenge with TCE, with or without pretreatment by the C5aR antagonist W54011. Kidney histopathology and the renal functional test were performed to assess renal injury, and immunohistochemistry and fluorescent labeling were carried out to assess C5a and C5aR expressions. TCE sensitization up-regulated C5a and C5aR expressions in kidney tissue, generated inflammatory infiltration, renal tubule damage, glomerular hypercellularity and impaired renal function. Antagonist pretreatment blocked C5a binding to C5aR and attenuated TCE-induced tissue damage and renal dysfunction. TCE sensitization also caused the deposition of major pro-inflammatory cytokines IL-2, TNF-α and IFN-γ in the kidney tissue (P < 0.05); this was accompanied by increased expression of P-p38, P-ERK and P-JNK proteins (P < 0.05). Pretreatment with the C5aR antagonist attenuated the increase of expression of P-p38, P-ERK and P-JNK proteins (P < 0.05) and also consistently reduced the TCE sensitization-induced increase of IL-2, TNF-α and IFN-γ (P < 0.05). These data identify C5a binding to C5aR, MAP kinase activation, and inflammatory cytokine release as a novel mechanism for complement-mediated renal injury by sensitization with TCE or other environmental chemicals. Copyright © 2015 John Wiley & Sons, Ltd.

Spinal Changes of a Newly Isolated Neuropeptide Endomorphin-2 Concomitant with Vincristine-Induced Allodynia

PubMed Central

Huang, Ben-Qing; Liu, Ji-Dong; Liu, Hui; Zhang, Nan; Li, Li; Chen, Jian-Hua

2014-01-01

Chemotherapy-induced neuropathic pain (CNP) is the major dose-limiting factor in cancer chemotherapy. However, the neural mechanisms underlying CNP remain unclear. There is increasing evidence implicating the involvement of spinal endomorphin-2 (EM2) in neuropathic pain. In this study, we used a vincristine-evoked rat CNP model displaying mechanical allodynia and central sensitization, and observed a significant decrease in the expression of spinal EM2 in CNP. Also, while intrathecal administration of exogenous EM2 attenuated allodynia and central sensitization, the mu-opioid receptor antagonist β-funaltrexamine facilitated these events. We found that the reduction in spinal EM2 was mediated by increased activity of dipeptidylpeptidase IV, possibly as a consequence of chemotherapy-induced oxidative stress. Taken together, our findings suggest that a decrease in spinal EM2 expression causes the loss of endogenous analgesia and leads to enhanced pain sensation in CNP. PMID:24586889

Pathophysiology and Treatment of Resistant Hypertension: The Role of Aldosterone and Amiloride-Sensitive Sodium Channels

PubMed Central

Judd, Eric K.; Calhoun, David A.; Warnock, David G.

2015-01-01

Summary Resistant hypertension is a clinically distinct subgroup of hypertension defined by the failure to achieve blood pressure control on optimal dosing of at least 3 antihypertensive medications of different classes, including a diuretic. The pathophysiology of hypertension can be attributed to aldosterone excess in more than 20% of patients with resistant hypertension. Existing dogma attributes the increase in blood pressure seen with increases in aldosterone to its antinatriuretic effects in the distal nephron. However, emerging research, which has identified and has begun to define the function of amiloride-sensitive sodium channels and mineralocorticoid receptors in the systemic vasculature, challenges impaired natriuresis as the sole cause of aldosterone-mediated resistant hypertension. This review integrates these findings to better define the role of the vasculature and aldosterone in the pathophysiology of resistant hypertension. In addition, a brief guide to the treatment of resistant hypertension is presented. PMID:25416662

Pathophysiology and treatment of resistant hypertension: the role of aldosterone and amiloride-sensitive sodium channels.

PubMed

Judd, Eric K; Calhoun, David A; Warnock, David G

2014-01-01

Resistant hypertension is a clinically distinct subgroup of hypertension defined by the failure to achieve blood pressure control on optimal dosing of at least 3 antihypertensive medications of different classes, including a diuretic. The pathophysiology of hypertension can be attributed to aldosterone excess in more than 20% of patients with resistant hypertension. Existing dogma attributes the increase in blood pressure seen with increases in aldosterone to its antinatriuretic effects in the distal nephron. However, emerging research, which has identified and has begun to define the function of amiloride-sensitive sodium channels and mineralocorticoid receptors in the systemic vasculature, challenges impaired natriuresis as the sole cause of aldosterone-mediated resistant hypertension. This review integrates these findings to better define the role of the vasculature and aldosterone in the pathophysiology of resistant hypertension. In addition, a brief guide to the treatment of resistant hypertension is presented.

The relationship between coefficient of restitution and state of charge of zinc alkaline primary LR6 batteries [Bouncing alkaline batteries: A basic solution

DOE PAGES

Bhadra, S.; Hertzberg, B. J.; Croft, M.; ...

2015-03-13

The coefficient of restitution of alkaline batteries had been shown to increase as a function of depth of discharge. In this work, using non-destructive mechanical testing, the change in coefficient of restitution is compared to in situ energy-dispersive x-ray diffraction data to determine the cause of the macroscopic change in coefficient of restitution. The increase in coefficient of restitution correlates to the formation of a percolation pathway of ZnO within the anode of the cell, and that the coefficient of restitution saturates at a value of 0.63 ± .05 at 50% state if charge when the anode has densified intomore » porous ZnO solid. Of note is the sensitivity of coefficient of restitution to the amount of ZnO formation that rivals the sensitivity on in situ energy-dispersive x-ray diffraction spectroscopy.« less

Beta-arrestin-1 protein represses diet-induced obesity.

PubMed

Zhuang, Le-nan; Hu, Wen-xiang; Zhang, Ming-liang; Xin, Shun-mei; Jia, Wei-ping; Zhao, Jian; Pei, Gang

2011-08-12

Diet-related obesity is a major metabolic disorder. Excessive fat mass is associated with type 2 diabetes, hepatic steatosis, and arteriosclerosis. Dysregulation of lipid metabolism and adipose tissue function contributes to diet-induced obesity. Here, we report that β-arrestin-1 knock-out mice are susceptible to diet-induced obesity. Knock-out of the gene encoding β-arrestin-1 caused increased fat mass accumulation and decreased whole-body insulin sensitivity in mice fed a high-fat diet. In β-arrestin-1 knock-out mice, we observed disrupted food intake and energy expenditure and increased macrophage infiltration in white adipose tissue. At the molecular level, β-arrestin-1 deficiency affected the expression of many lipid metabolic genes and inflammatory genes in adipose tissue. Consistently, transgenic overexpression of β-arrestin-1 repressed diet-induced obesity and improved glucose tolerance and systemic insulin sensitivity. Thus, our findings reveal that β-arrestin-1 plays a role in metabolism regulation.

A comparison between active and passive sensing of soil moisture from vegetated terrains

NASA Technical Reports Server (NTRS)

Fung, A. K.; Eom, H. J.

1985-01-01

A comparison between active and passive sensing of soil moisture over vegetated areas is studied via scattering models. In active sensing three contributing terms to radar backscattering can be identified: (1) the ground surface scatter term; (2) the volume scatter term representing scattering from the vegetation layer; and (3) the surface volume scatter term accounting for scattering from both surface and volume. In emission three sources of contribution can also be identified: (1) surface emission; (2) upward volume emission from the vegetation layer; and (3) downward volume emission scattered upward by the ground surface. As ground moisture increases, terms (1) and (3) increase due to increase in permittivity in the active case. However, in passive sensing, term (1) decreases but term (3) increases for the same reason. This self compensating effect produces a loss in sensitivity to change in ground moisture. Furthermore, emission from vegetation may be larger than that from the ground. Hence, the presence of vegetation layer causes a much greater loss of sensitivity to passive than active sensing of soil moisture.

A comparison between active and passive sensing of soil moisture from vegetated terrains

NASA Technical Reports Server (NTRS)

Fung, A. K.; Eom, H. J.

1984-01-01

A comparison between active and passive sensing of soil moisture over vegetated areas is studied via scattering models. In active sensing three contributing terms to radar backscattering can be identified: (1) the ground surface scatter term; (2) the volume scatter term representing scattering from the vegetation layer; and (3) the surface volume scatter term accounting for scattering from both surface and volume. In emission three sources of contribution can also be identified: (1) surface emission; (2) upward volume emission from the vegetation layer; and (3) downward volume emission scattered upward by the ground surface. As ground moisture increases, terms (1) and (3) increase due to increase in permittivity in the active case. However, in passive sensing, term (1) decreases but term (3) increases for the same reason. This self conpensating effect produces a loss in sensitivity to change in ground moisture. Furthermore, emission from vegetation may be larger than that from the ground. Hence, the presence of vegetation layer causes a much greater loss of sensitivity to passive than active sensing of soil moisture.

Mouse model of fragile X syndrome: behavioral and hormonal response to stressors.

PubMed

Nielsen, Darci M; Evans, Jeffrey J; Derber, William J; Johnston, Kenzie A; Laudenslager, Mark L; Crnic, Linda S; Maclean, Kenneth N

2009-06-01

Fragile X syndrome, a form of mental retardation caused by inadequate levels of fragile X mental retardation protein (FMRP), is characterized by extreme sensitivity to sensory stimuli and increased behavioral and hormonal reactivity to stressors. Fmr1 knockout mice lack FMRP and exhibit abnormal responses to auditory stimuli. This study sought to determine whether Fmr1 knockout mice on an F1 hybrid background are normal in their response to footshock. Knockout mice were also examined for signs of hyperexcitation across an extended trial range, and serum corticosterone levels were evaluated in response to various stressors. The ability to acquire conditioned taste aversion was also assessed. Knockout mice exhibited no impairment in associative aversive learning or memory, since they successfully expressed conditioned taste aversion. Footshock-sensitivity, freezing behavior, and corticosterone response to various stressors did not differ between knockout and wild-type mice. However, knockout mice exhibited significantly increased responses during the extended test. The knockout mice's increased responsiveness to footshock in the extended test may be an indication of increased vulnerability to stress or enhanced emotional reactivity. Copyright (c) 2009 APA, all rights reserved.

Improving Interstellar Medium Mitigation in Millisecond PulsarTiming Models for Gravitational Wave Detection Sensitivity

NASA Astrophysics Data System (ADS)

Wilson, Robert C.

2018-01-01

This study aims to increase the sensitivity of pulsar timing arrays (PTAs) used by astronomers ofthe North American Nanohertz Observatory for Gravitational Waves (NANOGrav) to detectgravitational waves (GWs). Millisecond pulsars with many epochs of observations will be used todetermine if dispersive, frequency-dependent pulse time-of-arrival (TOA) delays caused by theinterstellar medium (ISM) can be more accurately predicted over numerous frequency channels.This project will contribute to the ongoing work to detect low-frequency GWs using PTAs. Dataused for this study will be from both the 110m telescope at the Green Bank Observatory in WestVirginia and the 305m telescope at the Arecibo Observatory in Puerto Rico.

[Statocyst regulation of the heart and statokinetic reflexes in the crab, Hemigrapsus sanguineus, during linear acceleration].

PubMed

Kuntsova, M Ia; Sveshnikov, V G; Timofeeva, E V

1978-01-01

In experiments on the shore crab H. sanguineus studies have been made of the effect of variable longitudinal acceleration during swinging (for 15--30 min) upon cardiac activity and gravitational reflexes. High sensitivity of gravitational receptors of the canal statocyst to the effect of acceleration was demonstrated. Removal of the statocysts increases the frequency and amplitude of cardiac contractions as revealed by ECG recording. Changes in stato-kinetic coordinations cause both the disorder of overturning reactions and the disorder of reciprocal inhibition in antagonistic muscles of the dactylopodite. Statocyst regulation of skeletal muscles and heart is presumably realised via contralateral inhibitory canal which is sensitive to linear accelerations.

Cellular Action of Vasopressin in Medullary Tubules of Mice with Hereditary Nephrogenic Diabetes Insipidus

PubMed Central

Jackson, Brian A.; Edwards, Richard M.; Valtin, Heinz; Dousa, Thomas P.

1980-01-01

Our previous studies (1974. J. Clin. Invest.54: 753-762.) suggested that impaired metabolism of cyclic AMP (cAMP) may be involved in the renal unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI). To localize such a defect to specific segments of the nephron, we studied the activities of VP-sensitive adenylate cyclase, cAMP phosphodiesterase (cAMP-PDIE), as well as accumulation of cAMP in medullary collecting tubules (MCT) and in medullary thick ascending limbs of Henle's loop (MAL) microdissected from control mice with normal concentrating ability and from mice with hereditary NDI. Adenylate cyclase activity stimulated by VP or by NaF was only slightly lower (−24%) in MCT from NDI mice, compared with controls. In MAL of NDI mice, basal, VP-sensitive, and NaF-sensitive adenylate cyclase was markedly (> −60%) lower compared with MAL of controls. The specific activity of cAMP-PDIE was markedly higher in MCT of NDI mice compared with controls, but was not different between MAL of control and NDI mice. Under present in vitro conditions, incubation of intact MCT from control mice with VP caused a striking increase in cAMP levels (>10), but VP failed to elicit a change in cAMP levels in MCT from NDI mice. When the cAMP-PDIE inhibitor 1-methyl-3-isobutyl xanthine (MIX) was added to the above incubation, VP caused a significant increase in cAMP levels in MCT from both NDI mice and control mice. Under all tested conditions, cAMP levels in MCT of NDI mice were lower than corresponding values in control MCT. Under the present experimental setting, VP and other stimulating factors (MIX, cholera toxin) did not change cAMP levels in MAL from either control mice or from NDI mice. The results of the present in vitro experiments suggest that the functional unresponsiveness of NDI mice to VP is perhaps mainly the result of the inability of collecting tubules to increase intracellular cAMP levels in response to VP. In turn, this inability to increase cAMP in response to VP is at least partly the result of abnormally high activity of cAMP-PDIE, a somewhat lower activity of VP-sensitive adenylate cyclase in MCT of NDI mice, and perhaps to a deficiency of some other as yet unidentified factors. The possible contribution of low VP-sensitive adenylate cyclase activity in MAL of NDI mice to the renal resistance to VP remains to be defined. PMID:6249843

Acid sensitization of esophageal mucosal afferents: implication for symptom perception in patients across the gastroesophageal reflux disease spectrum.

PubMed

Szczesniak, Michal Marcin; Fuentealba, Sergio Enrique; Cook, Ian J

2013-01-01

Sensitization of esophageal chemoreceptors, either directly by intermittent acid exposure or indirectly through esophagitis-associated inflammatory mediators, is likely to be the mechanism underlying the perception of heartburn. To compare basal esophageal sensitivity with electrical stimulation and acid, and to compare the degree of acid-induced sensitization in controls and in patient groups across the entire spectrum of gastroesophageal reflux disease: erosive oesophagitis (EO), nonerosive reflux disease (NERD), and functional heartburn (FH). Esophageal sensory and pain thresholds to electrical stimulation were measured before, 30, and 60 minutes after an intraesophageal infusion of saline or HCl. Patients received a 30-minute infusion of 0.15 M HCl and controls were randomized to receive either HCl (n = 11) or saline (n = 10). After electrical sensory threshold testing, participants received another 30-minute infusion of HCl to determine whether sensitivity to acid is increased by prior acid exposure All patient groups had higher basal sensory thresholds than healthy controls (controls, 13 ± 1.4 mA; FH, 20 ± 5.1 mA; NERD, 21 ± 5.1 mA; EO, 23 ± 5.4 mA; P < 0.05). Acute esophageal acid exposure reduced sensory thresholds to electrical stimulation in FH and NERD patients (P < 0.05). The level of acid sensitivity during the first HCl infusion was comparable between all patient groups and controls. The secondary infusion caused increased discomfort in all participants (P < 0.01). This acid-induced sensitization to HCl was significantly elevated in the patient groups ( P < 0.05). (1) Esophageal acid infusion sensitizes it to subsequent electrical and chemical stimulation. (2) The acid-related sensitization is greater in gastroesophageal reflux disease than in controls and may influence in part symptom perception in this population. (3) Acid-related sensitization within the gastroesophageal reflux disease population is not dependant on mucosal inflammation.

Three-Dimensional Memory

DTIC Science & Technology

2000-01-01

compound when illuminated with light. This causes the refractive index to increase from n - 1.5 to n f- 1.6. The photopolymerizable solution was...obtained using an ordinary phase-contrast microscope. The photopolymer memory medium we used was monomer mixture composed of a methacryl compound and...an allyl compound with benzil as an initiator and michler’s ketone as a dye sensitizer.9 The metacryl compound polymerizes faster than the allyl

Intrapulpal temperatures during pulsed Nd:YAG laser treatment of dentin, in vitro.

PubMed

White, J M; Fagan, M C; Goodis, H E

1994-03-01

Lasers are being used for soft tissue removal, caries removal, and treatment of root surface sensitivity. One concern for laser safety is that the heat produced at the irradiated root surface may diffuse to the pulp causing irreversible pulpal damage. To test this heat diffusion, copper-constantan thermocouples were inserted into the radicular pulp canals of extracted teeth. Simulating direct exposure which might occur during gingival excision, superficial caries removal, and modification of the dentin surface for treatment of root surface sensitivity, a 2 mm2 area of the external root surface was uniformly irradiated with a pulsed Nd:YAG laser using a 320 microns diameter fiber optic contact probe. Power was varied from 0.3 to 3.0 W with frequencies of 10 and 20 Hz. Temperature changes during cavity preparations using a high speed handpiece with air coolant were also recorded. Repeated measures ANOVA (P < or = 0.05) indicated that intrapulpal temperatures increased as a function of power, frequency, and time. Intrapulpal temperatures decreased as remaining dentin thickness (0.2 to 2.0 mm) increased for each laser parameter. Irradiation of dentin using a Nd:YAG pulsed laser, within the treatment times, powers, and frequencies with adequate remaining dentin thickness, as outlined in this paper, should not cause devitalizing intrapulpal temperature rises.

Reversible loss of gravitropic sensitivity in maize roots after tip application of calcium chelators

NASA Technical Reports Server (NTRS)

Lee, J. S.; Mulkey, T. J.; Evans, M. L.

1983-01-01

The application of calcium chelating agents (EDTA or EGTA) to the tips of maize roots caused a loss of gravitropic sensitivity. When the chelator was replaced with calcium chloride, gravitropic sensitivity was restored. Asymmetric application of calcium chloride near the tip of a vertical root caused curvature toward the calcium source. When the calcium was applied to the upper surface of the tip of a root oriented horizontally, the root curved upward even though control roots exhibited strong downward curvature. Application of calcium chloride to the tips of decapped roots, which are known to be gravitropically insensitive, did not restore gravitropic sensitivity. However, asymmetric application of calcium chloride near the tips of decapped roots caused curvature toward the calcium source. Calcium may play a key role in linking gravity detection to gravitropic curvature in roots.

Salt stress causes cell wall damage in yeast cells lacking mitochondrial DNA.

PubMed

Gao, Qiuqiang; Liou, Liang-Chun; Ren, Qun; Bao, Xiaoming; Zhang, Zhaojie

2014-03-03

The yeast cell wall plays an important role in maintaining cell morphology, cell integrity and response to environmental stresses. Here, we report that salt stress causes cell wall damage in yeast cells lacking mitochondrial DNA (ρ 0 ). Upon salt treatment, the cell wall is thickened, broken and becomes more sensitive to the cell wall-perturbing agent sodium dodecyl sulfate (SDS). Also, SCW11 mRNA levels are elevated in ρ 0 cells. Deletion of SCW11 significantly decreases the sensitivity of ρ 0 cells to SDS after salt treatment, while overexpression of SCW11 results in higher sensitivity. In addition, salt stress in ρ 0 cells induces high levels of reactive oxygen species (ROS), which further damages the cell wall, causing cells to become more sensitive towards the cell wall-perturbing agent.

Potential impact of climate change on emerging vector-borne and other infections in the UK.

PubMed

Baylis, Matthew

2017-12-05

Climate is one of several causes of disease emergence. Although half or more of infectious diseases are affected by climate it appears to be a relatively infrequent cause of human disease emergence. Climate mostly affects diseases caused by pathogens that spend part of their lifecycle outside of the host, exposed to the environment. The most important routes of transmission of climate sensitive diseases are by arthropod (insect and tick) vectors, in water and in food. Given the sensitivity of many diseases to climate, it is very likely that at least some will respond to future climate change. In the case of vector-borne diseases this response will include spread to new areas. Several vector-borne diseases have emerged in Europe in recent years; these include vivax malaria, West Nile fever, dengue fever, Chikungunya fever, leishmaniasis, Lyme disease and tick-borne encephalitis. The vectors of these diseases are mosquitoes, sand flies and ticks. The UK has endemic mosquito species capable of transmitting malaria and probably other pathogens, and ticks that transmit Lyme disease. The UK is also threatened by invasive mosquito species known to be able to transmit West Nile, dengue, chikungunya and Zika, and sand flies that spread leishmaniasis. Warmer temperatures in the future will increase the suitability of the UK's climate for these invasive species, and increase the risk that they may spread disease. While much attention is on invasive species, it is important to recognize the threat presented by native species too. Proposed actions to reduce the future impact of emerging vector-borne diseases in the UK include insect control activity at points of entry of vehicles and certain goods, wider surveillance for mosquitoes and sand flies, research into the threat posed by native species, increased awareness of the medical profession of the threat posed by specific diseases, regular risk assessments, and increased preparedness for the occurrence of a disease emergency.

An Emerging Tick-Borne Disease of Humans Is Caused by a Subset of Strains with Conserved Genome Structure

PubMed Central

Barbet, Anthony F.; Al-Khedery, Basima; Stuen, Snorre; Granquist, Erik G.; Felsheim, Roderick F.; Munderloh, Ulrike G.

2013-01-01

The prevalence of tick-borne diseases is increasing worldwide. One such emerging disease is human anaplasmosis. The causative organism, Anaplasma phagocytophilum, is known to infect multiple animal species and cause human fatalities in the U.S., Europe and Asia. Although long known to infect ruminants, it is unclear why there are increasing numbers of human infections. We analyzed the genome sequences of strains infecting humans, animals and ticks from diverse geographic locations. Despite extensive variability amongst these strains, those infecting humans had conserved genome structure including the pfam01617 superfamily that encodes the major, neutralization-sensitive, surface antigen. These data provide potential targets to identify human-infective strains and have significance for understanding the selective pressures that lead to emergence of disease in new species. PMID:25437207

Comparative analysis of skin sensitization potency of acrylates (methyl acrylate, ethyl acrylate, butyl acrylate, and ethylhexyl acrylate) using the local lymph node assay.

PubMed

Dearman, Rebecca J; Betts, Catherine J; Farr, Craig; McLaughlin, James; Berdasco, Nancy; Wiench, Karin; Kimber, Ian

2007-10-01

There are currently available no systematic experimental data on the skin sensitizing properties of acrylates that are of relevance in occupational settings. Limited information from previous guinea-pig tests or from the local lymph node assay (LLNA) is available; however, these data are incomplete and somewhat contradictory. For those reasons, we have examined in the LLNA 4 acrylates: butyl acrylate (BA), ethyl acrylate (EA), methyl acrylate (MA), and ethylhexyl acrylate (EHA). The LLNA data indicated that all 4 compounds have some potential to cause skin sensitization. In addition, the relative potencies of these acrylates were measured by derivation from LLNA dose-response analyses of EC3 values (the effective concentration of chemical required to induce a threefold increase in proliferation of draining lymph node cells compared with control values). On the basis of 1 scheme for the categorization of skin sensitization potency, BA, EA, and MA were each classified as weak sensitizers. Using the same scheme, EHA was considered a moderate sensitizer. However, it must be emphasized that the EC3 value for this chemical of 9.7% is on the borderline between moderate (<10%) and weak (>10%) categories. Thus, the judicious view is that all 4 chemicals possess relatively weak skin sensitizing potential.

Antibiotic sensitivity pattern of bacteria from diabetic foot infections Haji Adam Malik central general hospital

NASA Astrophysics Data System (ADS)

Bulolo, B. A.; Pase, M. A.; Ginting, F.

2018-03-01

Increasing rate of Diabetic Foot Infections (DFIs) caused by multi-drug-resistance pathogens plays a huge role in the duration of hospitalization, morbidity, and mortality of diabetic patients. The aim of the study is to assess the antibiotic sensitivity pattern of bacteria in DFIs and causative microorganisms. Using cross-sectional retrospective study, data were collected from medical records of DFIs patients previously hospitalized atHaji Adam Malik Hospital, Medan from January to July 2017. 33 patients met the criteria and got enrolled in the study. The classification of DFIs was evaluated according to Wagner’s Classification. Evaluation of antibiotic sensitivity and identification of causative microorganisms were performed in standard microbiologic methods. The most common grade of DFIs was Grade-4 (48.5%), followed by Grade-3 (39.4%) and Grade-5 (9.1%). A total of 12 pathogens were identified. The most common infecting microorganism isolated on pus cultures was Klebsiella pneumonia (33.3%), followed by Escherichia coli (24.2%), Acinetobacter baumanni (12.1%), and Staphylococcus aureus (9.1%). Frequent susceptible antibiotics were Amikacin (88.8%), Imipenem (87%), Meropenem (84.6%), Erythromycin (75%), and Cefoperazone/Sulbactam (68.9%). DFIs are polymicrobial infections in this study K. pneumonia was the most common cause microorganism.

Photoresponse and learning behavior of ascidian larvae, a primitive chordate, to repeated stimuli of step-up and step-down of light.

PubMed

Kawakami, I; Shiraishi, S; Tsuda, M

2002-09-01

Ascidians are lower chordates and their simple tadpole-like larvae share a basic body plan with vertebrates. Newly hatched larvae show no response to a stimulus of light. 4 h after hatching, the larvae were induced to swim upon a step-down of light and stop swimming upon a step-up of light. At weaker intensity of light, the larvae show the same response to a stimulus after presentation of repeated stimuli. When intensity of actinic light was increased, the larvae show sensitization and habituation of the swimming response to a stimulus after repeated stimuli of step-down and step-up of the light. Between 2 h 20 min and 3 h 40 min after hatching the larvae did not show any response to the first stimulus, but after several repeatedstimuli they show swimming response to a step-down of light. A repeated series of stimulus cause sensitization. Between 4 h and 7 h after hatching, the larvae show photoresponse to the first stimulus, but after several repetition of the stimuli, the larvae could not stop swimming to a stimulus of a step-up of the actinic light. A repeated series of stimulus cause greaterhabituation. Both sensitization and habituation depend upon intensity ofactinic light.

Social Causes and Consequences of Rejection Sensitivity

ERIC Educational Resources Information Center

London, Bonita; Downey, Geraldine; Bonica, Cheryl; Paltin, Iris

2007-01-01

Predictions from the Rejection Sensitivity (RS) model concerning the social causes and consequences of RS were examined in a longitudinal study of 150 middle school students. Peer nominations of rejection, self-report measures of anxious and angry rejection expectations, and social anxiety, social withdrawal, and loneliness were assessed at two…

Water Vapor Permeation in Plastics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keller, Paul E.; Kouzes, Richard T.

Polyvinyl toluene (PVT) and polystyrene (PS) (referred to as “plastic scintillator”) are used for gamma ray detectors. A significant decrease in radiation detection performance has been observed in some PVT-based gamma-ray detectors in systems in outdoor environments as they age. Recent studies have revealed that plastic scintillator can undergo an environmentally related material degradation that adversely affects gamma ray detection performance under certain conditions and histories. A significant decrease in sensitivity has been seen in some gamma-ray detectors in some systems as they age. The degradation of sensitivity of plastic scintillator over time is due to a variety of factors,more » and the term “aging” is used to encompass all factors. Some plastic scintillator samples show no aging effects (no significant change in sensitivity over more than 10 years), while others show severe aging (significant change in sensitivity in less than 5 years). Aging effects arise from weather (variations in heat and humidity), chemical exposure, mechanical stress, light exposure, and loss of volatile components. The damage produced by these various causes can be cumulative, causing observable damage to increase over time. Damage may be reversible up to some point, but becomes permanent under some conditions. The objective of this report is to document the phenomenon of permeability of plastic scintillator to water vapor and to derive the relationship between time, temperature, humidity and degree of water penetration in plastic. Several conclusions are documented about the properties of water permeability of plastic scintillator.« less

Profiling secondary metabolites of needles of ozone-fumigated white pine (Pinus strobus) clones by thermally assisted hydrolysis/methylation GC/MS.

PubMed

Shadkami, F; Helleur, R J; Cox, R M

2007-07-01

Plant secondary metabolites have an important role in defense responses against herbivores and pathogens, and as a chemical barrier to elevated levels of harmful air pollutants. This study involves the rapid chemical profiling of phenolic and diterpene resin acids in needles of two (ozone-tolerant and ozone-sensitive) white pine (Pinus strobus) clones, fumigated with different ozone levels (control, and daily events peaking at 80 and 200 ppb) for 40 days. The phenolic and resin acids were measured using thermally assisted hydrolysis and methylation (THM) gas chromatography/mass spectrometry. Short-term fumigation affected the levels of two phenolic acids, i.e., 3-hydroxybenzoic and 3,4-dihydroxybenzoic acids, in that both showed a substantial decrease in concentration with increased ozone dose. The decrease in concentration of these THM products may be caused by inhibition of the plant's shikimate biochemical pathway caused by ozone exposure. The combined occurrence of these two ozone-sensitive indicators has a role in biomonitoring of ozone levels and its impact on forest productivity. In addition, chromatographic profile differences in the major diterpene resin acid components were observed between ozone-tolerant and ozone-sensitive clones. The resin acids anticopalic, 3-oxoanticopalic, 3beta-hydroxyanticopalic, and 3,4-cycloanticopalic acids were present in the ozone-sensitive pine; however, only anticopalic acid was present in the ozone-tolerant clone. This phenotypic variation in resin acid composition may be useful in distinguishing populations that are differentially adapted to air pollutants.

The interpersonally sensitive disposition and health: an integrative review.

PubMed

Marin, Teresa J; Miller, Gregory E

2013-09-01

This article reviews studies that have examined the association between constructs related to interpersonal sensitivity (IS) and morbidity and mortality from major medical illnesses. We define IS as a stable trait characterized by ongoing concerns about negative social evaluation. This disposition makes people vigilant for as well as sensitive to others' evaluations of them. To avoid negative social evaluation, they adopt defensive behaviors such as submission and inhibition. Aspects of IS are captured by various constructs, including introversion, rejection sensitivity, social inhibition, social anxiety, and submissiveness. The review includes 76 long-term prospective studies across 4 outcome categories, namely, infectious disease, cancer, cardiovascular disease (CVD), and all-cause mortality. Three general conclusions are established. First, IS individuals are at increased risk of infectious diseases and possibly CVD, but not cancer and not all-cause mortality. Second, the positive studies provide evidence that IS temporally precedes disease, and go a long way toward ruling out the most plausible alternative explanations based on confounders, supporting a tentative causal interpretation of the data. However, unmeasured potential confounders make it impossible to be certain about whether IS drives the effects on mortality and morbidity. Third, the effects of introversion are accentuated and may only become apparent in contexts that activate social-evaluative concerns (e.g., exposure to early life residential mobility, living with the stigma of human immunodeficiency virus). Findings are discussed in regard to potential psychosocial and psychobiological mechanisms as well as implications for future work concerning IS and health. (c) 2013 APA, all rights reserved.

Xanthine derivatives without PDE effect stimulate voltage-activated chloride conductance of toad skin.

PubMed

Nagel, Wolfram; Katz, Uri

2003-02-01

The effect of xanthine derivatives on the voltage-activated Cl(-) conductance (G(Cl)) of amphibian skin was analyzed. 3-Isobutyl-1-methylxanthine (IBMX) and the recently synthesized xanthine derivatives 3,7-dimethyl-1-propyl xanthine (X-32) and 3,7-dimethyl-1-isobutyl xanthine (X-33), which lack inhibitory effects on phosphodiesterases in CHO and Calu-3 cells, increased voltage-activated G(Cl) without effect on baseline conductance at inactivating voltage. Half-maximal stimulation of G(Cl) occurred at 108 +/- 9 microM for X-32 and X-33 after apical or basolateral application. The stimulation of G(Cl), which occurs only in the presence of Cl(-) in the mucosal solution, is caused by a shift of the voltage sensitivity to lower clamp potentials and an increase of the maximally activated level. Furosemide reversed both the shift of sensitivity and the increase in magnitude. These patterns are fundamentally different from those seen after application of membrane-permeant, nonmetabolized analogs of cAMP, and they indicate that the xanthines stimulate G(Cl) directly. This notion is strengthened by the lack of influence on intracellular cAMP content, which is consistent with the observations in CHO and Calu-3 cells. We propose that the xanthine derivatives increase the voltage sensitivity of a regulative component in the conductive Cl(-) pathway across amphibian skin.

Sensitivity of UV Erythemal Radiation to Total Ozone Changes under Different Sky Conditions: Results for Granada, Spain.

PubMed

Antón, Manuel; Cazorla, Alberto; Mateos, David; Costa, Maria J; Olmo, Francisco J; Alados-Arboledas, Lucas

2016-01-01

This study focuses on the analysis of the sensitivity of UV erythemal radiation (UVER) to variations in the total ozone column (TOC) under different sky conditions at Granada (southeastern Spain). The sensitivity is studied both in relative terms by means of the Radiation Amplification Factor (RAF) and in absolute terms using the Ozone Efficiency (OE). These two variables are determined for diverse sky conditions characterized by the cloud cover information given by a sky camera (in oktas) and the cloud optical depth (COD) estimated from global solar radiation measurements. As expected, in absolute terms, the TOC variations cause substantially smaller UVER changes during completely overcast situations than during cloud-free cases. For instance, the OE (SZA = 30°, TOC = 290 DU) decreases from 0.68 mW m(-2) per unit of TOC (0 oktas) to 0.50 mW m(-2) per unit of TOC (8 oktas). However, the opposite is observed when the analysis is performed in relative terms. Thus, the RAF (determined for SZA cases below 80°) increases from 1.1 for cloud-free cases (0 oktas) to 1.4 for completely overcast situations (8 oktas). This opposite behavior is also found when both RAF and OE are analyzed as functions of COD. Thus, while the OE strongly decreases with increasing COD, the RAF increases as COD increases. © 2015 The American Society of Photobiology.

Thermal effects on nonlinear vibration of a carbon nanotube-based mass sensor using finite element analysis

NASA Astrophysics Data System (ADS)

Kang, Dong-Keun; Kim, Chang-Wan; Yang, Hyun-Ik

2017-01-01

In the present study we carried out a dynamic analysis of a CNT-based mass sensor by using a finite element method (FEM)-based nonlinear analysis model of the CNT resonator to elucidate the combined effects of thermal effects and nonlinear oscillation behavior upon the overall mass detection sensitivity. Mass sensors using carbon nanotube (CNT) resonators provide very high sensing performance. Because CNT-based resonators can have high aspect ratios, they can easily exhibit nonlinear oscillation behavior due to large displacements. Also, CNT-based devices may experience high temperatures during their manufacture and operation. These geometrical nonlinearities and temperature changes affect the sensing performance of CNT-based mass sensors. However, it is very hard to find previous literature addressing the detection sensitivity of CNT-based mass sensors including considerations of both these nonlinear behaviors and thermal effects. We modeled the nonlinear equation of motion by using the von Karman nonlinear strain-displacement relation, taking into account the additional axial force associated with the thermal effect. The FEM was employed to solve the nonlinear equation of motion because it can effortlessly handle the more complex geometries and boundary conditions. A doubly clamped CNT resonator actuated by distributed electrostatic force was the configuration subjected to the numerical experiments. Thermal effects upon the fundamental resonance behavior and the shift of resonance frequency due to attached mass, i.e., the mass detection sensitivity, were examined in environments of both high and low (or room) temperature. The fundamental resonance frequency increased with decreasing temperature in the high temperature environment, and increased with increasing temperature in the low temperature environment. The magnitude of the shift in resonance frequency caused by an attached mass represents the sensing performance of a mass sensor, i.e., its mass detection sensitivity, and it can be seen that this shift is affected by the temperature change and the amount of electrostatic force. The thermal effects on the mass detection sensitivity are intensified in the linear oscillation regime and increase with increasing CNT length; this intensification can either improve or worsen the detection sensitivity.

Influence of environmental temperature on in vivo energy expenditure in vitro ouabain-sensitive respiration in duodenal mucosa and liver in rats fed different levels of dietary fiber or protein.

PubMed

Jørgensen, H; Zhao, X Q

1997-12-01

Seventy two Wistar rats were used in two repeat studies to investigate the effect of environmental temperature (18 degrees C or 28 degrees C) and increasing levels of dietary fibre (low, 68 g/kg DM; medium 110 g/kg DM; high, 157 g/kg DM) or protein (low, 91 g/kg DM; medium, 171 g/kg DM; high, 262 g/kg DM) on digestive tract, visceral organ size, energy metabolism, and respiration attributable to Na+,K(+)-ATPase activity in duodenal mucosa and liver. Total and ouabain-sensitive (a measure of Na+,K(+)-ATPase activity) O2 consumption in vitro of tissues were measured polarographically using a Clark-style YSI biological O2 monitor. Whole body heat production (in vivo) was measured using open-circuit respiration chambers. The weight of the visceral organs was higher in rats housed at 18 degrees C than at 28 degrees C. The empty weight of the small intestine, caecum, and colon increased as the level of dietary fibre increased (P 0.05). Heat production as a proportion of metabolizable energy was higher (P < 0.05) at 18 degrees C than at 28 degrees C in the first experiment but this difference was significant in the second experiment. Rats fed the low protein diet had significantly higher (P > 0.05) heat production than those fed medium or high protein diets. Compared to 28 degrees C, environmental temperature of 18 degrees C caused an increased total and ouabain-sensitive O2 consumption in duodenal mucosa. There was no significant effect of environmental temperature on total and ouabain-sensitive O2 consumption in the liver. However, ouabain-sensitive O2 consumption in liver was significantly higher (P 0.05) when rats were fed a low protein diet compared to the medium or high protein diet. Total and ouabain-sensitive O2 consumption increased in duodenal mucosa of rats fed low level of dietary fibre compared to the medium or high dietary fibre diets. The in vitro results corresponded with the whole animal energy expenditure and O2 consumption in vivo.

Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

PubMed Central

Nguyen, David; Deng, Ping; Matthews, Elizabeth A; Kim, Doo-Sik; Feng, Guoping; Dickenson, Anthony H; Xu, Zao C; Luo, Z David

2009-01-01

Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2δ1) has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2δ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia) similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2δ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR) neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2δ1 transgenic mice. Our data indicated that overexpression of Cavα2δ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2δ1-mediated spinal sensitization in which elevated Cavα2δ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal horn neurons to innocuous stimuli. This spinal sensitization mechanism may mediate at least partially the neuropathic pain states derived from increased pre-synaptic Cavα2δ1 expression. PMID:19216737

Potential Mechanisms of Exercise in Gestational Diabetes

PubMed Central

Golbidi, Saeid; Laher, Ismail

2013-01-01

Gestational diabetes mellitus (GDM) is defined as glucose intolerance first diagnosed during pregnancy. This condition shares same array of underlying abnormalities as occurs in diabetes outside of pregnancy, for example, genetic and environmental causes. However, the role of a sedentary lifestyle and/or excess energy intake is more prominent in GDM. Physically active women are less likely to develop GDM and other pregnancy-related diseases. Weight gain in pregnancy causes increased release of adipokines from adipose tissue; many adipokines increase oxidative stress and insulin resistance. Increased intramyocellular lipids also increase cellular oxidative stress with subsequent generation of reactive oxygen species. A well-planned program of exercise is an important component of a healthy lifestyle and, in spite of old myths, is also recommended during pregnancy. This paper briefly reviews the role of adipokines in gestational diabetes and attempts to shed some light on the mechanisms by which exercise can be beneficial as an adjuvant therapy in GDM. In this regard, we discuss the mechanisms by which exercise increases insulin sensitivity, changes adipokine profile levels, and boosts antioxidant mechanisms. PMID:23691290

Salt Sensitivity and Hypertension: A Paradigm Shift from Kidney Malfunction to Vascular Endothelial Dysfunction

PubMed Central

Choi, Hoon Young; Park, Hyeong Cheon

2015-01-01

Hypertension is a complex trait determined by both genetic and environmental factors and is a major public health problem due to its high prevalence and concomitant increase in the risk for cardiovascular disease. With the recent large increase of dietary salt intake in most developed countries, the prevalence of hypertension increases tremendously which is about 30% of the world population. There is substantial evidence that suggests some people can effectively excrete high dietary salt intake without an increase in arterial BP, and another people cannot excrete effectively without an increase in arterial BP. Salt sensitivity of BP refers to the BP responses for changes in dietary salt intake to produce meaningful BP increases or decreases. The underlying mechanisms that promote salt sensitivity are complex and range from genetic to environmental influences. The phenotype of salt sensitivity is therefore heterogeneous with multiple mechanisms that potentially link high salt intake to increases in blood pressure. Moreover, excess salt intake has functional and pathological effects on the vasculature that are independent of blood pressure. Epidemiologic data demonstrate the role of high dietary salt intake in mediating cardiovascular and renal morbidity and mortality. Almost five decades ago, Guyton and Coleman proposed that whenever arterial pressure is elevated, pressure natriuresis enhances the excretion of sodium and water until blood volume is reduced sufficiently to return arterial pressure to control values. According to this hypothesis, hypertension can develop only when something impairs the excretory ability of sodium in the kidney. However, recent studies suggest that nonosmotic salt accumulation in the skin interstitium and the endothelial dysfunction which might be caused by the deterioration of vascular endothelial glycocalyx layer (EGL) and the epithelial sodium channel on the endothelial luminal surface (EnNaC) also play an important role in nonosmotic storage of salt. These new concepts emphasize that sodium homeostasis and salt sensitivity seem to be related not only to the kidney malfunction but also to the endothelial dysfunction. Further investigations will be needed to assess the extent to which changes in the sodium buffering capacity of the skin interstitium and develop the treatment strategy for modulating the endothelial dysfunction. PMID:26240595

Ventral Tegmental Area Dopamine Cell Activation during Male Rat Sexual Behavior Regulates Neuroplasticity and d-Amphetamine Cross-Sensitization following Sex Abstinence.

PubMed

Beloate, Lauren N; Omrani, Azar; Adan, Roger A; Webb, Ian C; Coolen, Lique M

2016-09-21

Experience with sexual behavior causes cross-sensitization of amphetamine reward, an effect dependent on a period of sexual reward abstinence. We previously showed that ΔFosB in the nucleus accumbens (NAc) is a key mediator of this cross-sensitization, potentially via dopamine receptor activation. However, the role of mesolimbic dopamine for sexual behavior or cross-sensitization between natural and drug reward is unknown. This was tested using inhibitory designer receptors exclusively activated by designer drugs in ventral tegmental area (VTA) dopamine cells. rAAV5/hSvn-DIO-hm4D-mCherry was injected into the VTA of TH::Cre adult male rats. Males received clozapine N-oxide (CNO) or vehicle injections before each of 5 consecutive days of mating or handling. Following an abstinence period of 7 d, males were tested for amphetamine conditioned place preference (CPP). Next, males were injected with CNO or vehicle before mating or handling for analysis of mating-induced cFos, sex experience-induced ΔFosB, and reduction of VTA dopamine soma size. Results showed that CNO did not affect mating behavior. Instead, CNO prevented sexual experience-induced cross-sensitization of amphetamine CPP, ΔFosB in the NAc and medial prefrontal cortex, and decreases in VTA dopamine soma size. Expression of hm4D-mCherry was specific to VTA dopamine cells and CNO blocked excitation and mating-induced cFos expression in VTA dopamine cells. These findings provide direct evidence that VTA dopamine activation is not required for initiation or performance of sexual behavior. Instead, VTA dopamine directly contributes to increased vulnerability for drug use following loss of natural reward by causing neuroplasticity in the mesolimbic pathway during the natural reward experience. Drugs of abuse act on the neural pathways that mediate natural reward learning and memory. Exposure to natural reward behaviors can alter subsequent drug-related reward. Specifically, experience with sexual behavior, followed by a period of abstinence from sexual behavior, causes increased reward for amphetamine in male rats. This study demonstrates that activation of ventral tegmental area dopamine neurons during sexual experience regulates cross-sensitization of amphetamine reward. Finally, ventral tegmental area dopamine cell activation is essential for experience-induced neural adaptations in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. These findings demonstrate a role of mesolimbic dopamine in the interaction between natural and drug rewards, and identify mesolimbic dopamine as a key mediator of changes in vulnerability for drug use after loss of natural reward. Copyright © 2016 the authors 0270-6474/16/369949-13$15.00/0.

Antidepressant Medication Use and Its Association With Cardiovascular Disease and All-Cause Mortality in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

PubMed

Hansen, Richard A; Khodneva, Yulia; Glasser, Stephen P; Qian, Jingjing; Redmond, Nicole; Safford, Monika M

2016-04-01

Mixed evidence suggests that second-generation antidepressants may increase the risk of cardiovascular and cerebrovascular events. To assess whether antidepressant use is associated with acute coronary heart disease (CHD), stroke, cardiovascular disease (CVD) death, and all-cause mortality. Secondary analyses of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) longitudinal cohort study were conducted. Use of selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, bupropion, nefazodone, and trazodone was measured during the baseline (2003-2007) in-home visit. Outcomes of CHD, stroke, CVD death, and all-cause mortality were assessed every 6 months and adjudicated by medical record review. Cox proportional hazards time-to-event analysis followed patients until their first event on or before December 31, 2011, iteratively adjusting for covariates. Among 29 616 participants, 3458 (11.7%) used an antidepressant of interest. Intermediate models adjusting for everything but physical and mental health found an increased risk of acute CHD (hazard ratio [HR] = 1.21; 95% CI = 1.04-1.41), stroke (HR = 1.28; 95% CI = 1.02-1.60), CVD death (HR = 1.29; 95% CI = 1.09-1.53), and all-cause mortality (HR = 1.27; 95% CI = 1.15-1.41) for antidepressant users. Risk estimates trended in this direction for all outcomes in the fully adjusted model but only remained statistically associated with increased risk of all-cause mortality (HR = 1.12; 95% CI = 1.01-1.24). This risk was attenuated in sensitivity analyses censoring follow-up time at 2 years (HR = 1.37; 95% CI = 1.11-1.68). In fully adjusted models, antidepressant use was associated with a small increase in all-cause mortality. © The Author(s) 2016.

Detection of ultraviolet radiation using tissue equivalent radiochromic gel materials

NASA Astrophysics Data System (ADS)

Bero, M. A.; Abukassem, I.

2009-05-01

Ferrous Xylenol-orange Gelatin gel (FXG) is known to be sensitive to ionising radiation such as γ and X-rays. The effect of ionising radiation is to produce an increase in the absorption over a wide region of the visible spectrum, which is proportional to the absorbed dose. This study demonstrates that FXG gel is sensitive to ultraviolet radiation and therefore it could functions as UV detector. Short exposure to UV radiation produces linear increase in absorption measured at 550nm, however high doses of UV cause the ion indicator colour to fad away in a manner proportional to the incident UV energy. Light absorbance increase at the rate of 1.1% per minute of irradiation was monitored. The exposure level at which the detector has linear response is comparable to the natural summer UV radiation. Evaluating the UV ability to pass through tissue equivalent gel materials shows that most of the UV gets absorbed in the first 5mm of the gel materials, which demonstrate the damaging effects of this radiation type on human skin and eyes. It was concluded that FXG gel dosimeter has the potential to offer a simple, passive ultraviolet radiation detector with sensitivity suitable to measure and visualises the natural sunlight UV exposure directly by watching the materials colour changes.

The acute toxic effects of 1-alkyl-3-methylimidazolium nitrate ionic liquids on Chlorella vulgaris and Daphnia magna.

PubMed

Zhang, Cheng; Zhang, Shuai; Zhu, Lusheng; Wang, Jinhua; Wang, Jun; Zhou, Tongtong

2017-10-01

Given their increasingly widespread application, the toxic effects of ionic liquids (ILs) have become the subject of significant attention in recent years. Therefore, the present study assessed the acute toxic effects of 1-alkyl-3-methylimidazolium nitrate ([C n mim]NO 3 (n = 2, 4, 6, 8, 10, 12)) on Chlorella vulgaris and Daphnia magna. The sensitivity of the tested organism Daphnia magna and the investigated IL concentrations in water using high-performance liquid chromatography (HPLC) were also evaluated to demonstrate the reliability of the present study. The results illustrated that Daphnia magna is indeed sensitive to the reference toxicant and the investigated ILs were stable in the aquatic environment. The 50% effect concentration (EC 50 ) was used to represent the acute toxic effects on Chlorella vulgaris and Daphnia magna. With the increasing alkyl-chain lengths, the toxicity of the investigated ILs increased in both the test organisms. Accordingly, the alkyl-chain lengths can cause significantly toxic effects on aquatic organisms, and Daphnia magna are much more sensitive than Chlorella vulgaris to the imidazolium-based ILs used in the present study. Furthermore, the present study provides more information on the acute toxic effects of 1-alkyl-3-methylimidazolium nitrate. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ocean warming and acidification: Unifying physiological principles linking organism response to ecosystem change?

NASA Astrophysics Data System (ADS)

Pörtner, H. O.; Bock, C.; Lannig, G.; Lucassen, M.; Mark, F. C.; Stark, A.; Walther, K.; Wittmann, A.

2011-12-01

The effects of ocean warming and acidification on individual species of marine ectothermic animals may be based on some common denominators, i.e. physiological responses that can be assumed to reflect unifying principles, common to all marine animal phyla. Identification of these principles requires studies, which reach beyond the species-specific response, and consider multiple stressors, for example temperature, CO2 or extreme hypoxia. Analyses of response and acclimation include functional traits of physiological performance on various levels of biological organisation, from changes in the transcriptome to patterns of acid-base regulation and whole animal thermal tolerance. Conclusions are substantiated by comparisons of species and phyla from temperate, Arctic and Antarctic ecosystems and also benefit from the interpretation of paleo-patterns based on the use of a unifying physiological concept, suitable to integrate relevant environmental factors into a more comprehensive picture. Studying the differential specialization of animals on climate regimes and their sensitivity to climate leads to improved understanding of ongoing and past ecosystem change and should then support more reliable projections of future scenarios. For example, accumulating CO2 causes disturbances in acid-base status. Resilience to ocean acidification may be reflected in the capacity to compensate for these disturbances or their secondary effects. Ion and pH regulation comprise thermally sensitive active and passive transfer processes across membranes. Specific responses of ion transporter genes and their products to temperature and CO2 were found in fish, crustaceans and bivalves. However, compensation may cause unfavourable shifts in energy budget and beyond that hamper cellular and mitochondrial metabolism, which are directly linked to the animal's aerobic performance window. In crabs, oysters and, possibly, fishes, a narrowing of the thermal window is caused by moderate increases in CO2 levels. Furthermore, a decrease in the efficiency of energy production may occur and affect growth and fitness as well as larval development. Different sensitivities of life history stages indicate physiologically sensitive bottlenecks during the life cycle of marine organisms. Available evidence suggests that the concept of oxygen and capacity limited thermal tolerance (OCLTT) provides access to the physiological mechanisms closely defining the sensitivities and responses of species to various stressors. It provides causality and quantifies the levels and changes of performance and resistance, and supports more realistic estimates of species and ecosystem sensitivities to environmental change. The emerging picture of differential sensitivities across animal phyla is in line with existing categorizations of sensitivities from palaeo-observations during the Permian-Triassic mass extinctions (A.H. Knoll et al., Earth and Planetary Science Letters 256, 295-313, 2007).

[Antiseptic sensitivity of clinical strains of Pseudomonas aeruginosa].

PubMed

Adarchenko, A A; Krasil'nikov, A P; Sobeshchuk, O P

1989-12-01

MICs, the frequency of clinical and statistic resistance and the antiseptic activity index were studied in complex on out-of-hospital and hospital ecovars of P. aeruginosa. The forms resistant to a number of antiseptics, i.e. chloramine B, chlorhexidine, decamethoxine and dioxidine whose frequency eventually increased were shown to be widely distributed. The antiseptic sensitivity spectrum was more narrow and more heterogeneous than that of other bacteria, the heterogeneity level being dependent on the antiseptic type and bacterial ecovar. The activity of pervomur, phenol, resorcin and boric acid was higher against the clinical strains of P. aeruginosa while iodopyrin, sulfacetamide sodium and dioxidine were less active. The P. aeruginosa strains had natural resistance to cetylpyridinium chloride, rokkal, ethonium, sodium laurate and laurylsulfate and rivanol. It was recommended to assay antiseptic sensitivity of agents causing purulent inflammatory infections and to control circulation of antiseptic resistant variants of bacteria in hospitals.

Can increasing carbon dioxide cause climate change?

PubMed Central

Lindzen, Richard S.

1997-01-01

The realistic physical functioning of the greenhouse effect is reviewed, and the role of dynamic transport and water vapor is identified. Model errors and uncertainties are quantitatively compared with the forcing due to doubling CO2, and they are shown to be too large for reliable model evaluations of climate sensitivities. The possibility of directly measuring climate sensitivity is reviewed. A direct approach using satellite data to relate changes in globally averaged radiative flux changes at the top of the atmosphere to naturally occurring changes in global mean temperature is described. Indirect approaches to evaluating climate sensitivity involving the response to volcanic eruptions and Eocene climate change are also described. Finally, it is explained how, in principle, a climate that is insensitive to gross radiative forcing as produced by doubling CO2 might still be able to undergo major changes of the sort associated with ice ages and equable climates. PMID:11607742

Microbial functional diversity alters the structure and sensitivity of oxygen deficient zones

NASA Astrophysics Data System (ADS)

Penn, Justin; Weber, Thomas; Deutsch, Curtis

2016-09-01

Oxygen deficient zones (ODZs) below the ocean surface regulate marine productivity by removing bioavailable nitrogen (N). A complex microbial community mediates N loss, but the interplay of its diverse metabolisms is poorly understood. We present an ecosystem model of the North Pacific ODZ that reproduces observed chemical distributions yet predicts different ODZ structure, rates, and climatic sensitivity compared to traditional geochemical models. An emergent lower O2 limit for aerobic nitrification lies below the upper O2 threshold for anaerobic denitrification, creating a zone of microbial coexistence that causes a larger ODZ but slower total rates of N loss. The O2-dependent competition for the intermediate nitrite produces gradients in its oxidation versus reduction, anammox versus heterotrophic denitrification, and the net ecological stoichiometry of N loss. The latter effect implies that an externally driven ODZ expansion should favor communities that more efficiently remove N, increasing the sensitivity of the N cycle to climate change.

A Lateral Differential Resonant Pressure Microsensor Based on SOI-Glass Wafer-Level Vacuum Packaging.

PubMed

Xie, Bo; Xing, Yonghao; Wang, Yanshuang; Chen, Jian; Chen, Deyong; Wang, Junbo

2015-09-21

This paper presents the fabrication and characterization of a resonant pressure microsensor based on SOI-glass wafer-level vacuum packaging. The SOI-based pressure microsensor consists of a pressure-sensitive diaphragm at the handle layer and two lateral resonators (electrostatic excitation and capacitive detection) on the device layer as a differential setup. The resonators were vacuum packaged with a glass cap using anodic bonding and the wire interconnection was realized using a mask-free electrochemical etching approach by selectively patterning an Au film on highly topographic surfaces. The fabricated resonant pressure microsensor with dual resonators was characterized in a systematic manner, producing a quality factor higher than 10,000 (~6 months), a sensitivity of about 166 Hz/kPa and a reduced nonlinear error of 0.033% F.S. Based on the differential output, the sensitivity was increased to two times and the temperature-caused frequency drift was decreased to 25%.

A Lateral Differential Resonant Pressure Microsensor Based on SOI-Glass Wafer-Level Vacuum Packaging

PubMed Central

Xie, Bo; Xing, Yonghao; Wang, Yanshuang; Chen, Jian; Chen, Deyong; Wang, Junbo

2015-01-01

This paper presents the fabrication and characterization of a resonant pressure microsensor based on SOI-glass wafer-level vacuum packaging. The SOI-based pressure microsensor consists of a pressure-sensitive diaphragm at the handle layer and two lateral resonators (electrostatic excitation and capacitive detection) on the device layer as a differential setup. The resonators were vacuum packaged with a glass cap using anodic bonding and the wire interconnection was realized using a mask-free electrochemical etching approach by selectively patterning an Au film on highly topographic surfaces. The fabricated resonant pressure microsensor with dual resonators was characterized in a systematic manner, producing a quality factor higher than 10,000 (~6 months), a sensitivity of about 166 Hz/kPa and a reduced nonlinear error of 0.033% F.S. Based on the differential output, the sensitivity was increased to two times and the temperature-caused frequency drift was decreased to 25%. PMID:26402679

Category learning increases discriminability of relevant object dimensions in visual cortex.

PubMed

Folstein, Jonathan R; Palmeri, Thomas J; Gauthier, Isabel

2013-04-01

Learning to categorize objects can transform how they are perceived, causing relevant perceptual dimensions predictive of object category to become enhanced. For example, an expert mycologist might become attuned to species-specific patterns of spacing between mushroom gills but learn to ignore cap textures attributable to varying environmental conditions. These selective changes in perception can persist beyond the act of categorizing objects and influence our ability to discriminate between them. Using functional magnetic resonance imaging adaptation, we demonstrate that such category-specific perceptual enhancements are associated with changes in the neural discriminability of object representations in visual cortex. Regions within the anterior fusiform gyrus became more sensitive to small variations in shape that were relevant during prior category learning. In addition, extrastriate occipital areas showed heightened sensitivity to small variations in shape that spanned the category boundary. Visual representations in cortex, just like our perception, are sensitive to an object's history of categorization.

Clinical and economic consequences of vancomycin and fidaxomicin for the treatment of Clostridium difficile infection in Canada.

PubMed

Wagner, Monika; Lavoie, Louis; Goetghebeur, Mireille

2014-03-01

Clostridium difficile infection (CDI) represents a public health problem with increasing incidence and severity. To evaluate the clinical and economic consequences of vancomycin compared with fidaxomicin in the treatment of CDI from the Canadian health care system perspective. A decision-tree model was developed to compare vancomycin and fidaxomicin for the treatment of severe CDI. The model assumed identical initial cure rates and included first recurrent episodes of CDI (base case). Treatment of patients presenting with recurrent CDI was examined as an alternative analysis. Costs included were for study medication, physician services and hospitalization. Cost effectiveness was measured as incremental cost per recurrence avoided. Sensitivity analyses of key input parameters were performed. In a cohort of 1000 patients with an initial episode of severe CDI, treatment with fidaxomicin led to 137 fewer recurrences at an incremental cost of $1.81 million, resulting in an incremental cost of $13,202 per recurrence avoided. Among 1000 patients with recurrent CDI, 113 second recurrences were avoided at an incremental cost of $18,190 per second recurrence avoided. Incremental costs per recurrence avoided increased with increasing proportion of cases caused by the NAP1/B1/027 strain. Results were sensitive to variations in recurrence rates and treatment duration but were robust to variations in other parameters. The use of fidaxomicin is associated with a cost increase for the Canadian health care system. Clinical benefits of fidaxomicin compared with vancomycin depend on the proportion of cases caused by the NAP1/B1/027 strain in patients with severe CDI.

Pilocarpine-Induced Status Epilepticus Increases the Sensitivity of P2X7 and P2Y1 Receptors to Nucleotides at Neural Progenitor Cells of the Juvenile Rodent Hippocampus.

PubMed

Rozmer, Katalin; Gao, Po; Araújo, Michelle G L; Khan, Muhammad Tahir; Liu, Juan; Rong, Weifang; Tang, Yong; Franke, Heike; Krügel, Ute; Fernandes, Maria José S; Illes, Peter

2017-07-01

Patch-clamp recordings indicated the presence of P2X7 receptors at neural progenitor cells (NPCs) in the subgranular zone of the dentate gyrus in hippocampal brain slices prepared from transgenic nestin reporter mice. The activation of these receptors caused inward current near the resting membrane potential of the NPCs, while P2Y1 receptor activation initiated outward current near the reversal potential of the P2X7 receptor current. Both receptors were identified by biophysical/pharmacological methods. When the brain slices were prepared from mice which underwent a pilocarpine-induced status epilepticus or when brain slices were incubated in pilocarpine-containing external medium, the sensitivity of P2X7 and P2Y1 receptors was invariably increased. Confocal microscopy confirmed the localization of P2X7 and P2Y1 receptor-immunopositivity at nestin-positive NPCs. A one-time status epilepticus in rats caused after a latency of about 5 days recurrent epileptic fits. The blockade of central P2X7 receptors increased the number of seizures and their severity. It is hypothesized that P2Y1 receptors after a status epilepticus may increase the ATP-induced proliferation/ectopic migration of NPCs; the P2X7 receptor-mediated necrosis/apoptosis might counteract these effects, which would otherwise lead to a chronic manifestation of recurrent epileptic fits. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Massey, Veronica L.; Stocke, Kendall S.; Schmidt, Robin H.

Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD.more » Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects. - Highlights: • Arsenic (As) enhances liver damage caused by a high-fat (HFD) diet in mice. • Oligofructose protects against As-enhanced liver damage caused by HFD. • As causes dysbiosis in the GI tract and exacerbates the dysbiosis caused by HFD. • OFC prevents the dysbiosis caused by HFD and As, increasing commensal bacteria.« less

The etiology of anomalous sexual preferences in men.

PubMed

Quinsey, Vermon L

2003-06-01

People discover rather than choose their sexual interests. The process of discovery typically begins before the onset of puberty and is associated with an increase in the secretion of sex hormones from the adrenal glands. However, the determinants of the direction of sexual interest, in the sense of preferences for the same or opposite sex, are earlier. These preferences, although not manifest until much later in development, appear to be caused by the neural organizational effects of intrauterine hormonal events. Variations in these hormonal events likely have several causes and two of these appear to have been identified for males. One cause is genetic and the other involves the sensitization of the maternal immune system to some aspect of the male fetus. It is presently unclear how these two causes relate to each other. The most important question for future research is whether preferences for particular-aged partners and parts of the male courtship sequence share causes similar to those of erotic gender orientation.

Caffeine and length dependence of staircase potentiation in skeletal muscle.

PubMed

Rassier, D E; Tubman, L A; MacIntosh, B R

1998-01-01

Skeletal muscle sensitivity to Ca2+ is greater at long lengths, and this results in an optimal length for twitch contractions that is longer than optimal length for tetanic contractions. Caffeine abolishes this length dependence of Ca2+ sensitivity. Muscle length (ML) also affects the degree of staircase potentiation. Since staircase potentiation is apparently caused by an increased Ca2+ sensitivity of the myofilaments, we tested the hypothesis that caffeine depresses the length dependence of staircase potentiation. In situ isometric twitch contractions of rat gastrocnemius muscle before and after 10 s of 10-Hz stimulation were analyzed at seven different lengths to evaluate the length dependence of staircase potentiation. In the absence of caffeine, length dependence of Ca2+ sensitivity was observed, and the degree of potentiation after 10-Hz stimulation showed a linear decrease with increased length (DT = 1.47 - 0.05 ML, r2 = 0.95, where DT is developed tension). Length dependence of Ca2+ sensitivity was decreased by caffeine when caffeine was administered in amounts estimated to result in 0.5 and 0.75 mM concentrations. Furthermore, the negative slope of the relationship between staircase potentiation and muscle length was diminished at the lower caffeine dose, and the slope was not different from zero after the higher dose (DT = 1.53 - 0.009 ML, r2 = 0.43). Our study shows that length dependence of Ca2+ sensitivity in intact skeletal muscle is diminished by caffeine. Caffeine also suppressed the length dependence of staircase potentiation, suggesting that the mechanism of this length dependence may be closely related to the mechanism for length dependence of Ca2+ sensitivity.

The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1.

PubMed

Kulebyakin, Konstantin; Penkov, Dmitry; Blasi, Francesco; Akopyan, Zhanna; Tkachuk, Vsevolod

2016-12-02

Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. Copyright © 2016 Elsevier Inc. All rights reserved.

Re-establishment of Anxiety in Stress-Sensitized Mice Is Caused by Monocyte Trafficking from the Spleen to the Brain

PubMed Central

Wohleb, Eric S.; McKim, Daniel B.; Shea, Daniel T.; Powell, Nicole D.; Tarr, Andrew J.; Sheridan, John F.; Godbout, Jonathan P.

2014-01-01

Background Persistent anxiety-like symptoms may have an inflammatory-related pathophysiology. Our previous work using repeated social defeat (RSD) in mice showed that recruitment of peripheral myeloid cells to the brain is required for the development of anxiety. Here, we aimed to determine if 1) RSD promotes prolonged anxiety through redistribution of myeloid cells and 2) prior exposure to RSD sensitizes the neuroimmune axis to secondary subthreshold stress. Methods Mice were subjected to RSD and several immune and behavioral parameters were determined 0.5, 8, or 24 days later. In follow-up studies, control and RSD mice were subjected to subthreshold stress at 24 days. Results Repeated social defeat-induced macrophage recruitment to the brain corresponded with development and maintenance of anxiety-like behavior 8 days after RSD, but neither remained at 24 days. Nonetheless, social avoidance and an elevated neuroinflammatory profile were maintained at 24 days. Subthreshold social defeat in RSD-sensitized mice increased peripheral macrophage trafficking to the brain that promoted re-establishment of anxiety. Moreover, subthreshold social defeat increased social avoidance in RSD-sensitized mice compared with naïve mice. Stress-induced monocyte trafficking was linked to redistribution of myeloid progenitor cells in the spleen. Splenectomy before subthreshold stress attenuated macrophage recruitment to the brain and prevented anxiety-like behavior in RSD-sensitized mice. Conclusions These data indicate that monocyte trafficking from the spleen to the brain contributes re-establishment of anxiety in stress-sensitized mice. These findings show that neuroinflammatory mechanisms promote mood disturbances following stress-sensitization and outline novel neuroimmune interactions that underlie recurring anxiety disorders such as posttraumatic stress disorder. PMID:24439304

Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain.

PubMed

Wohleb, Eric S; McKim, Daniel B; Shea, Daniel T; Powell, Nicole D; Tarr, Andrew J; Sheridan, John F; Godbout, Jonathan P

2014-06-15

Persistent anxiety-like symptoms may have an inflammatory-related pathophysiology. Our previous work using repeated social defeat (RSD) in mice showed that recruitment of peripheral myeloid cells to the brain is required for the development of anxiety. Here, we aimed to determine if 1) RSD promotes prolonged anxiety through redistribution of myeloid cells and 2) prior exposure to RSD sensitizes the neuroimmune axis to secondary subthreshold stress. Mice were subjected to RSD and several immune and behavioral parameters were determined .5, 8, or 24 days later. In follow-up studies, control and RSD mice were subjected to subthreshold stress at 24 days. Repeated social defeat-induced macrophage recruitment to the brain corresponded with development and maintenance of anxiety-like behavior 8 days after RSD, but neither remained at 24 days. Nonetheless, social avoidance and an elevated neuroinflammatory profile were maintained at 24 days. Subthreshold social defeat in RSD-sensitized mice increased peripheral macrophage trafficking to the brain that promoted re-establishment of anxiety. Moreover, subthreshold social defeat increased social avoidance in RSD-sensitized mice compared with naïve mice. Stress-induced monocyte trafficking was linked to redistribution of myeloid progenitor cells in the spleen. Splenectomy before subthreshold stress attenuated macrophage recruitment to the brain and prevented anxiety-like behavior in RSD-sensitized mice. These data indicate that monocyte trafficking from the spleen to the brain contributes re-establishment of anxiety in stress-sensitized mice. These findings show that neuroinflammatory mechanisms promote mood disturbances following stress-sensitization and outline novel neuroimmune interactions that underlie recurring anxiety disorders such as posttraumatic stress disorder. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Influence of Varroa Mite (Varroa destructor) Management Practices on Insecticide Sensitivity in the Honey Bee (Apis mellifera)

PubMed Central

Rinkevich, Frank D.; Danka, Robert G.; Healy, Kristen B.

2017-01-01

Since Varroa mites may cause devastating losses of honey bees through direct feeding, transmitting diseases, and increasing pathogen susceptibility, chemical and mechanical practices commonly are used to reduce mite infestation. While miticide applications are typically the most consistent and efficacious Varroa mite management method, miticide-induced insecticide synergism in honey bees, and the evolution of resistance in Varroa mites are reasonable concerns. We treated colonies with the miticide amitraz (Apivar®), used IPM practices, or left some colonies untreated, and then measured the effect of different levels of mite infestations on the sensitivity of bees to phenothrin, amitraz, and clothianidin. Sensitivity to all insecticides varied throughout the year among and within treatment groups. Clothianidin sensitivity decreased with increasing mite levels, but no such correlation was seen with phenothrin or amitraz. These results show that insecticide sensitivity is dynamic throughout the 5 months test. In-hive amitraz treatment according to the labeled use did not synergize sensitivity to the pesticides tested and this should alleviate concern over potential synergistic effects. Since IPM practices were largely ineffective at reducing Varroa mite infestation, reliance on chemical methods of Varroa mite management is likely to continue. However, miticides must be used judiciously so the long term effectiveness of these compounds can be maximized. These data demonstrate the complex and dynamic variables that contribute to honey bee colony health. The results underscore the importance of controlling for as many of these variables as possible in order to accurately determine the effects of each of these factors as they act alone or in concert with others. PMID:28085045

Development of a high-sensitivity strain measurement system based on a SH SAW sensor

NASA Astrophysics Data System (ADS)

Oh, Haekwan; Lee, Keekeun; Eun, Kyoungtae; Choa, Sung-Hoon; Yang, Sang Sik

2012-02-01

A strain measurement system based on a shear horizontal surface acoustic wave (SH SAW) was developed. The developed system is composed of a SAW microsensor, a printed circuit board (PCB), an adhesive and a strain gauge. When a compression force is applied to the PCB by the strain gauge, the PCB is bent so that external strain energy can be evenly delivered to the microsensor without any detachment of the sensor from the board. When a stretching force is applied to the PCB under the condition that one side of the PCB is fixed and the other side is modulated, the actual length of the SAW delay line between the two interdigital transducers (IDTs) is increased. The increase in the delay line length causes a change in the time for the propagating SAW to reach the output IDT. If strain energy is applied to the piezoelectric substrate, the substrate density is changed, which then changes the propagation velocity of the SAW. Coupling-of-modes modeling was conducted prior to fabrication to determine the optimal device parameters. Depending on the strain, the frequency difference was linearly modulated. The obtained sensitivity for stretching was 17.3 kHz/% for the SH wave mode and split electrode. And the obtained sensitivity for bending was 46.1 kHz/% for the SH wave mode and split electrode. The SH wave showed about 15% higher sensitivity than the Rayleigh wave, and the dog-bone PCB showed about 8% higher sensitivity than the rectangular PCB. The obtained sensitivity was about five times higher than that of existing SAW-based strain sensors.

RasGRP1 confers the phorbol ester-sensitive phenotype to EL4 lymphoma cells.

PubMed

Han, Shujie; Knoepp, Stewart M; Hallman, Mark A; Meier, Kathryn E

2007-01-01

The murine EL4 lymphoma cell line exists in variants that are either sensitive or resistant to the tumor promoter phorbol 12-myristate 13-acetate (PMA). In sensitive EL4 cells, PMA causes robust Erk mitogen-activated protein kinase activation that results in growth arrest. In resistant cells, PMA induces minimal Erk activation, without growth arrest. PMA stimulates IL-2 production in sensitive, but not resistant, cells. The role of RasGRP1, a PMA-activated guanine nucleotide exchange factor for Ras, in EL4 phenotype was examined. Endogenous RasGRP1 protein is expressed at much higher levels in sensitive than in resistant cells. PMA-induced Ras activation is observed in sensitive cells but not in resistant cells lacking Ras-GRP1. PMA induces down-regulation of RasGRP1 protein in sensitive cells but increases RasGRP1 in resistant cells. Transfection of RasGRP1 into resistant cells enhances PMA-induced Erk activation. In the reverse experiment, introduction of small interfering RNA (siRNA) for RasGRP1 suppresses PMA-induced Ras and Erk activations in sensitive cells. Sensitive cells incubated with siRNA for RasGRP1 exhibit the PMA-resistant phenotype, in that they are able to proliferate in the presence of PMA and do not secrete IL-2 when stimulated with PMA. These studies indicate that the PMA-sensitive phenotype, as previously defined for the EL4 cell line, is conferred by endogenous expression of RasGRP1 protein.

Sensitivity ranking for freshwater invertebrates towards hydrocarbon contaminants.

PubMed

Gerner, Nadine V; Cailleaud, Kevin; Bassères, Anne; Liess, Matthias; Beketov, Mikhail A

2017-11-01

Hydrocarbons have an utmost economical importance but may also cause substantial ecological impacts due to accidents or inadequate transportation and use. Currently, freshwater biomonitoring methods lack an indicator that can unequivocally reflect the impacts caused by hydrocarbons while being independent from effects of other stressors. The aim of the present study was to develop a sensitivity ranking for freshwater invertebrates towards hydrocarbon contaminants, which can be used in hydrocarbon-specific bioindicators. We employed the Relative Sensitivity method and developed the sensitivity ranking S hydrocarbons based on literature ecotoxicological data supplemented with rapid and mesocosm test results. A first validation of the sensitivity ranking based on an earlier field study has been conducted and revealed the S hydrocarbons ranking to be promising for application in sensitivity based indicators. Thus, the first results indicate that the ranking can serve as the core component of future hydrocarbon-specific and sensitivity trait based bioindicators.

INCREASED RENAL OXIDATIVE STRESS IN SALT-SENSITIVE HUMAN GRK4γ486V TRANSGENIC MICE

PubMed Central

Diao, Zhenyu; Asico, Laureano D.; Villar, Van Anthony M.; Zheng, Xiaoxu; Cuevas, Santiago; Armando, Ines; Jose, Pedro A.; Wang, Xiaoyan

2017-01-01

We tested the hypothesis that salt-sensitive hypertension is caused by renal oxidative stress by measuring the blood pressure and reactive oxygen species-related proteins in the kidneys of human G protein-coupled receptor kinase 4γ (hGRK4γ) 486V transgenic mice and non-transgenic (Non-T) littermates on normal and high salt diets. High salt diet increased the blood pressure, associated with impaired sodium excretion, in hGRK4γ486V mice. Renal expressions of NOX isoforms were similar in both strains on normal salt diet but NOX2 was decreased by high salt diet to a greater extent in Non-T than hGRK4γ486V mice. Renal HO-2, but not HO-1, protein was greater in hGRK4γ486V than Non-T mice on normal salt diet and normalized by high salt diet. On normal salt diet, renal CuZnSOD and ECSOD proteins were similar but renal MnSOD was lower in hGRK4γ486V than Non-T mice and remained low on high salt diet. High salt diet decreased renal CuZnSOD in hGRK4γ486V but not Non-T mice and decreased renal ECSOD to a greater extent in hGRK4γ486V than Non-T mice. Renal SOD activity, superoxide production, and NOS3 protein were similar in two strains on normal salt diet. However, high salt diet decreased SOD activity and NOS3 protein and increased superoxide production in hGRK4γ486V mice but not in Non-T mice. High salt diet also increased urinary 8-isoprostane and 8-hydroxydeoxyguanosine to a greater extent in hGRK4γ486V than Non-T mice. hGRK4γwild-type mice were normotensive and hGRK4γ142V mice were hypertensive but both were salt-resistant and in normal redox balance. Chronic tempol treatment partially prevented the salt-sensitivity of hGRK4γ486V mice. Thus, hGRK4γ486V causes salt-sensitive hypertension due, in part, to defective renal antioxidant mechanisms. PMID:28189851

Gum Arabic as a Cause of Occupational Allergy

PubMed Central

Viinanen, Arja; Salokannel, Maija; Lammintausta, Kaija

2011-01-01

Background. Gum arabic is a potential sensitizer in food industry. Methods. We examined 11 candy factory workers referred to examinations due to respiratory and skin symptoms paying attention to exposure and sensitization to gum arabic. Skin tests, pulmonary function tests, and respiratory provocation tests were carried out as indicated by the symptoms and findings. Results. Occupational asthma, caused by gum arabic was diagnosed in 4/11 candy factory workers and two of them had also occupational contact urticaria and one had occupational rhinitis. One of them had oral symptoms associated with ingestion of products containing gum arabic. Conclusions. Airborne exposure to gum arabic may cause sensitization leading to allergic rhinitis, asthma, and urticaria. PMID:21747872

Prolonged Fasting Identifies Skeletal Muscle Mitochondrial Dysfunction as Consequence Rather Than Cause of Human Insulin Resistance

PubMed Central

Hoeks, Joris; van Herpen, Noud A.; Mensink, Marco; Moonen-Kornips, Esther; van Beurden, Denis; Hesselink, Matthijs K.C.; Schrauwen, Patrick

2010-01-01

OBJECTIVE Type 2 diabetes and insulin resistance have been associated with mitochondrial dysfunction, but it is debated whether this is a primary factor in the pathogenesis of the disease. To test the concept that mitochondrial dysfunction is secondary to the development of insulin resistance, we employed the unique model of prolonged fasting in humans. Prolonged fasting is a physiologic condition in which muscular insulin resistance develops in the presence of increased free fatty acid (FFA) levels, increased fat oxidation and low glucose and insulin levels. It is therefore anticipated that skeletal muscle mitochondrial function is maintained to accommodate increased fat oxidation unless factors secondary to insulin resistance exert negative effects on mitochondrial function. RESEARCH DESIGN AND METHODS While in a respiration chamber, twelve healthy males were subjected to a 60 h fast and a 60 h normal fed condition in a randomized crossover design. Afterward, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp, and mitochondrial function was quantified ex vivo in permeabilized muscle fibers using high-resolution respirometry. RESULTS Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity. Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density. CONCLUSIONS These findings confirm that the insulin-resistant state has secondary negative effects on mitochondrial function. Given the low insulin and glucose levels after prolonged fasting, hyperglycemia and insulin action per se can be excluded as underlying mechanisms, pointing toward elevated plasma FFA and/or intramuscular fat accumulation as possible causes for the observed reduction in mitochondrial capacity. PMID:20573749

Enhanced cortisol production rates, free cortisol, and 11beta-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss.

PubMed

Purnell, Jonathan Q; Kahn, Steven E; Samuels, Mary H; Brandon, David; Loriaux, D Lynn; Brunzell, John D

2009-02-01

Controversy exists as to whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test whether the relationships found are a consequence rather than a cause of obesity, eight men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free cortisol levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-h sampling; intra-abdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (S(I)) by frequently sampled intravenous glucose tolerance test; and adipocyte 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) gene expression by quantitative RT-PCR from subcutaneous biopsies. Increased CPR and FC correlated with increased IAF, but not SQF, and with decreased S(I). Increased 11beta-HSD-1 gene expression correlated with both IAF and SQF and with decreased S(I). With weight loss, CPR, FC, and MCR did not change compared with baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF and 11beta-HSD-1 decreased compared with baseline. These data support a model in which increased hypothalamic-pituitary-adrenal activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11beta-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity.

A review of enzyme changes in serum and urine due to treatment with drugs (tuberculostatics, contraceptive medication, diagnostics and drugs in real diseases).

PubMed

Haschen, R J

1980-01-01

Serum enzymes are sensitive tools for demonstration of injury to different organs of the body, including lesions that are side effects of drugs or the application of certain compounds for diagnostic purposes. It has been reported that tuberculosis therapy can cause liver damage of the unpredictable drug-induced liver lesion-type. The liver lesions due to tuberculostatics resemble an unspecific or viral hepatitis. Oral contraceptives can also cause hepatic lesions, some of them being quite serious. They have been known to cause hepatosis with or without cholestasis, drug-induced hepatitis, circulatory disturbances such as hepatic peliosis and Budd-Chiari syndrome, and benign and malignant tumors. Therapy control should be instituted in these cases. Enzymes can be used as indicators. A considerable increase of coeruloplasmin (or serum copper) is a useful marker for monitoring contraceptive medication; the aminotransferases initially show a slight increase while later, they may be decreasing to subnormal values. The appearance of serious morphological findings may necessitate delineation of normal ranges and alarm ranges. Serial enzyme determinations are suggested in: 1) high risk patients who have been suffering from hepatitis or intrahepatic cholestasis due to pregnancy or drugs, and 2) in persons complaining of signs or symptoms suggestive of liver involvement. The kidney is another organ which might be influenced by certain drugs leaving the organism via the urinary tract. The presence of enzymes in urine can serve as sensitive indicators of a proximal tubular lesion. The effects of certain hormones on the kidneys are discussed.

Attention-based long-lasting sensitization and suppression of colors.

PubMed

Tseng, Chia-Huei; Vidnyanszky, Zoltan; Papathomas, Thomas; Sperling, George

2010-02-22

In contrast to the short-duration and quick reversibility of attention, a long-term sensitization to color based on protracted attention in a visual search task was reported by Tseng, Gobell, and Sperling (2004). When subjects were trained for a few hours to search for a red object among colored distracters, sensitivity to red was increased for weeks. This sensitization was quantified using ambiguous motion displays containing isoluminant red-green and texture-contrast gratings, in which the perceived motion-direction depended both on the attended color and on the relative red-green saturation. Such long-term effects could result from either sensitization of the attended color, or suppression of unattended colors, or a combination of the two. Here we unconfound these effects by eliminating one of the paired colors of the motion display from the search task. The other paired color in the motion display can then be either a target or a distracter in the search task. Thereby, we separately measure the effect of attention on sensitizing the target color or suppressing distracter colors. The results indicate that only sensitization of the target color in the search task is statistically significant for the present experimental conditions. We conclude that selective attention to a color in our visual search task caused long-term sensitization to the attended color but not significant long-term suppression of the unattended color. Copyright 2009 Elsevier Ltd. All rights reserved.

Pharmacological causes of hyperprolactinemia

PubMed Central

Torre, Daria La; Falorni, Alberto

2007-01-01

Hyperprolactinemia is a common endocrinological disorder that may be caused by several physiological and pathological conditions. Several drugs may determine a significant increase in prolactin serum concentration that is frequently associated with symptoms. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. Risperidone is one of the atypical neuroleptics most likely to induce hyperprolactinemia, while other atypical drugs are unfrequenlty and only transiently associated with increase of prolactin levels. Women are more sensitive than men to the hyperprolactinemic effect of antipsychotics. Classical and risperidone-induced hyperprolactinemia may be revert when a gradual antipsychotic drug discontinuation is combined with olanzapine or clozapine initiation. Antidepressant drugs with serotoninergic activity, including selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAO-I) and some tricyclics, can cause hyperprolactinemia. A long list of other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Finally, hyperprolactinemia has also been documented during conditioning and after autologous blood stem-cell transplantation and during chemotherapy, even though disturbances of prolactin seem to occur less frequently than impairments of the hypothalamus-pituitary-gonad/thyroid axis after intensive treatment and blood marrow transplantation. PMID:18473017

Three methionine residues located within the regulator of conductance for K+ (RCK) domains confer oxidative sensitivity to large-conductance Ca2+-activated K+ channels

PubMed Central

Santarelli, Lindsey Ciali; Wassef, Ramez; Heinemann, Stefan H; Hoshi, Toshinori

2006-01-01

Methionine-directed oxidation of the human Slo1 potassium channel (hSlo1) shifts the half-activation voltage by −30 mV and markedly slows channel deactivation at low concentrations of intracellular Ca2+ ([Ca2+]i). We demonstrate here that the contemporaneous mutation of M536, M712 and M739 to leucine renders the channel functionally insensitive to methionine oxidation caused by the oxidant chloramine-T (Ch-T) without altering other functional characteristics. Coexpression with the auxiliary β1 subunit fails to restore the full oxidative sensitivity to this triple mutant channel. The Ch-T effect is mediated specifically by M536, M712 and M739 because even small changes in this residue combination interfere with the ability to remove the oxidant sensitivity following mutation. Replacement of M712 or M739, but not M536, with the hydrophilic residue glutamate largely mimics oxidation of the channel and essentially removes the Ch-T sensitivity, suggesting that M712 and M739 may be part of a hydrophobic pocket disrupted by oxidation of non-polar methionine to the more hydrophilic methionine sulfoxide. The increase in wild-type hSlo1 open probability caused by methionine oxidation disappears at high [Ca2+]i and biophysical modelling of the Ch-T effect on steady-state activation implicates a decrease in the allosteric coupling between Ca2+ binding and the pore. The dramatic increase in open probability at low [Ca2+]i especially within the physiological voltage range suggests that oxidation of M536, M712 or M739 may enhance the Slo1 BK activity during conditions of oxidative stress, such as those associated with ischaemia-reperfusion and neurodegenerative disease, or in response to metabolic cues. PMID:16396928

Cell-specific radiosensitization by gold nanoparticles at megavoltage radiation energies.

PubMed

Jain, Suneil; Coulter, Jonathan A; Hounsell, Alan R; Butterworth, Karl T; McMahon, Stephen J; Hyland, Wendy B; Muir, Mark F; Dickson, Glenn R; Prise, Kevin M; Currell, Fred J; O'Sullivan, Joe M; Hirst, David G

2011-02-01

Gold nanoparticles (GNPs) have been shown to cause sensitization with kilovoltage (kV) radiation. Differences in the absorption coefficient between gold and soft tissue, as a function of photon energy, predict that maximum enhancement should occur in the kilovoltage (kV) range, with almost no enhancement at megavoltage (MV) energies. Recent studies have shown that GNPs are not biologically inert, causing oxidative stress and even cell death, suggesting a possible biological mechanism for sensitization. The purpose of this study was to assess GNP radiosensitization at clinically relevant MV X-ray energies. Cellular uptake, intracellular localization, and cytotoxicity of GNPs were assessed in normal L132, prostate cancer DU145, and breast cancer MDA-MB-231 cells. Radiosensitization was measured by clonogenic survival at kV and MV photon energies and MV electron energies. Intracellular DNA double-strand break (DSB) induction and DNA repair were determined and GNP chemosensitization was assessed using the radiomimetic agent bleomycin. GNP uptake occurred in all cell lines and was greatest in MDA-MB-231 cells with nanoparticles accumulating in cytoplasmic lysosomes. In MDA-MB-231 cells, radiation sensitizer enhancement ratios (SERs) of 1.41, 1.29, and 1.16 were achieved using 160 kVp, 6 MV, and 15 MV X-ray energies, respectively. No significant effect was observed in L132 or DU145 cells at kV or MV energies (SER 0.97-1.08). GNP exposure did not increase radiation-induced DSB formation or inhibit DNA repair; however, GNP chemosensitization was observed in MDA-MB-231 cells treated with bleomycin (SER 1.38). We have demonstrated radiosensitization in MDA-MB-231 cells at MV X-ray energies. The sensitization was cell-specific with comparable effects at kV and MV energies, no increase in DSB formation, and GNP chemopotentiation with bleomycin, suggesting a possible biological mechanism of radiosensitization. Copyright © 2011 Elsevier Inc. All rights reserved.

Nitric oxide in B6 mouse and nitric oxide-sensitive soluble guanylate cyclase in cat modulate acetylcholine release in pontine reticular formation.

PubMed

Lydic, Ralph; Garza-Grande, Ricardo; Struthers, Richard; Baghdoyan, Helen A

2006-05-01

ACh regulates arousal, and the present study was designed to provide insight into the neurochemical mechanisms modulating ACh release in the pontine reticular formation. Nitric oxide (NO)-releasing beads microinjected into the pontine reticular formation of C57BL/6J (B6) mice significantly (P < 0.0001) increased ACh release. Microdialysis delivery of the NO donor N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine (NOC-12) to the mouse pontine reticular formation also caused a concentration-dependent increase in ACh release (P < 0.001). These are the first neurochemical data showing that ACh release in the pontine reticular formation of the B6 mouse is modulated by NO. The signal transduction cascade through which NO modulates ACh release in the pontine reticular formation has not previously been characterized. Therefore, an additional series of studies quantified the effects of a soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), on ACh release in the cat medial pontine reticular formation. During naturally occurring states of sleep and wakefulness, but not anesthesia, ODQ caused a significant (P < 0.001) decrease in ACh release. These results show for the first time that NO modulates ACh in the medial pontine reticular formation of the cat via an NO-sensitive sGC signal transduction cascade. Isoflurane and halothane anesthesia have been shown to decrease ACh release in the medial pontine reticular formation. The finding that ODQ did not alter ACh release during isoflurane or halothane anesthesia demonstrates that these anesthetics disrupt the NO-sensitive sGC-cGMP pathway. Considered together, results from the mouse and cat indicate that NO modulates ACh release in arousal-promoting regions of the pontine reticular formation via an NO-sensitive sGC-cGMP pathway.

Increased Susceptibility to Allergic Asthma with the Impairment of Respiratory Tolerance Caused by Psychological Stress.

PubMed

Kawano, Tasuku; Ouchi, Ryusuke; Ishigaki, Takahiro; Masuda, Chiaki; Miyasaka, Tomomitsu; Ohkawara, Yuichi; Ohta, Nobuo; Takayanagi, Motoaki; Takahashi, Tomoko; Ohno, Isao

2018-06-06

Bronchial asthma is characterized by type 2 T helper (Th2) cell inflammation, essentially due to a breakdown of immune tolerance to harmless environmental allergens. Etiologically, experiences of psychological stress can be associated with a heightened prevalence of asthma. However, the mechanisms underlying stress-related asthma development are unclear. In this study, we examined whether psychological stress increases susceptibility to allergic asthma by downregulating immune tolerance. Female BALB/c mice were sensitized with ovalbumin/alum, followed by ovalbumin inhalation. Ovalbumin inhalation induced immune tolerance before sensitization occurred. Some mice were exposed to restraint stress during tolerance induction or sensitization. Asthma development was evaluated by airway responsiveness, inflammation, cytokine expression, and IgE synthesis. Sensitization was evaluated by measuring proliferation and cytokine production by splenocytes. The effects of stress exposure on the numbers and functions of dendritic cells and regulatory T (Treg) cells in bronchial lymph nodes and spleens were evaluated. To investigate the role of endogenous glucocorticoid in inhibiting immune tolerance after stress exposure, we examined the effects of (i) a glucocorticoid-receptor antagonist administered prior to stress exposure, and (ii) exogenous gluco-corticoid (instead of stress exposure). Asthmatic responses and Th2-biased sensitization, which were suppressed in tolerized mice, re-emerged in tolerized mice stressed during tolerance induction in association with decreased tolerogenic dendritic and Treg cell numbers. The effects of stress exposure on tolerized mice were abolished by administering a glucocorticoid-receptor antagonist and reproduced by administering exogenous glucocorticoid without stress. Our findings suggested that psychological stress can potentially increase allergic asthma susceptibility by inhibiting immune tolerance. © 2018 S. Karger AG, Basel.

Insulin-like growth factor-I and insulin-like growth factor binding protein-3 cotreatment versus insulin-like growth factor-I alone in two brothers with growth hormone insensitivity syndrome: effects on insulin sensitivity, body composition and linear growth.

PubMed

Ekström, Klas; Carlsson-Skwirut, Christine; Ritzén, E Martin; Bang, Peter

2011-01-01

Growth hormone insensitivity syndrome (GHIS) is caused by a defective growth hormone receptor (GHR) and is associated with insulin-like growth factor-I (IGF-I) deficiency, severely short stature and, from adolescence, fasting hyperglycemia and obesity. We studied the effects of treatment with IGF-I in either a 1:1 molar complex with IGFBP-3 (IGF-I/BP-3-Tx) or with IGF-I alone (IGF-I-Tx) on metabolism and linear growth. Two brothers, compound heterozygous for a GHR gene defect, were studied. After 8 months without treatment, we examined the short- and long-term effects of IGF-I/BP-3-Tx and, subsequently, IGF-I-Tx on 12-hour overnight levels of IGF-I, GH, insulin, IGFBP-1, insulin sensitivity by hyperinsulinemic euglycemic clamp, body composition by dual-energy X-ray absorptiometry and linear growth. Mean overnight levels of insulin decreased and IGFBP-1, a measure of hepatic insulin sensitivity, increased on both regimens, but was more pronounced on IGF-I-Tx. Insulin sensitivity by clamp showed no consistent changes. Lean body mass increased and abdominal fat mass decreased in both subjects on IGF-I-Tx. However, the changes were inconsistent during IGF-I/BP-3-Tx. Height velocity was low without treatment, increased slightly on IGF-I/BP-3-Tx and doubled on IGF-I-Tx. Both modalities of IGF-I improved determinants of hepatic insulin sensitivity, body composition and linear growth rate; however, IGF-I alone seemed to be more efficient. Copyright © 2011 S. Karger AG, Basel.

GABAergic miniature postsynaptic currents in septal neurons show differential allosteric sensitivity after binge-like ethanol exposure.

PubMed

DuBois, Dustin W; Trzeciakowski, Jerome P; Parrish, Alan R; Frye, Gerald D

2006-05-17

Binge-like ethanol treatment of septal neurons blunts GABAAR-mediated miniature postsynaptic currents (mPSCs), suggesting it arrests synaptic development. Ethanol may disrupt postsynaptic maturation by blunting feedback signaling through immature GABAARs. Here, the impact of ethanol on the sensitivity of mPSCs to zolpidem, zinc and 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) was tested. The decay phase of mPSCs showed concentration-dependent potentiation by zolpidem (0.03-100 microM), which was substantially blunted after ethanol exposure. Since zolpidem potentiation exhibited a substantial age-dependent increase in untreated neurons, this finding supported the idea that ethanol arrests synaptic development. GABAAR alpha1 subunit protein also increased with age in untreated neurons, paralleling enhanced sensitivity to zolpidem. Surprisingly, alpha1 levels were not reduced by binge ethanol even though mPSCs were relatively zolpidem-insensitive. Zinc (3-30 microM) decreased mPSC parameters in a concentration- and age-related manner with older untreated cells showing less inhibition. However, there was no increase in mPSC zinc sensitivity after binge ethanol as would be expected if a general arrest of synaptic maturation had occurred. 3alpha-OH-DHP (3-1000 nM) induced concentration-dependent potentiation of mPSC decay. Although potentiation was age-independent, binge ethanol treatment exaggerated sensitivity to this neurosteroid. Finally, chronic picrotoxin pretreatment (100 microM) intended to mimic GABAAR inhibition from ethanol pretreatment did not significantly change mPSC modulation by zolpidem, zinc or 3alpha-OH-DHP. These results suggest that binge ethanol treatment selectively arrests a subset of processes important for maturation of postsynaptic GABAA Rs. However, it is unlikely that ethanol causes a broad arrest of postsynaptic development through a direct inhibition of GABAAR signaling.

Development and testing of vortex generators for small horizontal axis wind turbines

NASA Technical Reports Server (NTRS)

Gyatt, G. W.

1986-01-01

Vortex generators (VGs) for a small (32 ft diameter) horizontal axis wind turbine, the Carter Model 25, have been developed and tested. Arrays of VGs in a counterrotating arrangement were tested on the inbound half-span, outboard half-span, and on the entire blade. VG pairs had their centerlines spaced at a distance of 15% of blade chord, with a spanwise width of 10% of blade chord. Each VG had a length/height ratio of 4, with a height of between 0.5% and 1.0% of the blade chord. Tests were made with roughness strips to determine whether VGs alleviated the sensitivity of some turbines to an accumulation of bugs and dirt on the leading edge. Field test data showed that VGs increased power output up to 20% at wind speeds above 10 m/s with only a small (less than 4%) performance penalty at lower speeds. The VGs on the outboard span of the blade were more effective than those on inner sections. For the case of full span coverage, the energy yearly output increased almost 6% at a site with a mean wind speed of 16 mph. The VGs did reduce the performance loss caused by leading edge roughness. An increase in blade pitch angle has an effect on the power curve similar to the addition of VGs. VGs alleviate the sensitivity of wind turbine rotors to leading edge roughness caused by bugs and drift.

Generation and analysis of the thiazide-sensitive Na+ -Cl- cotransporter (Ncc/Slc12a3) Ser707X knockin mouse as a model of Gitelman syndrome.

PubMed

Yang, Sung-Sen; Lo, Yi-Fen; Yu, I-Shing; Lin, Shu-Wha; Chang, Tai-Hsiang; Hsu, Yu-Juei; Chao, Tai-Kuang; Sytwu, Huey-Kang; Uchida, Shinichi; Sasaki, Sei; Lin, Shih-Hua

2010-12-01

Gitelman syndrome (GS) is characterized by salt-losing hypotension, hypomagnesemia, hypokalemic metabolic alkalosis, and hypocalciuria. To better model human GS caused by a specific mutation in the thiazide-sensitive Na(+) -Cl(-) cotransporter (NCC) gene SLC12A3, we generated a nonsense Ncc Ser707X knockin mouse corresponding to human p.Ser710X (c.2135C>A), a recurrent mutation with severe phenotypes in Chinese GS patients. Compared with wild-type or heterozygous littermates, homozygous (Hom) knockin mice fully recapitulated the phenotype of human GS. The markedly reduced Ncc mRNA and virtually absent Ncc protein expression in kidneys of Hom mice was primarily due to nonsense-mediated mRNA decay (NMD) surveillance mechanisms. Expression of epithelial Na(+) channel (Enac), Ca(2+) channels (Trpv5 and Trpv6), and K(+) channels (Romk1 and maxi-K) were significantly increased. Late distal convoluted tubules (DCT) volume was increased and DCT cell ultrastructure appeared intact. High K(+) intake could not correct hypokalemia but caused a further increase in maxi-K but not Romk1 expression. Renal tissue from a patient with GS also showed the enhanced TRPV5 and ROMK1 expression in distal tubules. We suggest that the upregulation of TRPV5/6 and of ROMK1 and Maxi-K may contribute to hypocalciuria and hypokalemia in Ncc Ser707X knockin mice and human GS, respectively. © 2010 Wiley-Liss, Inc.

HCM and DCM cardiomyopathy-linked α-tropomyosin mutations influence off-state stability and crossbridge interaction on thin filaments.

PubMed

Farman, Gerrie P; Rynkiewicz, Michael J; Orzechowski, Marek; Lehman, William; Moore, Jeffrey R

2018-06-01

Calcium regulation of cardiac muscle contraction is controlled by the thin-filament proteins troponin and tropomyosin bound to actin. In the absence of calcium, troponin-tropomyosin inhibits myosin-interactions on actin and induces muscle relaxation, whereas the addition of calcium relieves the inhibitory constraint to initiate contraction. Many mutations in thin filament proteins linked to cardiomyopathy appear to disrupt this regulatory switching. Here, we tested perturbations caused by mutant tropomyosins (E40K, DCM; and E62Q, HCM) on intra-filament interactions affecting acto-myosin interactions including those induced further by myosin association. Comparison of wild-type and mutant human α-tropomyosin (Tpm1.1) behavior was carried out using in vitro motility assays and molecular dynamics simulations. Our results show that E62Q tropomyosin destabilizes thin filament off-state function by increasing calcium-sensitivity, but without apparent affect on global tropomyosin structure by modifying coiled-coil rigidity. In contrast, the E40K mutant tropomyosin appears to stabilize the off-state, demonstrates increased tropomyosin flexibility, while also decreasing calcium-sensitivity. In addition, the E40K mutation reduces thin filament velocity at low myosin concentration while the E62Q mutant tropomyosin increases velocity. Corresponding molecular dynamics simulations indicate specific residue interactions that are likely to redefine underlying molecular regulatory mechanisms, which we propose explain the altered contractility evoked by the disease-causing mutations. Copyright © 2018 Elsevier Inc. All rights reserved.

Next-generation sequencing-based method shows increased mutation detection sensitivity in an Indian retinoblastoma cohort

PubMed Central

Singh, Jaya; Mishra, Avshesh; Pandian, Arunachalam Jayamuruga; Mallipatna, Ashwin C.; Khetan, Vikas; Sripriya, S.; Kapoor, Suman; Agarwal, Smita; Sankaran, Satish; Katragadda, Shanmukh; Veeramachaneni, Vamsi; Hariharan, Ramesh; Subramanian, Kalyanasundaram

2016-01-01

Purpose Retinoblastoma (Rb) is the most common primary intraocular cancer of childhood and one of the major causes of blindness in children. India has the highest number of patients with Rb in the world. Mutations in the RB1 gene are the primary cause of Rb, and heterogeneous mutations are distributed throughout the entire length of the gene. Therefore, genetic testing requires screening of the entire gene, which by conventional sequencing is time consuming and expensive. Methods In this study, we screened the RB1 gene in the DNA isolated from blood or saliva samples of 50 unrelated patients with Rb using the TruSight Cancer panel. Next-generation sequencing (NGS) was done on the Illumina MiSeq platform. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. Results We were able to detect germline pathogenic mutations in 66% (33/50) of the cases, 12 of which were novel. We were able to detect all types of mutations, including missense, nonsense, splice site, indel, and structural variants. When we considered bilateral Rb cases only, the mutation detection rate increased to 100% (22/22). In unilateral Rb cases, the mutation detection rate was 30% (6/20). Conclusions Our study suggests that NGS-based approaches increase the sensitivity of mutation detection in the RB1 gene, making it fast and cost-effective compared to the conventional tests performed in a reflex-testing mode. PMID:27582626

Patient-specific structural effects on hemodynamics in the ischemic lower limb artery

NASA Astrophysics Data System (ADS)

Xu, Pengcheng; Liu, Xin; Song, Qi; Chen, Guishan; Wang, Defeng; Zhang, Heye; Yan, Li; Liu, Dan; Huang, Wenhua

2016-12-01

Lower limb peripheral artery disease is a prevalent chronic non-communicable disease without obvious symptoms. However, the effect of ischemic lower limb peripheral arteries on hemodynamics remains unclear. In this study, we investigated the variation of the hemodynamics caused by patient-specific structural artery characteristics. Computational fluid dynamic simulations were performed on seven lower limb (including superficial femoral, deep femoral and popliteal) artery models that were reconstructed from magnetic resonance imaging. We found that increased wall shear stress (WSS) was mainly caused by the increasing severity of stenosis, bending, and branching. Our results showed that the increase in the WSS value at a stenosis at the bifurcation was 2.7 Pa. In contrast, the isolated stenosis and branch caused a WSS increase of 0.7 Pa and 0.5 Pa, respectively. The WSS in the narrow popliteal artery was more sensitive to a reduction in radius. Our results also demonstrate that the distribution of the velocity and pressure gradient are highly structurally related. At last, Ultrasound Doppler velocimeter measured result was presented as a validation. In conclusion, the distribution of hemodynamics may serve as a supplement for clinical decision-making to prevent the occurrence of a morbid or mortal ischemic event.

Clostridium difficile in the ICU: the struggle continues.

PubMed

Bobo, Linda D; Dubberke, Erik R; Kollef, Marin

2011-12-01

Clostridium difficile infection (CDI) management has become more daunting over the past decade because of alarming increases in CDI incidence and severity both in the hospital and in the community. This increase has concomitantly caused significant escalation of the health-care economic burden caused by CDI, and it will likely be translated to increased ICU admission and attributable mortality. Some possible causes for difficulty in management of CDI are as follows: (1) inability to predict and prevent development of severe/complicated or relapsing CDI in patients who initially present with mild symptoms; (2) lack of a method to determine who would have benefited a priori from initiating vancomycin treatment first instead of treatment with metronidazole; (3) lack of sensitive and specific CDI diagnostics; (4) changing epidemiology of CDI, including the emergence of a hypervirulent, epidemic C difficile strain associated with increased morbidity and mortality; (5) association of certain high-usage nonantimicrobial medications with CDI; and (6) lack of treatment regimens that leave the normal intestinal flora undisturbed while treating the primary infection. The objective of this article is to present current management and prevention guidelines for CDI based on recommendations by the Society for Healthcare Epidemiology of America and Infectious Diseases Society of America and potential new clinical management strategies on the horizon.

Clostridium difficile in the ICU

PubMed Central

Dubberke, Erik R.; Kollef, Marin

2011-01-01

Clostridium difficile infection (CDI) management has become more daunting over the past decade because of alarming increases in CDI incidence and severity both in the hospital and in the community. This increase has concomitantly caused significant escalation of the health-care economic burden caused by CDI, and it will likely be translated to increased ICU admission and attributable mortality. Some possible causes for difficulty in management of CDI are as follows: (1) inability to predict and prevent development of severe/complicated or relapsing CDI in patients who initially present with mild symptoms; (2) lack of a method to determine who would have benefited a priori from initiating vancomycin treatment first instead of treatment with metronidazole; (3) lack of sensitive and specific CDI diagnostics; (4) changing epidemiology of CDI, including the emergence of a hypervirulent, epidemic C difficile strain associated with increased morbidity and mortality; (5) association of certain high-usage nonantimicrobial medications with CDI; and (6) lack of treatment regimens that leave the normal intestinal flora undisturbed while treating the primary infection. The objective of this article is to present current management and prevention guidelines for CDI based on recommendations by the Society for Healthcare Epidemiology of America and Infectious Diseases Society of America and potential new clinical management strategies on the horizon. PMID:22147824

SUBCHRONIC ENDOTOXIN INHALATION CAUSES CHRONIC AIRWAY DISEASE IN ENDOTOXIN-SENSITIVE BUT NOT ENDOTOXIN-RESISTANT MICE

EPA Science Inventory

SUBCHRONIC ENDOTOXIN INHALATION CAUSES CHRONIC AIRWAY DISEASE IN ENDOTOXIN-SENSITIVE BUT NOT ENDOTOXIN-RESISTANT MICE. D. M. Brass, J. D. Savov, *S. H. Gavett, ?C. George, D. A. Schwartz. Duke Univ Medical Center Durham, NC, *U.S. E.P.A. Research Triangle Park, NC, ?Univ of Iowa,...

Metabolic acidosis and 5-oxoprolinuria induced by flucloxacillin and acetaminophen: a case report.

PubMed

Lanoy, Charlotte; Bouckaert, Yves

2016-06-23

Frequent causes of high anion gap metabolic acidosis are well known: ethanol, methanol, and ethylene glycol intoxication; hyperglycemia; lactic or D-lactic acidosis; and impaired renal function. There are other causes, less frequent but also important. This report illustrates a rare case of a patient with increased anion gap metabolic acidosis due to a deficit of the γ-glutamyl cycle that led to 5-oxoproline (acid pyroglutamic) accumulation. An 82-year-old white woman was admitted to our intensive care unit because of septic shock caused by right knee methicillin-sensitive Staphylococcus aureus-induced arthritis. She was treated for 10 days with flucloxacillin and rifampicin and developed metabolic acidosis with high anion gap. Her test results for methanol, ethanol, ethylene glycol, and acetylsalicylic acid were negative. Her glycemia, lactate level, and renal function were normal. However, the result of a urinary assay for pyroglutamate was positive. We concluded that the patient had metabolic acidosis induced by accumulation of 5-oxoproline. We modified her antibiotic treatment, administered acetylcysteine, and her acidosis resolved. 5-Oxoprolinuria (pyroglutamic acid accumulation) is a rare, probably underdiagnosed cause of transient metabolic acidosis with increased anion gap.

Anisotropic analysis for seismic sensitivity of groundwater monitoring wells

NASA Astrophysics Data System (ADS)

Pan, Y.; Hsu, K.

2011-12-01

Taiwan is located at the boundaries of Eurasian Plate and the Philippine Sea Plate. The movement of plate causes crustal uplift and lateral deformation to lead frequent earthquakes in the vicinity of Taiwan. The change of groundwater level trigged by earthquake has been observed and studied in Taiwan for many years. The change of groundwater may appear in oscillation and step changes. The former is caused by seismic waves. The latter is caused by the volumetric strain and reflects the strain status. Since the setting of groundwater monitoring well is easier and cheaper than the setting of strain gauge, the groundwater measurement may be used as a indication of stress. This research proposes the concept of seismic sensitivity of groundwater monitoring well and apply to DonHer station in Taiwan. Geostatistical method is used to analysis the anisotropy of seismic sensitivity. GIS is used to map the sensitive area of the existing groundwater monitoring well.

Retrospective Validation of a Surveillance System for Unexplained Illness and Death: New Haven County, Connecticut

PubMed Central

Kluger, Michael D.; Sofair, Andre N.; Heye, Constance J.; Meek, James I.; Sodhi, Rajesh K.; Hadler, James L.

2001-01-01

Objectives. This study investigated retrospective validation of a prospective surveillance system for unexplained illness and death due to possibly infectious causes. Methods. A computerized search of hospital discharge data identified patients with potential unexplained illness and death due to possibly infectious causes. Medical records for such patients were reviewed for satisfaction of study criteria. Cases identified retrospectively were combined with prospectively identified cases to form a reference population against which sensitivity could be measured. Results. Retrospective validation was 41% sensitive, whereas prospective surveillance was 73% sensitive. The annual incidence of unexplained illness and death due to possibly infectious causes during 1995 and 1996 in the study county was conservatively estimated to range from 2.7 to 6.2 per 100 000 residents aged 1 to 49 years. Conclusions. Active prospective surveillance for unexplained illness and death due to possibly infectious causes is more sensitive than retrospective surveillance conducted through a published list of indicator codes. However, retrospective surveillance can be a feasible and much less labor-intensive alternative to active prospective surveillance when the latter is not possible or desired. PMID:11499106

Increases in tibial force imbalance but not changes in tibiofemoral laxities are caused by varus-valgus malalignment of the femoral component in kinematically aligned TKA.

PubMed

Riley, Jeremy; Roth, Joshua D; Howell, Stephen M; Hull, Maury L

2018-01-29

The purposes of this study were to quantify the increase in tibial force imbalance (i.e. magnitude of difference between medial and lateral tibial forces) and changes in laxities caused by 2° and 4° of varus-valgus (V-V) malalignment of the femoral component in kinematically aligned total knee arthroplasty (TKA) and use the results to detemine sensitivities to errors in making the distal femoral resections. Because V-V malalignment would introduce the greatest changes in the alignment of the articular surfaces at 0° flexion, the hypotheses were that the greatest increases in tibial force imbalance would occur at 0° flexion, that primarily V-V laxity would significantly change at this flexion angle, and that the tibial force imbalance would increase and laxities would change in proportion to the degree of V-V malalignment. Kinematically aligned TKA was performed on ten human cadaveric knee specimens using disposable manual instruments without soft tissue release. One 3D-printed reference femoral component, with unmodified geometry, was aligned to restore the native distal and posterior femoral joint lines. Four 3D-printed femoral components, with modified geometry, introduced V-V malalignments of 2° and 4° from the reference component. Medial and lateral tibial forces were measured during passive knee flexion-extension between 0° to 120° using a custom tibial force sensor. Eight laxities were measured from 0° to 120° flexion using a six degree-of-freedom load application system. With the tibial component kinematically aligned, the increase in the tibial force imbalance from that of the reference component at 0° of flexion was sensitive to the degree of V-V malalignment of the femoral component. Sensitivities were 54 N/deg (medial tibial force increasing > lateral tibial force) (p < 0.0024) and 44 N/deg (lateral tibial force increasing > medial tibial force) (p < 0.0077) for varus and valgus malalignments, respectively. Varus-valgus malalignment did not significantly change varus, internal-external rotation, anterior-posterior, and compression-distraction laxities from 0° to 120° flexion. At only 30° of flexion, 4° of varus malalignment increased valgus laxity 1° (p = 0.0014). At 0° flexion, V-V malalignment of the femoral component caused the tibial force imbalance to increase significantly, whereas the laxities were relatively unaffected. Because tibial force imbalance has the potential to adversely affect patient-reported outcomes and satisfaction, surgeons should strive to limit errors in resecting the distal femoral condyles to within ± 0.5 mm which in turn limits the average increase in tibial force imbalance to 68 N. Because laxities were generally unaffected, instability resulting from large increases in laxity is not a clinical concern within the ± 4° range tested. Therapeutic, Level II.

Pessimistic, Anxious, and Depressive Personality Traits Predict All-Cause Mortality: The Mayo Clinic Cohort Study of Personality and Aging

PubMed Central

Grossardt, Brandon R.; Bower, James H.; Geda, Yonas E.; Colligan, Robert C.; Rocca, Walter A.

2011-01-01

Objective To study the association between several personality traits and all-cause mortality. Methods We established a historical cohort of 7216 subjects who completed the Minnesota Multiphasic Personality Inventory (MMPI) for research at the Mayo Clinic from 1962 to 1965, and who resided within a 120-mile radius centered in Rochester, MN. A total of 7080 subjects (98.1%) were followed over four decades either actively (via a direct or proxy telephone interview) or passively (via review of medical records or by obtaining their death certificates). We examined the association of pessimistic, anxious, and depressive personality traits (as measured using MMPI scales) with all-cause mortality. Results A total of 4634 subjects (65.5%) died during follow-up. Pessimistic, anxious, and depressive personality traits were associated with increased all-cause mortality in both men and women. In addition, we observed a linear trend of increasing risk from the first to the fourth quartile for all three scales. Results were similar in additional analyses considering the personality scores as continuous variables, in analyses combining the three personality traits into a composite neuroticism score, and in several sets of sensitivity analyses. These associations remained significant even when personality was measured early in life (ages 20 to 39 years). Conclusions Our findings suggest that personality traits related to neuroticism are associated with an increased risk of all-cause mortality even when they are measured early in life. PMID:19321849

SRAM As An Array Of Energetic-Ion Detectors

NASA Technical Reports Server (NTRS)

Buehler, Martin G.; Blaes, Brent R.; Lieneweg, Udo; Nixon, Robert H.

1993-01-01

Static random-access memory (SRAM) designed for use as array of energetic-ion detectors. Exploits well-known tendency of incident energetic ions to cause bit flips in cells of electronic memories. Design of ion-detector SRAM involves modifications of standard SRAM design to increase sensitivity to ions. Device fabricated by use of conventional complementary metal oxide/semiconductor (CMOS) processes. Potential uses include gas densimetry, position sensing, and measurement of cosmic-ray spectrum.

[Hereditary fructose intolerance (HFI) as cause of isolated gamma GT rise in a 5-year old boy with hepatomegaly].

PubMed

Wössmann, W; Wiemann, J; Körber, F; Gortner, L

2000-01-01

The diagnosis of HFI is easily missed during childhood. It should be suspected in children presenting with hepatomegaly and an isolated increase in GGT. A carefully taken nutritional history forms the basis of the diagnosis of HFI which can be confirmed by molecular analysis with a sensitivity of > 95%. I.v. fructose tolerance tests and liver biopsies often can be omitted.

Private Information Retrieval Techniques for Enabling Location Privacy in Location-Based Services

NASA Astrophysics Data System (ADS)

Khoshgozaran, Ali; Shahabi, Cyrus

The ubiquity of smartphones and other location-aware hand-held devices has resulted in a dramatic increase in popularity of location-based services (LBS) tailored to user locations. The comfort of LBS comes with a privacy cost. Various distressing privacy violations caused by sharing sensitive location information with potentially malicious services have highlighted the importance of location privacy research aiming to protect user privacy while interacting with LBS.

Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.

PubMed

de Lemos, James A; Drazner, Mark H; Omland, Torbjorn; Ayers, Colby R; Khera, Amit; Rohatgi, Anand; Hashim, Ibrahim; Berry, Jarett D; Das, Sandeep R; Morrow, David A; McGuire, Darren K

2010-12-08

Detectable levels of cardiac troponin T (cTnT) are strongly associated with structural heart disease and increased risk of death and adverse cardiovascular events; however, cTnT is rarely detectable in the general population using standard assays. To determine the prevalence and determinants of detectable cTnT in the population using a new highly sensitive assay and to assess whether cTnT levels measured with the new assay associate with pathological cardiac phenotypes and subsequent mortality. Cardiac troponin T levels were measured using both the standard and the highly sensitive assays in 3546 individuals aged 30 to 65 years enrolled between 2000 and 2002 in the Dallas Heart Study, a multiethnic, population-based cohort study. Mortality follow-up was complete through 2007. Participants were placed into 5 categories based on cTnT levels. Magnetic resonance imaging measurements of cardiac structure and function and mortality through a median of 6.4 (interquartile range, 6.0-6.8) years of follow-up. In Dallas County, the prevalence of detectable cTnT (≥0.003 ng/mL) was 25.0% (95% confidence interval [CI], 22.7%-27.4%) with the highly sensitive assay vs 0.7% (95% CI, 0.3%-1.1%) with the standard assay. Prevalence was 37.1% (95% CI, 33.3%-41.0%) in men vs 12.9% (95% CI, 10.6%-15.2%) in women and 14.0% (95% CI, 11.2%-16.9%) in participants younger than 40 years vs 57.6% (95% CI, 47.0%-68.2%) in those 60 years and older. Prevalence of left ventricular hypertrophy increased from 7.5% (95% CI, 6.4%-8.8%) in the lowest cTnT category (<0.003 ng/mL) to 48.1% (95% CI, 36.7%-59.6%) in the highest (≥0.014 ng/mL) (P < .001); prevalence of left ventricular systolic dysfunction and chronic kidney disease also increased across categories (P < .001 for each). During a median follow-up of 6.4 years, there were 151 total deaths, including 62 cardiovascular disease deaths. All-cause mortality increased from 1.9% (95% CI, 1.5%-2.6%) to 28.4% (95% CI, 21.0%-37.8%) across higher cTnT categories (P < .001). After adjustment for traditional risk factors, C-reactive protein level, chronic kidney disease, and N-terminal pro-brain-type natriuretic peptide level, cTnT category remained independently associated with all-cause mortality (adjusted hazard ratio, 2.8 [95% CI, 1.4-5.2] in the highest category). Adding cTnT categories to the fully adjusted mortality model modestly improved model fit (P = .02) and the integrated discrimination index (0.010 [95% CI, 0.002-0.018]; P = .01). In this population-based cohort, cTnT detected with a highly sensitive assay was associated with structural heart disease and subsequent risk for all-cause mortality.

Multiple P2Y receptor subtypes in the apical membranes of polarized epithelial cells

PubMed Central

McAlroy, H L; Ahmed, S; Day, S M; Baines, D L; Wong, H Y; Yip, C Y; Ko, W H; Wilson, S M; Collett, A

2000-01-01

Apical ATP, ATP, UTP and UDP evoked transient increases in short circuit current (ISC, a direct measure of transepithelial ion transport) in confluent Caco-2 cells grown on permeable supports. These responses were mediated by a population of at least three pharmacologically distinct receptors. Experiments using cells grown on glass coverslips showed that ATP and UTP consistently increased intracellular free calcium ([Ca2+]i) whilst sensitivity to UDP was variable. Cross desensitization experiments suggested that the responses to UTP and ATP were mediated by a common receptor population. Messenger RNA transcripts corresponding to the P2Y2, P2Y4 and P2Y6 receptors genes were detected in cells grown on Transwell membranes by the reverse transcriptase–polymerase chain reaction. Identical results were obtained for cells grown on glass. Experiments in which ISC and [Ca2+]i were monitored simultaneously in cells on Transwell membranes, confirmed that apical ATP and UTP increased both parameters and showed that the UDP-evoked increase in ISC was accompanied by a [Ca2+]i-signal. Ionomycin consistently increased [Ca2+]i in such polarized cells but caused no discernible change in ISC. However, subsequent application of apical ATP or UTP evoked a small rise in ISC but no rise in [Ca2+]i. UDP evoked no such response. As well as evoking increases in [Ca2+]i, the ATP/UTP-sensitive receptors present in Caco-2 cells thus allow direct control over ion channels in the apical membrane. The UDP-sensitive receptors, however, appear to simply evoke a rise in [Ca2+]i. PMID:11139443

Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and alzheimer disease: results from the Framingham Heart Study.

PubMed

van Himbergen, Thomas M; Beiser, Alexa S; Ai, Masumi; Seshadri, Sudha; Otokozawa, Seiko; Au, Rhoda; Thongtang, Nuntakorn; Wolf, Philip A; Schaefer, Ernst J

2012-05-01

To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A(2) levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia. Prospective cohort study. Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia. Eight hundred forty (541 women, median age of 76 years) subjects participated in the study. We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ε4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD. Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P=.054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P=.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P=.04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P=.01) as compared with those with values less than the median. In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.

S-nitrosylation and S-glutathionylation of Cys134 on troponin I have opposing competitive actions on Ca2+ sensitivity in rat fast-twitch muscle fibers.

PubMed

Dutka, T L; Mollica, J P; Lamboley, C R; Weerakkody, V C; Greening, D W; Posterino, G S; Murphy, R M; Lamb, G D

2017-03-01

Nitric oxide is generated in skeletal muscle with activity and decreases Ca 2+ sensitivity of the contractile apparatus, putatively by S- nitrosylation of an unidentified protein. We investigated the mechanistic basis of this effect and its relationship to the oxidation-induced increase in Ca 2+ sensitivity in mammalian fast-twitch (FT) fibers mediated by S- glutathionylation of Cys134 on fast troponin I (TnI f ). Force-[Ca 2+ ] characteristics of the contractile apparatus in mechanically skinned fibers were assessed by direct activation with heavily Ca 2+ -buffered solutions. Treatment with S- nitrosylating agents, S- nitrosoglutathione (GSNO) or S- nitroso- N -acetyl-penicillamine (SNAP), decreased pCa 50 ( = -log 10 [Ca 2+ ] at half-maximal activation) by ~-0.07 pCa units in rat and human FT fibers without affecting maximum force, but had no effect on rat and human slow-twitch fibers or toad or chicken FT fibers, which all lack Cys134. The Ca 2+ sensitivity decrease was 1 ) fully reversed with dithiothreitol or reduced glutathione, 2 ) at least partially reversed with ascorbate, indicative of involvement of S-nitrosylation, and 3 ) irreversibly blocked by low concentration of the alkylating agent, N -ethylmaleimide (NEM). The biotin-switch assay showed that both GSNO and SNAP treatments caused S- nitrosylation of TnI f S- glutathionylation pretreatment blocked the effects of S- nitrosylation on Ca 2+ sensitivity, and vice-versa. S- nitrosylation pretreatment prevented NEM from irreversibly blocking S- glutathionylation of TnI f and its effects on Ca 2+ sensitivity, and likewise S- glutathionylation pretreatment prevented NEM block of S- nitrosylation. Following substitution of TnI f into rat slow-twitch fibers, S- nitrosylation treatment caused decreased Ca 2+ sensitivity. These findings demonstrate that S- nitrosylation and S- glutathionylation exert opposing effects on Ca 2+ sensitivity in mammalian FT muscle fibers, mediated by competitive actions on Cys134 of TnI f . Copyright © 2017 the American Physiological Society.

Impact of the Mycobaterium africanum West Africa 2 Lineage on TB Diagnostics in West Africa: Decreased Sensitivity of Rapid Identification Tests in The Gambia.

PubMed

Ofori-Anyinam, Boatema; Kanuteh, Fatoumatta; Agbla, Schadrac C; Adetifa, Ifedayo; Okoi, Catherine; Dolganov, Gregory; Schoolnik, Gary; Secka, Ousman; Antonio, Martin; de Jong, Bouke C; Gehre, Florian

2016-07-01

MPT64 rapid speciation tests are increasingly being used in diagnosis of tuberculosis (TB). Mycobacterium africanum West Africa 2 (Maf 2) remains an important cause of TB in West Africa and causes one third of disease in The Gambia. Since the introduction of MPT64 antigen tests, a higher than expected rate of suspected non-tuberculous mycobacteria (NTM) was seen among AFB smear positive TB suspects, which led us to prospectively assess sensitivity of the MPT64 antigen test in our setting. We compared the abundance of mRNA encoded by the mpt64 gene in sputa of patients with untreated pulmonary TB caused by Maf 2 and Mycobacterium tuberculosis (Mtb). Subsequently, prospectively collected sputum samples from presumptive TB patients were inoculated in the BACTEC MGIT 960 System. One hundred and seventy-three acid fast bacilli (AFB)-positive and blood agar negative MGIT cultures were included in the study. Cultures were tested on the day of MGIT positivity with the BD MGIT TBc Identification Test. A random set of positives and all negatives were additionally tested with the SD Bioline Ag MPT64 Rapid. MPT64 negative cultures were further incubated at 37°C and retested until positive. Bacteria were spoligotyped and assigned to different lineages. Maf 2 isolates were 2.52-fold less likely to produce a positive test result and sensitivity ranged from 78.4% to 84.3% at the beginning and end of the recommended 10 day testing window, respectively. There was no significant difference between the tests. We further showed that the decreased rapid test sensitivity was attributable to variations in mycobacterial growth behavior and the smear grades of the patient. In areas where Maf 2 is endemic MPT64 tests should be cautiously used and MPT64 negative results confirmed by a second technique, such as nucleic acid amplification tests, to avoid their misclassification as NTMs.

Neonatal Diabetes Caused by Mutations in Sulfonylurea Receptor 1: Interplay between Expression and Mg-Nucleotide Gating Defects of ATP-Sensitive Potassium Channels

PubMed Central

Zhou, Qing; Garin, Intza; Castaño, Luis; Argente, Jesús; Muñoz-Calvo, Ma. Teresa; Perez de Nanclares, Guiomar; Shyng, Show-Ling

2010-01-01

Context: ATP-sensitive potassium (KATP) channels regulate insulin secretion by coupling glucose metabolism to β-cell membrane potential. Gain-of-function mutations in the sulfonylurea receptor 1 (SUR1) or Kir6.2 channel subunit underlie neonatal diabetes. Objective: The objective of the study was to determine the mechanisms by which two SUR1 mutations, E208K and V324M, associated with transient neonatal diabetes affect KATP channel function. Design: E208K or V324M mutant SUR1 was coexpressed with Kir6.2 in COS cells, and expression and gating properties of the resulting channels were assessed biochemically and electrophysiologically. Results: Both E208K and V324M augment channel response to MgADP stimulation without altering sensitivity to ATP4− or sulfonylureas. Surprisingly, whereas E208K causes only a small increase in MgADP response consistent with the mild transient diabetes phenotype, V324M causes a severe activating gating defect. Unlike E208K, V324M also impairs channel expression at the cell surface, which is expected to dampen its functional impact on β-cells. When either mutation was combined with a mutation in the second nucleotide binding domain of SUR1 previously shown to abolish Mg-nucleotide response, the activating effect of E208K and V324M was also abolished. Moreover, combination of E208K and V324M results in channels with Mg-nucleotide sensitivity greater than that seen in individual mutations alone. Conclusion: The results demonstrate that E208K and V324M, located in distinct domains of SUR1, enhance transduction of Mg-nucleotide stimulation from the SUR1 nucleotide binding folds to Kir6.2. Furthermore, they suggest that diabetes severity is determined by interplay between effects of a mutation on channel expression and channel gating. PMID:20810569

Relative Sensitivity of Photosynthesis and Respiration to Freeze-Thaw Stress in Herbaceous Species 1

PubMed Central

Steffen, Kenneth L.; Arora, Rajeev; Palta, Jiwan P.

1989-01-01

The relative effect of a freeze-thaw cycle on photosynthesis, respiration, and ion leakage of potato leaf tissue was examined in two potato species, Solanum acaule Bitt. and Solanum commersonii Dun. Photosynthesis was found to be much more sensitive to freezing stress than was respiration, and demonstrated more than a 60% inhibition before any impairment of respiratory function was observed. Photosynthesis showed a slight to moderate inhibition when only 5 to 10% of the total electrolytes had leaked from the tissue (reversible injury). This was in contrast to respiration which showed no impairment until temperatures at which about 50% ion leakage (irreversible injury) had occurred. The influence of freeze-thaw protocol was further examined in S. acaule and S. commersonii, in order to explore discrepancies in the literature as to the relative sensitivities of photosynthesis and respiration. As bath cooling rates increased from 1°C/hour to about 3 or 6°C/hour, there was a dramatic increase in the level of damage to all measured cellular functions. The initiation of ice formation in deeply supercooled tissue caused even greater damage. As the cooling rates used in stress treatments increased, the differential sensitivity between photosynthesis and respiration nearly disappeared. Examination of agriculturally relevant, climatological data from an 11 year period confirmed that air cooling rates in the freezing range do not exceed 2°C/hour. It was demonstrated, in the studies presented here, that simply increasing the actual cooling rate from 1.0 to 2.9°C/hour, in frozen tissue from paired leaflet halves, meant the difference between cell survival and cell death. Images Figure 4 Figure 5 PMID:16666712

Involvement of urban living environments in atopy and enhanced eosinophil activity: potential risk factors of airway allergic symptoms.

PubMed

Kuwahara, Y; Kondoh, J; Tatara, K; Azuma, E; Nakajima, T; Hashimoto, M; Komachi, Y

2001-03-01

Airway allergic diseases, such as bronchial asthma and allergic rhinitis, have increased, especially in urban areas. These diseases are characterized by airway inflammation with enhanced eosinophil activity, and the risk of disease development has been shown to increase with the prevalence of atopy. Questionnaires were administered to 426 healthy adult women aged 30-74 years, living in an urban area of Osaka, Japan, to survey individual living environments and airway allergic symptoms such as cough, sputum, and wheezing. Moreover, serum house-dust-mite (Dermatophagoides pteronyssinus, [Der p])-specific immunoglobulin E (IgE) and serum eosinophil cationic protein (ECP) were examined by radioimmunoassay, and the atopic status (atopic sensitization) and enhanced eosinophil activity were assessed as Der p-specific IgE RAST scores of 2-6 and ECP levels of more than 10 ng/ml, respectively. Intensive use of electric air conditioners in hot weather (odds ratio: 2.07 [95% CI: 1.11-3.87]) and mold proliferation in the kitchen (2.77 [1.34-5.73]) significantly increased the risk of atopic sensitization. Poor home ventilation and family smoking appeared to be positively but not significantly associated with atopic sensitization. Personal smoking and intensive use of the air conditioner appeared to be positively related to enhanced eosinophil activity. Atopic status showed significant involvement in the development of wheezing, and the development of cough was significantly associated with enhanced eosinophil activity. The results suggest that some urban styles of living are involved in atopic sensitization and enhanced eosinophil activity in the Japanese urban population, probably due to living conditions, such as indoor dampness and poor home ventilation, caused by tight insulation, which increase exposure to indoor air pollutants, such as respirable mite allergens and tobacco smoke.

Repeated thermal stressor causes chronic elevation of baseline corticosterone and suppresses the physiological endocrine sensitivity to acute stressor in the cane toad (Rhinella marina).

PubMed

Narayan, Edward J; Hero, Jean-Marc

2014-04-01

Extreme environmental temperature could impact the physiology and ecology of animals. The stress endocrine axis provides necessary physiological stress response to acute (day-day) stressors. Presently, there are no empirical evidences showing that exposure to extreme thermal stressor could cause chronic stress in amphibians. This could also modulate the physiological endocrine sensitivity to acute stressors and have serious implications for stress coping in amphibians, particularly those living in fragmented and disease prone environments. We addressed this important question using the cane toad (Rhinella marina) model from its introduced range in Queensland, Australia. We quantified their physiological endocrine sensitivity to a standard acute (capture and handling) stressor after exposing the cane toads to thermal shock at 35°C for 30min daily for 34 days. Corticosterone (CORT) responses to the capture and handling protocol were measured on three sampling intervals (days 14, 24, and 34) to determine whether the physiological endocrine sensitivity was maintained or modulated over-time. Two control groups (C1 for baseline CORT measurement only and C2 acute handled only) and two temperature treatment groups (T1 received daily thermal shock up to day 14 only and a recovery phase of 20 days and T2 received thermal shock daily for 34 days). Results showed that baseline CORT levels remained high on day 14 (combined effect of capture, captivity and thermal stress) for both T1 and T2. Furthermore, baseline CORT levels decreased for T1 once the thermal shock was removed after day 14 and returned to baseline by day 29. On the contrary, baseline CORT levels kept on increasing for T2 over the 34 days of daily thermal shocks. Furthermore, the magnitudes of the acute CORT responses or physiological endocrine sensitivity were consistently high for both C1 and T1. However, acute CORT responses for T2 toads were dramatically reduced between days 24 and 34. These novel findings suggest that repeated exposure to extreme thermal stressor could cause chronic stress and consequently suppress the physiological endocrine sensitivity to acute stressors (e.g. pathogenic diseases) in amphibians. Copyright © 2014 Elsevier Ltd. All rights reserved.

Influences of large- and regional-scale climate on fish recruitment in the Skagerrak-Kattegat over the last century

NASA Astrophysics Data System (ADS)

Linderholm, Hans W.; Cardinale, Massimiliano; Bartolino, Valerio; Chen, Deliang; Ou, Tinghai; Svedäng, Henrik

2014-06-01

Dynamics of commercial fish stocks are generally associated with fishing pressure and climate variability. Due to short time series, past studies of the relationships between fish stock dynamics and climate have mainly been restricted to the last few decades. Here we analyzed a century-long time series of plaice, cod and haddock from the Skagerrak-Kattegat, to assess the long-term influence of climate on recruitment. Recruitment success (RS) was compared against sea-surface temperature (SST) and atmospheric circulation indices on large (North Atlantic) and regional (Skagerrak-Kattegat) scales. Our results show that the influence of climate on RS was more pronounced on longer, than on shorter timescales. Over the century-long period, a shift from low to high climate sensitivity was seen from the early to the late part for plaice and cod, while the opposite was found for haddock. This shift suggests that the increasing fishing pressure and the climate change in the Skagerrak-Kattegat have resulted in an increased sensitivity of RS to climate for plaice and cod. The diminishing of climate sensitivity in haddock RS, on the other hand, may be linked to the early twentieth century collapse of the stock in the region. While no long-term relationship between RS and the Atlantic Multidecadal Oscillation (AMO) could be found, large RS fluctuations during the positive phase of the AMO (1935-1960), relative to the cold phases, suggests a changed pattern in recruitment during warm periods. On the other hand, this could be due to the increased fishing pressure in the area. Thus, reported correlations between climate and fish may be caused by strong trends in climate in the late-twentieth century, and coincident reduction in fish stocks caused by intense fishing, rather than a stable relationship between climate and fish recruitment per se.

Cardio-oncology: cardiovascular complications of cancer therapy.

PubMed

Henning, Robert J; Harbison, Raymond D

2017-07-01

This paper focuses on three classes of commonly used anticancer drugs, which can cause cardiotoxicity: anthracyclines, monoclonal antibodies exemplified by trastuzumab and tyrosine kinase inhibitors. Anthracyclines can induce cardiomyocyte necrosis and fibrosis. Trastuzumab can cause cardiac stunning. The tyrosine kinase inhibitors can increase systemic arterial pressure and impair myocyte contractility. In addition, radiation therapy to the mediastinum or left chest can exacerbate the cardiotoxicity of these anticancer drugs and can also cause accelerated atherosclerosis, myocardial infarction, heart failure and arrhythmias. Left ventricular ejection fraction measurements are most commonly used to assess cardiac function in patients who receive chemo- or radiation-therapy. However, echocardiographic determinations of global longitudinal strain are more sensitive for detection of early left ventricular systolic dysfunction. Information on patient-risk stratification and monitoring is presented and guidelines for the medical treatment of cardiac dysfunction due to cancer therapies are summarized.

AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue.

PubMed

Steculorum, Sophie M; Ruud, Johan; Karakasilioti, Ismene; Backes, Heiko; Engström Ruud, Linda; Timper, Katharina; Hess, Martin E; Tsaousidou, Eva; Mauer, Jan; Vogt, Merly C; Paeger, Lars; Bremser, Stephan; Klein, Andreas C; Morgan, Donald A; Frommolt, Peter; Brinkkötter, Paul T; Hammerschmidt, Philipp; Benzing, Thomas; Rahmouni, Kamal; Wunderlich, F Thomas; Kloppenburg, Peter; Brüning, Jens C

2016-03-24

Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis. Copyright © 2016 Elsevier Inc. All rights reserved.

Overcoming the errors of in-house PCR used in the clinical laboratory for the diagnosis of extrapulmonary tuberculosis.

PubMed

Kunakorn, M; Raksakai, K; Pracharktam, R; Sattaudom, C

1999-03-01

Our experiences from 1993 to 1997 in the development and use of IS6110 base PCR for the diagnosis of extrapulmonary tuberculosis in a routine clinical setting revealed that error-correcting processes can improve existing diagnostic methodology. The reamplification method initially used had a sensitivity of 90.91% and a specificity of 93.75%. The concern was focused on the false positive results of this method caused by product-carryover contamination. This method was changed to single round PCR with carryover prevention by uracil DNA glycosylase (UDG), resulting in a 100% specificity but only 63% sensitivity. Dot blot hybridization was added after the single round PCR, increasing the sensitivity to 87.50%. However, false positivity resulted from the nonspecific dot blot hybridization signal, reducing the specificity to 89.47%. The hybridization of PCR was changed to a Southern blot with a new oligonucleotide probe giving the sensitivity of 85.71% and raising the specificity to 99.52%. We conclude that the PCR protocol for routine clinical use should include UDG for carryover prevention and hybridization with specific probes to optimize diagnostic sensitivity and specificity in extrapulmonary tuberculosis testing.

Ultrahigh sensitivity of anomalous Hall effect sensor based on Cr-doped Bi 2Te 3 topological insulator thin films

DOE PAGES

Ni, Y.; Zhang, Z.; Nlebedim, I. C.; ...

2016-07-01

Anomalous Hall effect (AHE) was recently discovered in magnetic element-doped topological insulators (TIs), which promises low power consumption and high efficiency spintronics and electronics. This discovery broadens the family of Hall sensors. In this paper, AHE sensors based on Cr-doped Bi 2Te 3 topological insulator thin films are studied with two thicknesses (15 and 65 nm). It is found, in both cases, that ultrahigh Hall sensitivity can be obtained in Cr-doped Bi 2Te 3. Hall sensitivity reaches 1666 Ω/T in the sensor with the 15 nm TI thin film, which is higher than that of the conventional semiconductor HE sensor.more » The AHE of 65 nm sensors is even stronger, which causes the sensitivity increasing to 2620 Ω/T. Furthermore, after comparing Cr-doped Bi 2Te 3 with the previously studied Mn-doped Bi 2Te 3 TI Hall sensor, the sensitivity of the present AHE sensor shows about 60 times higher in 65 nm sensors. Furthermore, the implementation of AHE sensors based on a magnetic-doped TI thin film indicates that the TIs are good candidates for ultrasensitive AHE sensors.« less

Near-infrared spectroscopy assessment of divided visual attention task-invoked cerebral hemodynamics during prolonged true driving

NASA Astrophysics Data System (ADS)

Li, Ting; Zhao, Yue; Sun, Yunlong; Gao, Yuan; Su, Yu; Hetian, Yiyi; Chen, Min

2015-03-01

Driver fatigue is one of the leading causes of traffic accidents. It is imperative to develop a technique to monitor fatigue of drivers in real situation. Near-infrared spectroscopy (fNIRS) is now capable of measuring brain functional activity noninvasively in terms of hemodynamic responses sensitively, which shed a light to us that it may be possible to detect fatigue-specified brain functional activity signal. We developed a sensitive, portable and absolute-measure fNIRS, and utilized it to monitor cerebral hemodynamics on car drivers during prolonged true driving. An odd-ball protocol was employed to trigger the drivers' visual divided attention, which is a critical function in safe driving. We found that oxyhemoglobin concentration and blood volume in prefrontal lobe dramatically increased with driving duration (stand for fatigue degree; 2-10 hours), while deoxyhemoglobin concentration increased to the top at 4 hours then decreased slowly. The behavior performance showed clear decrement only after 6 hours. Our study showed the strong potential of fNIRS combined with divided visual attention protocol in driving fatigue degree monitoring. Our findings indicated the fNIRS-measured hemodynamic parameters were more sensitive than behavior performance evaluation.

Glucose-responsive hydrogel electrode for biocompatible glucose transistor

NASA Astrophysics Data System (ADS)

Kajisa, Taira; Sakata, Toshiya

2017-12-01

In this paper, we propose a highly sensitive and biocompatible glucose sensor using a semiconductor-based field effect transistor (FET) with a functionalized hydrogel. The principle of the FET device contributes to the easy detection of ionic charges with high sensitivity, and the hydrogel coated on the electrode enables the specific detection of glucose with biocompatibility. The copolymerized hydrogel on the Au gate electrode of the FET device is optimized by controlling the mixture ratio of biocompatible 2-hydroxyethylmethacrylate (HEMA) as the main monomer and vinylphenylboronic acid (VPBA) as a glucose-responsive monomer. The gate surface potential of the hydrogel FETs shifts in the negative direction with increasing glucose concentration from 10 μM to 40 mM, which results from the increase in the negative charges on the basis of the diol-binding of PBA derivatives with glucose molecules in the hydrogel. Moreover, the hydrogel coated on the gate suppresses the signal noise caused by the nonspecific adsorption of proteins such as albumin. The hydrogel FET can serve as a highly sensitive and biocompatible glucose sensor in in vivo or ex vivo applications such as eye contact lenses and sheets adhering to the skin.

Organic matter and the geotechnical properties of submarine sediments

NASA Astrophysics Data System (ADS)

Keller, George H.

1982-09-01

Continental slope deposits off Peru and Oregon where coastal upwelling is a pronounced oceanographic process possess significant concentrations of organic carbon. Geotechnical properties are altered to varying degrees by the organic matter. Organic matter absorbs water and causes clay-size particles to aggregate forming an open fabric. This causes unusually high water contents and plasticity and exceptionally low wet bulk densities. Some of these deposits show notable increases in shear strength, sensitivity and degree of apparent overconsolidation. Owing to the unique geotechnical properties, sediment stability characteristics are considered to be poor in situations of excess pore pressures. Failure appears to take the form of a fluidized flow somewhat similar to the quick clays of Scandinavia.

[Comparative Sensitivity of the Luminescent Photobacterium phosphoreum, Escherichia coli, and Bacillus subtilis Strains to Toxic Effects of Carbon-Based Nanomaterials and Metal Nanoparticles].

PubMed

Deryabina, D G; Efremova, L V; Karimov, I F; Manukhov, I V; Gnuchikh, E Yu; Miroshnikov, S A

2016-01-01

A comparative analysis of the four commercially available and laboratory luminescent sensor strains to the toxic effect of 10 carbon-based nanomatherials (CBNs) and 10 metal nanoparticles (MNPs) was carried out in this study. The bioluminescence inhibition assays with marine Photobacterium phosphoreum and recombinant Escherichia coli strains were varied in minimal toxic concentrations and EC50 values but led to well correlated biotoxicity evaluation for the most active compounds were ranked as Cu > (MgO, CuO) > (fullerenol, graphene oxide). The novel sensor strain Bacillus subtilis EG 168-1 exhibited the highest sensitivity to CBNs and MNPs that increased significantly number of toxic compounds causing the bacterial bioluminescence inhibition effect.

Contrast enhancement in EIT imaging of the brain.

PubMed

Nissinen, A; Kaipio, J P; Vauhkonen, M; Kolehmainen, V

2016-01-01

We consider electrical impedance tomography (EIT) imaging of the brain. The brain is surrounded by the poorly conducting skull which has low conductivity compared to the brain. The skull layer causes a partial shielding effect which leads to weak sensitivity for the imaging of the brain tissue. In this paper we propose an approach based on the Bayesian approximation error approach, to enhance the contrast in brain imaging. With this approach, both the (uninteresting) geometry and the conductivity of the skull are embedded in the approximation error statistics, which leads to a computationally efficient algorithm that is able to detect features such as internal haemorrhage with significantly increased sensitivity and specificity. We evaluate the approach with simulations and phantom data.

Para-phenylenediamine allergy: current perspectives on diagnosis and management

PubMed Central

Mukkanna, Krishna Sumanth; Stone, Natalie M; Ingram, John R

2017-01-01

Para-phenylenediamine (PPD) is the commonest and most well-known component of hair dyes. Oxidative hair dyes and dark henna temporary tattoos contain PPD. Individuals may be sensitized to PPD by temporary henna tattooing in addition to dyeing their hair. PPD allergy can cause severe reactions and may result in complications. In recent years, frequency of positive patch test reactions to PPD has been increasing. Cross-sensitization to other contact allergens may occur, in particular to other hair dye components. Hairdressers are at a high risk for PPD allergy and require counseling regarding techniques to minimize exposure and protective measures while handling hair dye. We focus this review on the current perspectives of diagnosis and management of PPD allergy. PMID:28176912

Lipid composition affects the rate of photosensitized dissipation of cross-membrane diffusion potential on liposomes

PubMed Central

Ytzhak, Shany; Wuskell, Joseph P.; Loew, Leslie M.; Ehrenberg, Benjamin

2010-01-01

Hydrophobic or amphiphilic tetrapyrrole sensitizers are taken up by cells and are usually located in cellular lipid membranes. Singlet oxygen is photogenerated by the sensitizer and it diffuses in the membrane and causes oxidative damage to membrane components. This damage can occur to membrane lipids and to membrane-localized proteins. Depolarization of the Nernst electric potential on cells’ membranes has been observed in cellular photosensitization, but it was not established whether lipid oxidation is a relevant factor leading to abolishing the resting potential of cells’ membranes and to their death. In this work we studied the effect of liposomes’ lipid composition on the kinetics of hematoporphyrin-photosensitized dissipation of K+-diffusion electric potential that was generated across the membranes. We employed an electrochromic voltage-sensitive spectroscopic probe that possesses a high fluorescence signal response to the potential. We found a correlation between the structure and unsaturation of lipids and the leakage of the membrane, following photosensitization. As the extent of non-conjugated unsaturation of the lipids is increased from 1 to 6 double bonds, the kinetics of depolarization become faster. We also found that the kinetics of depolarization is affected by the percentage of the unsaturated lipids in the liposome: as the fraction of the unsaturated lipids increases the leakage trough the membrane is enhanced. When liposomes are composed of a lipid mixture similar to that of natural membranes and photosensitization is being carried out under usual photodynamic therapy (PDT) conditions, photodamage to the lipids is not likely to cause enhanced permeability of ions through the membrane, which would have been a mechanism that leads to cell death. PMID:20536150

Developmental nephrotoxicity of aristolochic acid in a zebrafish model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Yu-Ju; Chen, Yau-Hung, E-mail: yauhung@mail.tku.edu.tw

2012-05-15

Aristolochic acid (AA) is a component of Aristolochia plant extracts which is used as a treatment for different pathologies and their toxicological effects have not been sufficiently studied. The aim of this study was to evaluate AA-induced nephrotoxicity in zebrafish embryos. After soaking zebrafish embryos in AA, the embryos displayed malformed kidney phenotypes, such as curved, cystic pronephric tubes, pronephric ducts, and cases of atrophic glomeruli. The percentages of embryos with malformed kidney phenotypes increased as the exposure dosages of AA increased. Furthermore, AA-treated embryos exhibited significantly reduced glomerular filtration rates (GFRs) in comparison with mock-control littermates (mock-control: 100 ±more » 2.24% vs. 10 ppm AA treatment for 3–5 h: 71.48 ± 18.84% ∼ 39.41 ± 15.88%), indicating that AA treatment not only caused morphological kidney changes but also induced renal failure. In addition to kidney malformations, AA-treated zebrafish embryos also exhibited deformed hearts, swollen pericardiums, impaired blood circulation and the accumulation(s) of red blood cells. Whole-mount in situ hybridization studies using cmlc2 and wt1b as riboprobes indicated that the kidney is more sensitive than the heart to AA damage. Real-time PCR showed that AA can up-regulate the expression of proinflammatory genes like TNFα, cox2 and mpo. These results support the following conclusions: (1) AA-induced renal failure is mediated by inflammation, which causes circulation dysfunction followed by serious heart malformation; and (2) the kidney is more sensitive than the heart to AA injury. -- Highlights: ► Zebrafish were used to evaluate aristolochic acid (AA)-induced nephrotoxicity. ► AA-treated zebrafish embryos exhibited deformed heart as well as malformed kidney. ► Kidney is more sensitive to AA injury than the heart.« less

Long noncoding RNA MALAT1 regulates generation of reactive oxygen species and the insulin responses in male mice.

PubMed

Chen, Jingshu; Ke, Sui; Zhong, Lei; Wu, Jing; Tseng, Alexander; Morpurgo, Benjamin; Golovko, Andrei; Wang, Gang; Cai, James J; Ma, Xi; Li, Defa; Tian, Yanan

2018-06-01

The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA and its overexpression is associated with the development of many types of malignancy. MALAT1 null mice show no overt phenotype. However, in transcriptome analysis of MALAT1 null mice we found significant upregulation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulated antioxidant genes including Nqo1 and Cat with significant reduction in reactive oxygen species (ROS) and greatly reduced ROS-generated protein carbonylation in hepatocyte and islets. We performed lncRNA pulldown assay using biotinylated antisense oligonucleotides against MALAT1 and found MALAT1 interacted with Nrf2, suggesting Nrf2 is transcriptionally regulated by MALAT1. Exposure to excessive ROS has been shown to cause insulin resistance through activation of c-Jun N-terminal kinase (JNK) which leads to inhibition of insulin receptor substrate 1 (IRS-1) and insulin-induced phosphorylation of serine/threonine kinase Akt. We found MALAT1 ablation suppressed JNK activity with concomitant insulin-induced activation of IRS-1 and phosphorylation of Akt suggesting MALAT1 regulated insulin responses. MALAT1 null mice exhibited sensitized insulin-signaling response to fast-refeeding and glucose/insulin challenges and significantly increased insulin secretion in response to glucose challenge in isolated MALAT1 null islets, suggesting an increased insulin sensitivity. In summary, we demonstrate that MALAT1 plays an important role in regulating insulin sensitivity and has the potential as a therapeutic target for the treatment of diabetes as well as other diseases caused by excessive exposure to ROS. Copyright © 2018. Published by Elsevier Inc.

Antibiotic sensitivity pattern of uropathogens from pregnant women with urinary tract infection in Abakaliki, Nigeria.

PubMed

Onoh, Rc; Umeora, Ouj; Egwuatu, Ve; Ezeonu, Po; Onoh, Tjp

2013-01-01

Urinary tract infection (UTI) is a common bacterial infection during pregnancy and a significant cause of perinatal and maternal morbidity and mortality. The causative bacteria have remained virtually the same although with variations in individual prevalence. There has been an increasing resistance by these bacteria to the commonly available antibiotics. To determine the prevalence of UTI, the common causative bacteria, and their antibiotic sensitivity pattern among pregnant women with UTI. This is a descriptive study that was carried out at the Obstetrics Department of two tertiary institutions in Abakaliki, Ebonyi State, Nigeria (Federal Medical Center and Ebonyi State University Teaching Hospital) over a period of 12 months. Midstream urine specimens from selected pregnant women with clinical features of UTI were collected for microscopy, culture, and sensitivity. The results were analyzed with the 2008 Epi Info™ software. A total of 542 pregnant women presented with symptoms of UTI and were recruited for the study over the study period. Of the 542 pregnant women, 252 (46.5%) had significant bacteriuria with positive urine culture and varying antibiotic sensitivity pattern. The prevalence of symptomatic UTI was 3%. Escherichia coli was the most common bacteria isolated with a percentage of 50.8%. Other isolated micro organisms included Stapylococcus aereus (52 cultures, 20.6%), Proteus mirabilis (24 cultures, 9.5%), S. saprophyticus (18 cultures, 7.1%), Streptococcus spp. (14 cultures, 5.6%), Citrobacter spp. (5 cultures, 2.0%), Klebsiella spp. (4 cultures, 1.6%), Enterobacter spp. (4 cultures, 1.6%), and Pseudomonas spp. (3 cultures, 1.2%). Levofloxacin had the highest overall antibiotic sensitivity of 92.5%. Others with overall antibiotic sensitivity pattern greater than 50% included cefpodoxime (87.3%), ofloxacin (77.4%), ciprofloxacin (66.7%), ceftriaxone (66.7%), and gentamicin (50.8%). E. coli was the most common etiological agent of UTI in pregnancy with Enterococcus (Staphylococcus) gaining prominence. Cephalosporin and quinolones were shown to be very effective against the organisms causing UTI in these pregnant women.

Validation of Systemic Lupus Erythematosus Diagnosis as the Primary Cause of Renal Failure in the US Renal Data System.

PubMed

Broder, Anna; Mowrey, Wenzhu B; Izmirly, Peter; Costenbader, Karen H

2017-04-01

Using American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC) criteria for systemic lupus erythematosus (SLE) classification as gold standards, we determined sensitivity, specificity, positive and negative predictive values (PPV and NPV) of having SLE denoted as the primary cause of end-stage renal disease (ESRD) in the US Renal Data System (USRDS). ESRD patients were identified by International Classification of Diseases, Ninth Revision codes in electronic medical records of 1 large tertiary care center, Montefiore Hospital, from 2006 to 2012. Clinical data were extracted and reviewed to establish SLE diagnosis. Data were linked by social security number, name, and date of birth to the USRDS, where primary causes of ESRD were ascertained. Of 7,396 ESRD patients at Montefiore, 97 met ACR/SLICC SLE criteria, and 86 had SLE by record only. Among the 97 SLE patients, the attributed causes of ESRD in the USRDS were 77 SLE and 12 with other causes (unspecified glomerulonephritis, hypertension, scleroderma), and 8 missing. Sensitivity, specificity, PPV, and NPV for SLE in the USRDS were 79%, 99.9%, 93%, and 99.7%, respectively. Of the 60 patients with biopsy-proven lupus nephritis, 44 (73%) had SLE as primary ESRD cause in the USRDS. Attribution of the primary ESRD causes among SLE patients with ACR/SLICC criteria differed by race, ethnicity, and transplant status. The diagnosis of SLE as the primary cause of ESRD in the USRDS has good sensitivity, and excellent specificity, PPV, and NPV. Nationwide access to medical records and biopsy reports may significantly improve sensitivity of SLE diagnosis. © 2016, American College of Rheumatology.

Pentose Phosphate Pathway Function Affects Tolerance to the G-Quadruplex Binder TMPyP4

PubMed Central

Andrew, Elizabeth J.; Merchan, Stephanie; Lawless, Conor; Banks, A. Peter; Wilkinson, Darren J.; Lydall, David

2013-01-01

G-quadruplexes form in guanine-rich regions of DNA and the presence of these structures at telomeres prevents the activity of telomerase in vitro. Ligands such as the cationic porphyrin TMPyP4 stabilise G-quadruplexes and are therefore under investigation for their potential use as anti-cancer drugs. In order to investigate the mechanism of action of TMPyP4 in vivo, we carried out a genome-wide screen in the budding yeast Saccharomyces cerevisiae. We found that deletion of key pentose phosphate pathway (PPP) genes increased the sensitivity of yeast to the presence of TMPyP4. The PPP plays an important role in the oxidative stress response and sensitivity to TMPyP4 also increased when genes involved in the oxidative stress response, CCS1 and YAP1, were deleted. For comparison we also report genome wide-screens using hydrogen peroxide, which causes oxidative stress, RHPS4, another G-quadruplex binder and hydroxyurea, an S phase poison. We found that a number of TMPyP4-sensitive strains are also sensitive to hydrogen peroxide in a genome-wide screen. Overall our results suggest that treatment with TMPyP4 results in light-dependent oxidative stress response in budding yeast, and that this, rather than G-quadruplex binding, is the major route to cytotoxicity. Our results have implications for the usefulness and mechanism of action of TMPyP4. PMID:23776642

Involvement of alternative oxidase in the regulation of sensitivity of Sclerotinia sclerotiorum to the fungicides azoxystrobin and procymidone.

PubMed

Xu, Ting; Wang, Ya-Ting; Liang, Wu-Sheng; Yao, Fei; Li, Yong-Hong; Li, Dian-Rong; Wang, Hao; Wang, Zheng-Yi

2013-06-01

Sclerotinia sclerotiorum is a filamentous fungal pathogen that can infect many economically important crops and vegetables. Alternative oxidase is the terminal oxidase of the alternative respiratory pathway in fungal mitochondria. The function of alternative oxidase was investigated in the regulation of sensitivity of S. sclerotiorum to two commercial fungicides, azoxystrobin and procymidone which have different fungitoxic mechanisms. Two isolates of S. sclerotiorum were sensitive to both fungicides. Application of salicylhydroxamic acid, a specific inhibitor of alternative oxidase, significantly increased the values of effective concentration causing 50% mycelial growth inhibition (EC50) of azoxystrobin to both S. sclerotiorum isolates, whereas notably decreased the EC50 values of procymidone. In mycelial respiration assay azoxystrobin displayed immediate inhibitory effect on cytochrome pathway capacity, but had no immediate effect on alternative pathway capacity. In contrast, procymidone showed no immediate impact on capacities of both cytochrome and alternative pathways in the mycelia. However, alternative oxidase encoding gene (aox) transcript and protein levels, alternative respiration pathway capacity of the mycelia were obviously increased by pre-treatment for 24 h with both azoxystrobin and procymidone. These results indicate that alternative oxidase was involved in the regulation of sensitivity of S. sclerotiorum to the fungicides azoxystrobin and procymidone, and that both fungicides could affect aox gene expression and the alternative respiration pathway capacity development in mycelia of this fungal pathogen.

ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin.

PubMed

Li, Ke; Yan, Huaying; Guo, Wenhao; Tang, Mei; Zhao, Xinyu; Tong, Aiping; Peng, Yong; Li, Qintong; Yuan, Zhu

2018-05-01

PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects. We found that KU-60019 preferentially sensitizes PTEN-deficient MDA-MB-468 breast cancer cells to cisplatin, though it also slightly enhances sensitivity of PTEN wild-type breast cancer cells. The increased cytotoxic sensitivity is associated with apoptosis, as evidenced by flow cytometry and PARP cleavage. Additionally, the increase of DNA damage accumulation due to the decreased capability of DNA repair, as indicated by γ-H2AX and Rad51 foci, also contributed to this selective cytotoxicity. Mechanistically, compared with PTEN wild-type MDA-MB-231 cells, PTEN-deficient MDA-MB-468 cells have lower level of Rad51, higher ATM kinase activity, and display the elevated level of DNA damage. Moreover, these differences could be further enlarged by cisplatin. Our findings suggest that ATM is a promising target for PTEN-defective breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of high altitude on sensitivity to the taste of phenylthiocarbamide

NASA Astrophysics Data System (ADS)

Singh, S. B.; Chatterjee, A.; Panjwani, U.; Yadav, D. K.; Selvamurthy, W.; Sharma, K. N.

Sensitivity to the taste of phenylthiocarbamide (PTC) was studied using the Harris-Kalmus method in healthy human volunteers at sea level and then subsequently at an altitude of 3500 m over a period of 3 weeks, after which they were brought back to sea level. Blood sugar, insulin and blood cortisol levels were estimated weekly. The results indicated that, out of 51 subjects studied, 26 (55%) were PTC tasters at sea level. Eight of those unable to taste PTC at sea level tested as tasters at high altitude, and 2 of them reverted to being non-tasters on return to sea level. In the blood, an increase in cortisol and blood insulin levels was seen without any significant change in sugar levels. All the changes recorded at high altitude tended to return to basal values after re-induction to sea level. The study suggests that high-altitude hypoxia in some way, possibly involving changes in hormonal profile among other factors, causes an alteration in sensitivity to the taste of PTC, resulting in some of the individuals shifting to lower PTC sensitivity.

[The history of hepatitis B virus-related determination tests and inspection and the measurements of problems in Japan].

PubMed

Shibata, Hiroshi

2013-09-01

Since Hepatitis B virus was detected as the cause of hepatitis, many high-sensitive measurement methods have been developed. In the development history, there are many problems in accuracy, sensitivity and health insurance regulations among different types of kits with different measurement principles. Advanced medical treatments cause problems of gene mutation or reactivation of HBV, leading to the necessity for high sensitive and sophisticated determination. The history of clinical analysis for the detection of HBV was reviewed from the viewpoint of our experiences.

Nanotechnology in the management of cervical cancer.

PubMed

Chen, Jiezhong; Gu, Wenyi; Yang, Lei; Chen, Chen; Shao, Renfu; Xu, Kewei; Xu, Zhi Ping

2015-03-01

Cervical cancer is a major disease with high mortality. All cervical cancers are caused by infection with human papillomaviruses (HPV). Although preventive vaccines for cervical cancer are successful, treatment of cervical cancer is far less satisfactory because of multidrug resistance and side effects. In this review, we summarize the recent application of nanotechnology to the diagnosis and treatment of cervical cancer as well as the development of HPV vaccines. Early detection of cervical cancer enables tumours to be efficiently removed by surgical procedures, leading to increased survival rate. The current method of detecting cervical cancer by Pap smear can only achieve 50% sensitivity, whereas nanotechnology has been used to detect HPVs with greatly improved sensitivity. In cervical cancer treatment, nanotechnology has been used for the delivery of anticancer drugs to increase treatment efficacy and decrease side effects. Nanodelivery of HPV preventive and therapeutic vaccines has also been investigated to increase vaccine efficacy. Overall, these developments suggest that nanoparticle-based vaccine may become the most effective way to prevent and treat cervical cancer, assisted or combined with some other nanotechnology-based therapy. Copyright © 2015 John Wiley & Sons, Ltd.

Altered perineal microbiome is associated with vulvovaginitis and urinary tract infection in preadolescent girls.

PubMed

Gorbachinsky, Ilya; Sherertz, Robert; Russell, Gregory; Krane, L Spencer; Hodges, Steve J

2014-12-01

Vulvovaginitis has a known association with urinary tract infections (UTIs) in girls. We hypothesize that vulvovaginitis is a major contributor to UTIs in prepubertal girls by increasing periurethral colonization with uropathogens. Periurethral swabs and urine specimens were obtained from a total of 101 girls (58 with vulvovaginitis and 43 without vulvovaginitis). Specimens were cultured for bacterial growth. The dominant organism in the periurethral swabs and urine cultures was recorded and antibiotic sensitivity profiles were compared. Periurethral swabs from children with vulvovaginitis were associated with a statistically significant increase in uropathogenic bacteria (79% Enterococcus species or Escherichia coli) as the dominant culture compared with swabs from girls without vaginitis (18%) (p < 0.05). In children with vulvovaginitis, 52% of the urine cultures were positive for UTIs, and the dominant organism in the urine cultures matched the species and antibiotic sensitivity profile of the corresponding periurethral swab. Only 11% of the urine cultures from girls without vulvovaginitis were positive for UTIs. Vulvovaginitis may cause UTIs by altering the perineal biome such that there is increased colonization of uropathogens.

Altered perineal microbiome is associated with vulvovaginitis and urinary tract infection in preadolescent girls

PubMed Central

Gorbachinsky, Ilya; Sherertz, Robert; Russell, Gregory; Krane, L Spencer

2014-01-01

Background: Vulvovaginitis has a known association with urinary tract infections (UTIs) in girls. We hypothesize that vulvovaginitis is a major contributor to UTIs in prepubertal girls by increasing periurethral colonization with uropathogens. Methods: Periurethral swabs and urine specimens were obtained from a total of 101 girls (58 with vulvovaginitis and 43 without vulvovaginitis). Specimens were cultured for bacterial growth. The dominant organism in the periurethral swabs and urine cultures was recorded and antibiotic sensitivity profiles were compared. Results: Periurethral swabs from children with vulvovaginitis were associated with a statistically significant increase in uropathogenic bacteria (79% Enterococcus species or Escherichia coli) as the dominant culture compared with swabs from girls without vaginitis (18%) (p < 0.05). In children with vulvovaginitis, 52% of the urine cultures were positive for UTIs, and the dominant organism in the urine cultures matched the species and antibiotic sensitivity profile of the corresponding periurethral swab. Only 11% of the urine cultures from girls without vulvovaginitis were positive for UTIs. Conclusions: Vulvovaginitis may cause UTIs by altering the perineal biome such that there is increased colonization of uropathogens. PMID:25435916

Loss of the Mono-ADP-ribosyltransferase, Tiparp, Increases Sensitivity to Dioxin-induced Steatohepatitis and Lethality*

PubMed Central

Ahmed, Shaimaa; Bott, Debbie; Gomez, Alvin; Tamblyn, Laura; Rasheed, Adil; Cho, Tiffany; MacPherson, Laura; Sugamori, Kim S.; Yang, Yang; Grant, Denis M.; Cummins, Carolyn L.; Matthews, Jason

2015-01-01

The aryl hydrocarbon receptor (AHR) mediates the toxic effects of the environmental contaminant dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD). Dioxin causes a range of toxic responses, including hepatic damage, steatohepatitis, and a lethal wasting syndrome; however, the mechanisms are still unknown. Here, we show that the loss of TCDD-inducible poly(ADP-ribose) polymerase (Tiparp), an ADP-ribosyltransferase and AHR repressor, increases sensitivity to dioxin-induced toxicity, steatohepatitis, and lethality. Tiparp−/− mice given a single injection of 100 μg/kg dioxin did not survive beyond day 5; all Tiparp+/+ mice survived the 30-day treatment. Dioxin-treated Tiparp−/− mice exhibited increased liver steatosis and hepatotoxicity. Tiparp ADP-ribosylated AHR but not its dimerization partner, the AHR nuclear translocator, and the repressive effects of TIPARP on AHR were reversed by the macrodomain containing mono-ADP-ribosylase MACROD1 but not MACROD2. These results reveal previously unidentified roles for Tiparp, MacroD1, and ADP-ribosylation in AHR-mediated steatohepatitis and lethality in response to dioxin. PMID:25975270

DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons.

PubMed

Santoro, Anna; Campolo, Michela; Liu, Chen; Sesaki, Hiromi; Meli, Rosaria; Liu, Zhong-Wu; Kim, Jung Dae; Diano, Sabrina

2017-03-07

Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1 fl/fl -POMC-cre:ER T2 ) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1 fl/fl -POMC-cre:ER T2 mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons. Copyright © 2017 Elsevier Inc. All rights reserved.

Evidence for a direct effect of captopril on early steps of insulin action in BC3H-1 myocytes.

PubMed

Moisés, Regina S; Carvalho, Carla R O; Shiota, Debora; Saad, Mario J A

2003-03-01

Captopril, an angiotensin-converting enzyme (ACE) inhibitor, has been reported to improve insulin sensitivity. However, despite extensive investigation, the mechanisms responsible for this effect are not fully understood. Reduction of plasma angiotensin II and inhibition of kininase II have been suggested to contribute to improve insulin sensitivity. Insulin binding was measured at tracer insulin concentration in intact cells with or without captopril treatment. Specific binding, expressed as percent of total insulin added, was not different in control and captopril-treated cells. However, captopril treatment caused an increase in insulin-induced insulin receptor substrate-1 (IRS-1) phosphorylation accompanied by an increased association of IRS-1 with phosphoinositide-3 kinase (PI-3 kinase), despite no change on insulin receptor (IR) autophosphorylation. There was also an increased threonine kinase B (AKT) phosphorylation in captopril-treated cells followed by enhanced basal and insulin-stimulated glucose uptake. These results indicate that captopril treatment has a direct effect on early phosphorylation events induced by insulin in BC3H-1 myocytes. Copyright 2003, Elsevier Science (USA). All rights reserved.

Hypothermia augments non-cholinergic neuronal bronchoconstriction in pithed guinea-pigs.

PubMed

Rechtman, M P; King, R G; Boura, A L

1991-08-16

Electrical stimulation at C4-C7 in the spinal canal of pithed guinea-pigs injected with atropine, d-tubocurarine and pentolinium caused frequency-dependent bronchoconstriction. Such non-cholinergic responses to electrical stimulation, unlike responses to substance P, were abolished by pretreatment with capsaicin but not by mepyramine or propranolol. Bronchoconstrictor responses to electrical stimulation were inversely related to rectal temperature (between 30-40 degrees C) whereas responses to substance P increased with increasing temperature over the same range. Ouabain (i.v.) augmented responses to electrical stimulation at 35-37 degrees C but depressed those at 30-32 degrees C. Both morphine and the alpha 2-adrenoceptor agonist B-HT920 (i.v.) inhibited non-cholinergic-mediated bronchoconstrictor responses at 30-32 degrees C. These results stress the importance of adequate control of body temperature in this preparation. Lowered body temperature may increase neuronal output of neuropeptides whilst depressing bronchial smooth muscle sensitivity. The data support previous conclusions regarding the role of Na+/K+ activated ATPase in temperature-induced changes in sensitivity to bronchoconstrictor stimuli.

Sensitivity quantification of remote detection NMR and MRI

NASA Astrophysics Data System (ADS)

Granwehr, J.; Seeley, J. A.

2006-04-01

A sensitivity analysis is presented of the remote detection NMR technique, which facilitates the spatial separation of encoding and detection of spin magnetization. Three different cases are considered: remote detection of a transient signal that must be encoded point-by-point like a free induction decay, remote detection of an experiment where the transient dimension is reduced to one data point like phase encoding in an imaging experiment, and time-of-flight (TOF) flow visualization. For all cases, the sensitivity enhancement is proportional to the relative sensitivity between the remote detector and the circuit that is used for encoding. It is shown for the case of an encoded transient signal that the sensitivity does not scale unfavorably with the number of encoded points compared to direct detection. Remote enhancement scales as the square root of the ratio of corresponding relaxation times in the two detection environments. Thus, remote detection especially increases the sensitivity of imaging experiments of porous materials with large susceptibility gradients, which cause a rapid dephasing of transverse spin magnetization. Finally, TOF remote detection, in which the detection volume is smaller than the encoded fluid volume, allows partial images corresponding to different time intervals between encoding and detection to be recorded. These partial images, which contain information about the fluid displacement, can be recorded, in an ideal case, with the same sensitivity as the full image detected in a single step with a larger coil.

Assessing the ecological vulnerability of the upper reaches of the Minjiang River.

PubMed

Zhang, Jifei; Sun, Jian; Ma, Baibing; Du, Wenpeng

2017-01-01

The upper reaches of the Minjiang River (URMR), located on the eastern edge of the Tibetan Plateau in southwestern China, are an important component of the ecological barrier of the Upper Yangtze River Basin. Climate change and human activities have increased the ecological sensitivity and vulnerability of the region, which may pose a threat to the ecological security of the Yangtze River Basin and have negative impacts on local social and economic development. In this study, we analyzed land use and cover change (LUCC) of the URMR between 2000 and 2010, and found that the total rate of LUCC was less than 0.50% during this period. In addition, net primary production (NPP) was employed to describe the changes in ecosystem sensitivity and vulnerability, and the results demonstrated that slightly and moderately sensitive and vulnerable zones occupied the largest area, distributed mainly in forest, shrub, and grassland ecosystems. However, compared with the period from 2000 to 2005, the ecological sensitivity and vulnerability showed a worsening trend in the period 2005-2010. Exploring the relationship between vulnerability/sensitivity and environmental factors, we found that sensitivity and vulnerability were positively correlated with precipitation (>700 mm) and aridity index (>36 mm/°C). The results highlight that the future ecological sensitivity and vulnerability of URMR should be further investigated, and that the LUCC induced by human activities and climate change have caused alteration of in ecosystem vulnerability.

Response of Benthic Foraminifera to Organic Matter Quantity and Quality and Bioavailable Concentrations of Metals in Aveiro Lagoon (Portugal)

PubMed Central

Martins, Maria Virgínia Alves; Silva, Frederico; Laut, Lazaro L. M.; Frontalini, Fabrizio; Clemente, Iara M. M. M.; Miranda, Paulo; Figueira, Rubens; Sousa, Silvia H. M.; Dias, João M. Alveirinho

2015-01-01

This work analyses the distribution of living benthic foraminiferal assemblages of surface sediments in different intertidal areas of Ria de Aveiro (Portugal), a polihaline and anthropized coastal lagoon. The relationships among foraminiferal assemblages in association with environmental parameters (temperature, salinity, Eh and pH), grain size, the quantity and quality of organic matter (enrichment in carbohydrates, proteins and lipids), pollution caused by metals, and mineralogical data are studied in an attempt to identify indicators of adaptability to environmental stress. In particular, concentrations of selected metals in the surficial sediment are investigated to assess environmental pollution levels that are further synthetically parameterised by the Pollution Load Index (PLI). The PLI variations allowed the identification of five main polluted areas. Concentrations of metals were also analysed in three extracted phases to evaluate their possible mobility, bioavailability and toxicity in the surficial sediment. Polluted sediment in the form of both organic matter and metals can be found in the most confined zones. Whereas enrichment in organic matter and related biopolymers causes an increase in foraminifera density, pollution by metals leads to a decline in foraminiferal abundance and diversity in those zones. The first situation may be justified by the existence of opportunistic species (with high reproduction rate) that can live in low oxic conditions. The second is explained by the sensitivity of some species to pressure caused by metals. The quality of the organic matter found in these places and the option of a different food source should also explain the tolerance of several species to pollution caused by metals, despite their low reproductive rate in the most polluted areas. In this study, species that are sensitive and tolerant to organic matter and metal enrichment are identified, as is the differential sensitivity/tolerance of some species to metals enrichment. PMID:25706860

Accelerated Aging Test for Plastic Scintillator Gamma Ray Detectors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kouzes, Richard T.

Polyvinyl toluene (PVT) and polystyrene (PS), collectively referred to as “plastic scintillator,” are synthetic polymer materials used to detect gamma radiation, and are commonly used in instrumentation. Recent studies have revealed that plastic scintillator undergoes an environmentally related material degradation that adversely affects performance under certain conditions and histories. A significant decrease in gamma ray sensitivity has been seen in some detectors in systems as they age. The degradation of sensitivity of plastic scintillator over time is due to a variety of factors, and the term “aging” is used to encompass all factors. Some plastic scintillator samples show no agingmore » effects (no significant change in sensitivity over more than 10 years), while others show severe aging (significant change in sensitivity in less than 5 years). Aging effects arise from weather (variations in heat and humidity), chemical exposure, mechanical stress, light exposure, and loss of volatile components. The damage produced by these various causes can be cumulative, causing observable damage to increase over time. Damage may be reversible up to some point, but becomes permanent under some conditions. It has been demonstrated that exposure of plastic scintillator in an environmental chamber to 30 days of high temperature and humidity (90% relative humidity and 55°C) followed by a single cycle to cold temperature (-30°C) will produce severe fogging in all PVT samples. This thermal cycle will be referred to as the “Accelerated Aging Test.” This document describes the procedure for performing this Accelerated Aging Test.« less

Placental restriction of fetal growth reduces cutaneous responses to antigen after sensitization in sheep.

PubMed

Wooldridge, Amy L; Bischof, Robert J; Meeusen, Els N; Liu, Hong; Heinemann, Gary K; Hunter, Damien S; Giles, Lynne C; Kind, Karen L; Owens, Julie A; Clifton, Vicki L; Gatford, Kathryn L

2014-04-01

Prenatal and early childhood exposures are implicated as causes of allergy, but the effects of intrauterine growth restriction on immune function and allergy are poorly defined. We therefore evaluated effects of experimental restriction of fetal growth on immune function and allergic sensitization in adolescent sheep. Immune function (circulating total red and white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, and basophils, and the antibody response to Clostridial vaccination) and responses to house dust mite (HDM) allergen and ovalbumin (OVA) antigen sensitization (specific total Ig, IgG1, and IgE antibodies, and cutaneous hypersensitivity) were investigated in adolescent sheep from placentally restricted (PR, n = 23) and control (n = 40) pregnancies. Increases in circulating HDM-specific IgE (P = 0.007) and OVA-specific IgE (P = 0.038) were greater in PR than control progeny. PR did not alter total Ig, IgG1, or IgM responses to either antigen. PR increased OVA-specific but not HDM-specific IgA responses in females only (P = 0.023). Multiple birth increased Ig responses to OVA in a sex-specific manner. PR decreased the proportion of positive cutaneous hypersensitivity responders to OVA at 24 h (P = 0.030) but had no effect on cutaneous responses to HDM. Acute wheal responses to intradermal histamine correlated positively with birth weight in singletons (P = 0.023). Intrauterine growth restriction may suppress inflammatory responses in skin downstream of IgE induction, without impairment in antibody responses to a nonpolysaccharide vaccine. Discord between cutaneous and IgE responses following sensitization suggests new mechanisms for prenatal allergy programming.

p53-regulated autophagy is controlled by glycolysis and determines cell fate

PubMed Central

Duan, Lei; Perez, Ricardo E.; Davaadelger, Batzaya; Dedkova, Elena N.; Blatter, Lothar A.; Maki, Carl G.

2015-01-01

The tumor suppressor p53 regulates downstream targets that determine cell fate. Canonical p53 functions include inducing apoptosis, growth arrest, and senescence. Non-canonical p53 functions include its ability to promote or inhibit autophagy and its ability to regulate metabolism. The extent to which autophagy and/or metabolic regulation determines cell fate by p53 is unclear. To address this, we compared cells resistant or sensitive to apoptosis by the p53 activator Nutlin-3a. In resistant cells, glycolysis was maintained upon Nutlin-3a treatment, and activated p53 promoted prosurvival autophagy. In contrast, in apoptosis sensitive cells activated p53 increased superoxide levels and inhibited glycolysis through repression of glycolytic pathway genes. Glycolysis inhibition and increased superoxide inhibited autophagy by repressing ATG genes essential for autophagic vesicle maturation. Inhibiting glycolysis increased superoxide and blocked autophagy in apoptosis-resistant cells, causing p62-dependent caspase-8 activation. Finally, treatment with 2-DG or the autophagy inhibitors chloroquine or bafilomycin A1 sensitized resistant cells to Nutlin-3a-induced apoptosis. Together, these findings reveal novel links between glycolysis and autophagy that determine apoptosis-sensitivity in response to p53. Specifically, the findings indicate 1) that glycolysis plays an essential role in autophagy by limiting superoxide levels and maintaining expression of ATG genes required for autophagic vesicle maturation, 2) that p53 can promote or inhibit autophagy depending on the status of glycolysis, and 3) that inhibiting protective autophagy can expand the breadth of cells susceptible to Nutlin-3a induced apoptosis. PMID:26337205

The Fanconi anemia (FA) pathway confers glioma resistance to DNA alkylating agents.

PubMed

Chen, Clark C; Taniguchi, Toshiyasu; D'Andrea, Alan

2007-05-01

DNA alkylating agents including temozolomide (TMZ) and 1,3-bis[2-chloroethyl]-1-nitroso-urea (BCNU) are the most common form of chemotherapy in the treatment of gliomas. Despite their frequent use, the therapeutic efficacy of these agents is limited by the development of resistance. Previous studies suggest that the mechanism of this resistance is complex and involves multiple DNA repair pathways. To better define the pathways contributing to the mechanisms underlying glioma resistance, we tested the contribution of the Fanconi anemia (FA) DNA repair pathway. TMZ and BCNU treatment of FA-proficient cell lines led to a dose- and time-dependent increase in FANCD2 mono-ubiquitination and FANCD2 nuclear foci formation, both hallmarks of FA pathway activation. The FA-deficient cells were more sensitive to TMZ/BCNU relative to their corrected, isogenic counterparts. To test whether these observations were pertinent to glioma biology, we screened a panel of glioma cell lines and identified one (HT16) that was deficient in the FA repair pathway. This cell line exhibited increased sensitivity to TMZ and BCNU relative to the FA-proficient glioma cell lines. Moreover, inhibition of FA pathway activation by a small molecule inhibitor (curcumin) or by small interference RNA suppression caused increased sensitivity to TMZ/BCNU in the U87 glioma cell line. The BCNU sensitizing effect of FA inhibition appeared additive to that of methyl-guanine methyl transferase inhibition. The results presented in this paper underscore the complexity of cellular resistance to DNA alkylating agents and implicate the FA repair pathway as a determinant of this resistance.

Increased sensitivity of anodic stripping voltammetry at the hanging mercury drop electrode by ultracathodic deposition.

PubMed

Rodrigues, José A; Rodrigues, Carlos M; Almeida, Paulo J; Valente, Inês M; Gonçalves, Luís M; Compton, Richard G; Barros, Aquiles A

2011-09-09

An improved approach to the anodic stripping voltammetric (ASV) determination of heavy metals, using the hanging mercury drop electrode (HMDE), is reported. It was discovered that using very cathodic accumulation potentials, at which the solvent reduction occurs (overpotential deposition), the voltammetric signals of zinc(II), cadmium(II), lead(II) and copper(II) increase. When compared with the classical methodology a 5 to 10-fold signal increase is obtained. This effect is likely due to both mercury drop oscillation at such cathodic potentials and added local convection at the mercury drop surface caused by the evolution of hydrogen bubbles. Copyright © 2011 Elsevier B.V. All rights reserved.

Testicle pain

MedlinePlus

... Causes The testicles are very sensitive. Even a minor injury can cause pain. In some conditions, abdominal ... Non-urgent causes of testicle pain, such as minor injuries and fluid collection, can often be treated ...

Mold and Health

EPA Pesticide Factsheets

Molds have the potential to cause health problems. Molds produce allergens (substances that can cause allergic reactions) and irritants. Inhaling or touching mold or mold spores may cause allergic reactions in sensitive individuals.

Sensitization of TRPA1 by Protein Kinase A

PubMed Central

Meents, Jannis E.; Fischer, Michael J. M.; McNaughton, Peter A.

2017-01-01

The TRPA1 ion channel is expressed in nociceptive (pain-sensitive) somatosensory neurons and is activated by a wide variety of chemical irritants, such as acrolein in smoke or isothiocyanates in mustard. Here, we investigate the enhancement of TRPA1 function caused by inflammatory mediators, which is thought to be important in lung conditions such as asthma and COPD. Protein kinase A is an important kinase acting downstream of inflammatory mediators to cause sensitization of TRPA1. By using site-directed mutagenesis, patch-clamp electrophysiology and calcium imaging we identify four amino acid residues, S86, S317, S428, and S972, as the principal targets of PKA-mediated phosphorylation and sensitization of TRPA1. PMID:28076424

Understanding Socio-Hydrology System in the Kissimmee River Basin

NASA Astrophysics Data System (ADS)

Chen, X.; Wang, D.; Tian, F.; Sivapalan, M.

2014-12-01

This study is to develop a conceptual socio-hydrology model for the Kissimmee River Basin. The Kissimmee River located in Florida was channelized in mid-20 century for flood protection. However, the environmental issues caused by channelization led Floridians to conduct a restoration project recently, focusing on wetland recovery. As a complex coupled human-water system, Kissimmee River Basin shows the typical socio-hydrology interactions. Hypothetically, the major reason to drive the system from channelization to restoration is that the community sensitivity towards the environment has changed from controlling to restoring. The model developed in this study includes 5 components: water balance, flood risk, wetland area, crop land area, and community sensitivity. Furthermore, urban population and rural population in the basin have different community sensitivities towards the hydrologic system. The urban population, who live further away from the river are more sensitive to wetland restoration; while the rural population, who live closer to the river are more sensitive to flood protection. The power dynamics between the two groups and its impact on management decision making is described in the model. The model is calibrated based on the observed watershed outflow, wetland area and crop land area. The results show that the overall focus of community sensitivity has changed from flood protection to wetland restoration in the past 60 years in Kissimmee River Basin, which confirms the study hypothesis. There are two main reasons for the community sensitivity change. Firstly, people's flood memory is fading because of the effective flood protection, while the continuously shrinking wetland and the decreasing bird and fish population draw more and more attention. Secondly, in the last 60 years, the urban population in Florida drastically increased compared with a much slower increase of rural population. As a result, the community sensitivity of urban population towards wetland restoration has more weight than the rural population's towards flood protection.

Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats

PubMed Central

Eagle, Andrew L.; Singh, Robby; Kohler, Robert J.; Friedman, Amy L.; Liebowitz, Chelsea P.; Galloway, Matthew P.; Enman, Nicole M.; Jutkiewicz, Emily M.; Perrine, Shane A.

2017-01-01

Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague–Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0,10 or 20mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, asexpected. However, compared to control ratson Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. PMID:25712697

TRPV1 receptors on unmyelinated C-fibres mediate colitis-induced sensitization of pelvic afferent nerve fibres in rats

PubMed Central

De Schepper, H U; De Winter, B Y; Van Nassauw, L; Timmermans, J-P; Herman, A G; Pelckmans, P A; De Man, J G

2008-01-01

Patients with inflammatory bowel disease often suffer from gastrointestinal motility and sensitivity disorders. The aim of the current study was to investigate the role of transient receptor potential of the vanilloid type 1 (TRPV1) receptors in the pathophysiology of colitis-induced pelvic afferent nerve sensitization. Trinitrobenzene sulphate (TNBS) colitis (7.5 mg, 30% ethanol) was induced in Wistar rats 72 h prior to the experiment. Single-fibre recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root. Fibres responding to colorectal distension (CRD) were identified in controls and rats with TNBS colitis. The effect of the TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 0.25–5 mg kg−1) or its vehicle (hydroxypropyl-β-cyclodextrin) was tested on the afferent response to repetitive distensions (60 mmHg). Immunocytochemical staining of TRPV1 and NF200, a marker for A-fibre neurons, was performed in the dorsal root ganglia L6–S1. TNBS colitis significantly increased the response to colorectal distension of pelvic afferent C-fibres. BCTC did not significantly affect the C-fibre response in controls, but normalized the sensitized response in rats with colitis. TNBS colitis increased the spontaneous activity of C-fibres, an effect which was insensitive to administration of BCTC. TNBS colitis had no effect on Aδ-fibres, nor was their activity modulated by BCTC. TNBS colitis caused an immunocytochemical up-regulation of TRPV1 receptors in the cell bodies of pelvic afferent NF200 negative neurons. TRPV1 signalling mediates the colitis-induced sensitization of pelvic afferent C-fibres to CRD, while Aδ-fibres are neither sensitized by colitis nor affected by TRPV1 inhibition. PMID:18755744

Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats.

PubMed

Eagle, Andrew L; Singh, Robby; Kohler, Robert J; Friedman, Amy L; Liebowitz, Chelsea P; Galloway, Matthew P; Enman, Nicole M; Jutkiewicz, Emily M; Perrine, Shane A

2015-05-01

Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague-Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0, 10 or 20 mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, as expected. However, compared to control rats on Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement. Copyright © 2015. Published by Elsevier B.V.

Aeroallergen Sensitization in Wheezing Children From Rosario, Argentina

PubMed Central

Pendino, Patricia; Agüero, Claudio; Cavagnero, Paola; Lopez, Karina; Molinas, Jorge

2011-01-01

Background Wheezing is a highly frequent symptom in infants and children. Its major causes are respiratory infections and bronchial asthma. In this context, allergen sensitization plays an important role, and it can be detected by a skin prick test, a safe and effective technique that can be easily performed on any age-group. To assess the prevalence of aeroallergen sensitization in a pediatric population with recurrent episodes of wheezing. Materials and Methods Cross-sectional study that evaluated 100 patients, 50 (50%) girls and 50 (50%) boys, from 6 months to 10 years. These children had consulted frequently at the Allergy and Immunology Division of the Eva Perón School Hospital due to recurrent episodes of wheezing. Skin prick test were performed on all of them and also on 20 healthy children. Results Overall, 58% of the patients presented sensitization to dust mite, 13% to pollen, 9% to epithelium, 8% to fungi, 6% to cockroach, and 1% to soybean hull. Overall, 60% of the patients were positive to at least one of the extracts, and we observed a significant and gradual increase in the frequency of sensitization in older age-groups (P < 0.005). This increase persisted when analyzing separately the dust mite group and the pollen group. None of the cases presented any adverse local or systemic reaction during the procedure or the following 24 hours after the procedure. The 20 individuals in the control group turned out negative when tested. Conclusions This study found high aeroallergen sensitization prevalence in a pediatric population with recurrent episodes of wheezing examined in the Allergy and Immunology Division of the Eva Perón School Hospital, which is in the southern area of the province of Santa Fe in Argentina. PMID:23268433

Cultural Resources Survey of the Western Sections of the Larose to Golden Meadow Hurricane Protection Project, Lafourche Parish, Louisiana.

DTIC Science & Technology

1986-09-18

plain, where plant and animal communities are highly sensitive to changes in elevation and salinity , changing shorelines and stream patterns can...material accumulates, shallow bodies of water and intertidal mudflats are created. Along the seaward edge, brackish and saline marshes develop. The...old lobe allow the salinity of inland swamps to increase, causing them to die out. The natural levees of the abandoned distributaries, in the absence

Report of a Workshop on the Geoelectric and Geomagnetic Environment of Continental Margins Held in Arlington, Virginia on November 1989

DTIC Science & Technology

1990-04-01

tiltmeters and a few electric field sensors would be useful. Ancillary environmental measurements will also be needed. These should include sensors to...Applied research issues such as sensor development, technological improvements, and signal processing needs are not specifically addressed. This is... sensors of increased sensitivity. A submarine may have static magnetic and electric dipole moments caused by residual mag- netization of the machinery and

A comparison between ERS-1, JERS-1, and Radarsat-1 radar satellite imaging systems and Landsat MSS & TM and Spot Optical Satellite Imaging System to detect and monitor mangrove deforestation in East Kalimantan, Indonesia

Treesearch

Mahfud M. Zuhair; Yousif Ali Hussin; Michael Weir

2000-01-01

Mangrove forests are one of the primary features of coastal ecosystems throughout the tropical and subtropical regions of the world. Mangroves are very sensitive and fragile resources, and the pressures of increasing population, food production, and industrial and urban development have caused a significant proportion of the world's mangroves to be destroyed....

Proximal Gut Mucosal Epithelial Homeostasis in Aged IL-1 Type I Receptor Knockout Mice After Starvation

DTIC Science & Technology

2011-08-01

increases whole-body lean mass and insulin sensitivity in elderly subjects with sarcopenia . Am J Cardiol. 2008; 101:69E. [PubMed: 18157968] 11. Iwakiri R...nutritional deficiencies in the elderly can be corrected by nutritional supplementation [5-7], especially among patients who are fed enterally [8-10...mechanistic approach regarding intestinal cell dysfunction in the elderly . Starvation causes mucosal atrophy and loss of mucosal height [32], and glutamine

Role of Prefrontal Cortex Glucocorticoid Receptors in Stress and Emotion

PubMed Central

McKlveen, Jessica M.; Myers, Brent; Flak, Jonathan N.; Bundzikova, Jana; Solomon, Matia B.; Seroogy, Kim B.; Herman, James P.

2013-01-01

Background Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation. Methods We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor [GR]) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic (n = 44) or infralimbic (n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field. Results The GR knockdown confined to the infralimbic PFC caused acute stress hyper-responsiveness, sensitization of stress responses after chronic variable stress, and induced depression-like behavior (increased immobility in the forced swim test). Knockdown of GR in the neighboring prelimbic PFC increased hypothalamic-pituitary-adrenocortical axis responses to acute stress and caused hyper-locomotion in the open field, but did not affect stress sensitization or helplessness behavior. Conclusions The data indicate a marked functional heterogeneity of glucocorticoid action in the PFC and highlight a prominent role for the infralimbic GR in appropriate stress adaptation, emotional control, and mood regulation. PMID:23683655

Concurrent infection with porcine reproductive and respiratory syndrome virus and Haemophilus parasuis in two types of porcine macrophages: apoptosis, production of ROS and formation of multinucleated giant cells.

PubMed

Kavanová, Lenka; Matiašková, Katarína; Levá, Lenka; Štěpánová, Hana; Nedbalcová, Kateřina; Matiašovic, Ján; Faldyna, Martin; Salát, Jiří

2017-05-04

Porcine reproductive and respiratory syndrome (PRRS) is one of the most significant and economically important infectious diseases affecting swine worldwide and can predispose pigs to secondary bacterial infections caused by, e.g. Haemophilus parasuis. The aim of the presented study was to compare susceptibility of two different types of macrophages which could be in contact with both pathogens during infection with PRRS virus (PRRSV) and in co-infection with H. parasuis. Alveolar macrophages (PAMs) as resident cells provide one of the first lines of defence against microbes invading lung tissue. On the other hand, monocyte derived macrophages (MDMs) represent inflammatory cells accumulating at the site of inflammation. While PAMs were relatively resistant to cytopathogenic effect caused by PRRSV, MDMs were much more sensitive to PRRSV infection. MDMs infected with PRRSV increased expression of pro-apoptotic Bad, Bax and p53 mRNA. Increased mortality of MDMs may be also related to a higher intensity of ROS production after infection with PRRSV. In addition, MDMs (but not PAMs) infected with H. parasuis alone formed multinucleated giant cells (MGC); these cells were not observed in MDMs infected with both pathogens. Higher sensitivity of MDMs to PRRSV infection, which is associated with limited MDMs survival and restriction of MGC formation, could contribute to the development of multifactorial respiratory disease of swine.

Maternal stress during pregnancy increases neonatal allergy susceptibility: role of glucocorticoids.

PubMed

Lim, Robert; Fedulov, Alexey V; Kobzik, Lester

2014-07-15

We sought to test experimentally whether maternal stress can promote susceptibility to development of asthma-like allergic airways disease in offspring. Normal pregnant mice (day 15) were subjected to a single restraint stress exposure. We subsequently tested their offspring for the development of airway hyperreactivity (AHR) and allergic airway inflammation (AI), after an intentionally suboptimal sensitization protocol. The offspring of stressed mothers showed levels of AI and enhanced airway responses to methacholine comparable to those seen in fully sensitized and challenged positive control animals; in contrast, minimal effects were seen in control offspring. Restraint stress caused a rapid and large increase in plasma corticosterone levels. Maternal treatment with dexamethasone on day 15 of pregnancy mimicked the stress effect and reproduced the AI and AHR outcomes, whereas blockade of the stress-induced corticosterone surge with metyrapone pretreatment of pregnant mice abrogated the effect. We conclude that stress-triggered glucocorticoids during pregnancy can increase susceptibility to allergy in offspring. Because inflammation typically includes a stress hormone response, the results also suggest a common pathway by which various injurious exposures during pregnancy might increase offspring susceptibility to asthma. Copyright © 2014 the American Physiological Society.

Impact of changing from staining to culture techniques on detection rates of Campylobacter spp. in routine stool samples in Chile.

PubMed

Porte, Lorena; Varela, Carmen; Haecker, Thomas; Morales, Sara; Weitzel, Thomas

2016-05-13

Campylobacter is a leading cause of bacterial gastroenteritis, but sensitive diagnostic methods such as culture are expensive and often not available in resource limited settings. Therefore, direct staining techniques have been developed as a practical and economical alternative. We analyzed the impact of replacing Campylobacter staining with culture for routine stool examinations in a private hospital in Chile. From January to April 2014, a total of 750 consecutive stool samples were examined in parallel by Hucker stain and Campylobacter culture. Isolation rates of Campylobacter were determined and the performance of staining was evaluated against culture as the gold standard. Besides, isolation rates of Campylobacter and other enteric pathogens were compared to those of past years. Campylobacter was isolated by culture in 46 of 750 (6.1 %) stool samples. Direct staining only identified three samples as Campylobacter positive and reached sensitivity and specificity values of 6.5 and 100 %, respectively. In comparison to staining-based detection rates of previous years, we observed a significant increase of Campylobacter cases in our patients. Direct staining technique for Campylobacter had a very low sensitivity compared to culture. Staining methods might lead to a high rate of false negative results and an underestimation of the importance of campylobacteriosis. With the inclusion of Campylobacter culture, this pathogen became a leading cause of intestinal infection in our patient population.

A catalytic beacon sensor for uranium with parts-per-trillion sensitivity and millionfold selectivity.

PubMed

Liu, Juewen; Brown, Andrea K; Meng, Xiangli; Cropek, Donald M; Istok, Jonathan D; Watson, David B; Lu, Yi

2007-02-13

Here, we report a catalytic beacon sensor for uranyl (UO2(2+)) based on an in vitro-selected UO2(2+)-specific DNAzyme. The sensor consists of a DNA enzyme strand with a 3' quencher and a DNA substrate with a ribonucleotide adenosine (rA) in the middle and a fluorophore and a quencher at the 5' and 3' ends, respectively. The presence of UO2(2+) causes catalytic cleavage of the DNA substrate strand at the rA position and release of the fluorophore and thus dramatic increase of fluorescence intensity. The sensor has a detection limit of 11 parts per trillion (45 pM), a dynamic range up to 400 nM, and selectivity of >1-million-fold over other metal ions. The most interfering metal ion, Th(IV), interacts with the fluorescein fluorophore, causing slightly enhanced fluorescence intensity, with an apparent dissociation constant of approximately 230 microM. This sensor rivals the most sensitive analytical instruments for uranium detection, and its application in detecting uranium in contaminated soil samples is also demonstrated. This work shows that simple, cost-effective, and portable metal sensors can be obtained with similar sensitivity and selectivity as much more expensive and sophisticated analytical instruments. Such a sensor will play an important role in environmental remediation of radionuclides such as uranium.