Effect of dietary sodium intake on the responses to bicuculline in the paraventricular nucleus of rats.

PubMed

DiBona, G F; Jones, S Y

2001-08-01

The tachycardic, pressor, and renal sympathoexcitatory responses produced by administration of the gamma-aminobutyric acid antagonist bicuculline into the paraventricular nucleus of the rat are attenuated by the administration of losartan, an angiotensin II type 1 receptor antagonist, into the ipsilateral rostroventrolateral medulla. Therefore, excitatory synaptic inputs to pressor neurons in the rostroventrolateral medulla that arise from activation of the paraventricular nucleus are mediated predominantly by the action of angiotensin II on angiotensin II type 1 receptors. To examine whether such responses are influenced by physiological changes in the activity of the renin-angiotensin system, we measured heart rate, arterial pressure, and renal sympathetic nerve activity responses to the administration of bicuculline in the paraventricular nucleus in normal rats that were fed low-, normal-, and high-sodium diets and in rats with congestive heart failure. The rank order of both plasma renin activity and renal sympathoexcitatory responses was congestive heart failure>low-sodium diet>normal-sodium diet>high-sodium diet. The rank order of pressor and tachycardic responses exhibited a similar trend, but the differences between the groups were smaller and not statistically significant. The results indicate that the renal sympathoexcitatory responses to activation of the paraventricular nucleus are modulated by physiological alterations in the activity of the renin-angiotensin system.

Seasonal variation and meteotropism in various self-rated psychological and physiological features of a normal couple

NASA Astrophysics Data System (ADS)

Maes, Michael; de Meyer, Frans; Peeters, Dirk; Meltzer, Herbert; Cosyns, Paul; Schotte, Chris

1992-12-01

Recently, true seasonal variation with significant periodicities (circannual, semiannual, circatrimensual, circabimensual) and a significant meteotropism have been observed in a number of self-rated characteristics of normal man (arousal, mood, physiology and social behaviour). In order to replicate these findings, two normal controls (a married couple) were asked daily to complete a self-rating scale concerned with the characteristics mentioned above during one calendar year. By means of time series analysis, significant rhythmicities with recurrent cycles in the autorhythmometric data of all of the above characteristics were found. An important part of the variance in these characteristics was found, using multiple regression, to be related to various weather variables, such as mean atmospheric pressure, temperature, relative humidity, wind speed, minutes of sunlight/day and precipitation/day. These results support the hypothesis that temporal variations in human psychological and physiological characteristics may be dictated by the composite effects of past and present atmospheric activity.

Digital Health: Tracking Physiomes and Activity Using Wearable Biosensors Reveals Useful Health-Related Information

PubMed Central

Zhou, Gao; Zhou, Wenyu; Schüssler-Fiorenza Rose, Sophia Miryam; Perelman, Dalia; Colbert, Elizabeth; Runge, Ryan; Rego, Shannon; Sonecha, Ria; Datta, Somalee; McLaughlin, Tracey; Snyder, Michael P.

2017-01-01

A new wave of portable biosensors allows frequent measurement of health-related physiology. We investigated the use of these devices to monitor human physiological changes during various activities and their role in managing health and diagnosing and analyzing disease. By recording over 250,000 daily measurements for up to 43 individuals, we found personalized circadian differences in physiological parameters, replicating previous physiological findings. Interestingly, we found striking changes in particular environments, such as airline flights (decreased peripheral capillary oxygen saturation [SpO2] and increased radiation exposure). These events are associated with physiological macro-phenotypes such as fatigue, providing a strong association between reduced pressure/oxygen and fatigue on high-altitude flights. Importantly, we combined biosensor information with frequent medical measurements and made two important observations: First, wearable devices were useful in identification of early signs of Lyme disease and inflammatory responses; we used this information to develop a personalized, activity-based normalization framework to identify abnormal physiological signals from longitudinal data for facile disease detection. Second, wearables distinguish physiological differences between insulin-sensitive and -resistant individuals. Overall, these results indicate that portable biosensors provide useful information for monitoring personal activities and physiology and are likely to play an important role in managing health and enabling affordable health care access to groups traditionally limited by socioeconomic class or remote geography. PMID:28081144

Effect of endogenous angiotensin II on the frequency response of the renal vasculature.

PubMed

Dibona, Gerald F; Sawin, Linda L

2004-12-01

The renal vasculature functions as an efficient low-pass filter of the multiple frequencies contained within renal sympathetic nerve activity. This study examined the effect of angiotensin II on the frequency response of the renal vasculature. Physiological changes in the activity of the endogenous renin-angiotensin system were produced by alterations in dietary sodium intake. The frequency response of the renal vasculature was evaluated using pseudorandom binary sequence renal nerve stimulation, and the role of angiotensin II was evaluated by the administration of the angiotensin II AT(1)-receptor antagonist losartan. In low-sodium-diet rats with increased renin-angiotensin system activity, losartan steepened the renal vascular frequency response (i.e., greater attenuation); this was not seen in normal- or high-sodium-diet rats with normal or decreased renin-angiotensin system activity. Analysis of the transfer function from arterial pressure to renal blood flow, i.e., dynamic autoregulation, showed that the tubuloglomerular feedback but not the myogenic component was enhanced in low- and normal- but not in high-sodium-diet rats and that this was reversed by losartan administration. Thus physiological increases in endogenous renin-angiotensin activity inhibit the renal vascular frequency response to renal nerve stimulation while selectively enhancing the tubuloglomerular feedback component of dynamic autoregulation of renal blood flow.

AMPK Agonist AICAR Improves Cognition and Motor Coordination in Young and Aged Mice

ERIC Educational Resources Information Center

Kobilo, Tali; Guerrieri, Davide; Zhang, Yongqing; Collica, Sarah C.; Becker, Kevin G.; van Praag, Henriette

2014-01-01

Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging-associated frailty can preclude physical activity. In young sedentary animals, pharmacological activation of AMP-activated protein kinase (AMPK), a transcriptional regulator important for muscle physiology, enhanced…

Probiotics normalize the gut-brain-microbiota axis in immunodeficient mice

PubMed Central

Smith, Carli J.; Emge, Jacob R.; Berzins, Katrina; Lung, Lydia; Khamishon, Rebecca; Shah, Paarth; Rodrigues, David M.; Sousa, Andrew J.; Reardon, Colin; Sherman, Philip M.; Barrett, Kim E.

2014-01-01

The gut-brain-microbiota axis is increasingly recognized as an important regulator of intestinal physiology. Exposure to psychological stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis and causes altered intestinal barrier function, intestinal dysbiosis, and behavioral changes. The primary aim of this study was to determine whether the effects of psychological stress on intestinal physiology and behavior, including anxiety and memory, are mediated by the adaptive immune system. Furthermore, we wanted to determine whether treatment with probiotics would normalize these effects. Here we demonstrate that B and T cell-deficient Rag1−/− mice displayed altered baseline behaviors, including memory and anxiety, accompanied by an overactive HPA axis, increased intestinal secretory state, dysbiosis, and decreased hippocampal c-Fos expression. Both local (intestinal physiology and microbiota) and central (behavioral and hippocampal c-Fos) changes were normalized by pretreatment with probiotics, indicating an overall benefit on health conferred by changes in the microbiota, independent of lymphocytes. Taken together, these findings indicate a role for adaptive immune cells in maintaining normal intestinal and brain health in mice and show that probiotics can overcome this immune-mediated deficit in the gut-brain-microbiota axis. PMID:25190473

Physiological work performance in chronic low back disability: effects of a progressive activity program.

PubMed

Thomas, L K; Hislop, H J; Waters, R L

1980-04-01

Fifteen patients were tested before and after treatment in a multifaceted inpatient program for chronic low back pain to determine if a gradually progressive activity program affected gait performance and physiological capacity. Before treatment, all patients demonstrated decreased physiological conditioning by higher-than-expected values for oxygen consumption and heart rate and by lower-than-normal gait velocity, stride length, and cadence. After treatment, an increase in mean walking velocity of 19 meters/minute reflected parallel gains in cadence and stride length. Improved mechanical performance resulted in improved "energetics." Energy spent per unit of distance walked decreased by 18 percent after treatment, providing a useful measure of increased physiological efficiency. Results indicated that patients with chronic low back disability can derive significant conditioning effects from an exercise program based on general function.

Effects of scopolamine on autonomic profiles underlying motion sickness susceptibility

NASA Technical Reports Server (NTRS)

Uijtdehaage, Sebastian H. J.; Stern, Robert M.; Koch, Kenneth L.

1993-01-01

The purpose of this study was to examine the effects of scopolamine on the physiological patterns occurring prior to and during motion sickness stimulation. In addition, the use of physiological profiles in the prediction of motion sickness was evaluated. Sixty subjects ingested either 0.6 mg scopolamine, 2.5 mg methoscopolamine, or a placebo. Heart rate (HR), respiratory sinus arrhythmia (an index of vagal tone), and electrogastrograms were measured prior to and during the exposure to a rotating optokinetic drum. Compared to the other groups, the scopolamine group reported fewer motion sickness symptoms, and displayed lower HR, higher vagal tone, enhanced normal gastric myoelectric activity, and depressed gastric dysrhythmias before and during motion sickness induction. Distinct physiological profiles prior to drum rotation could reliably differentiate individuals who would develop gastric discomfort from those who would not. Symptom-free subjects were characterized by high levels of vagal tone and low HR across conditions, and by maintaining normal (3 cpm) electrogastrographic activity during drum rotation. It was concluded that scopolamine offered motion sickness protection by initiating a pattern of increased vagal tone and gastric myoelectric stability.

[The biological action of chromium in relation to its valency].

PubMed

Vishniakov, S I; Levantovskiĭ, S A; Ryzhkova, G F

1992-01-01

The biological action of chromium in the human or animal organism depends on valency: normal physiological activity is displayed at the expense of CrIII, but toxic activity is more characteristic of CrVI. In the digestive tract and pulmonary tissue CrVI may restore in CrIII.

Restricted feeding-induced sleep, activity, and body temperature changes in normal and preproghrelin-deficient mice

USDA-ARS?s Scientific Manuscript database

Behavioral and physiological rhythms can be entrained by daily restricted feeding (RF), indicating the existence of a food-entrainable oscillator (FEO). One manifestation of the presence of FEO is anticipatory activity to regularly scheduled feeding. In the present study, we tested if intact ghrelin...

The Interaction of Motor Performance and Psycho-Physiological Effects During Acceleration to Hypergravity

NASA Astrophysics Data System (ADS)

Guardiera, Simon; Schneider, Stefan

2008-06-01

Several studies reported that human motor performance is impaired during acceleration to hypergravity. While physiological explanations (e.g. vestibular activity) are widely discussed, psycho-physiological reasons (e.g. stress) are less considered. The present study therefore evaluates the interaction between psycho-physiological effects and motor performance in hypergravity. Eleven subjects performed a manual tracking task. Additionally, stress hormone concentration, EEG and subjective mood were evaluated. All measurements were performed in normal (+1Gz), and in (or directly after) three times gravitational acceleration (+3Gz). Motor performance decreased, while all determined stress hormone concentrations increased in +3Gz. EEG analysis revealed an increase of brain cortical activity in right frontal lobe in +3Gz. Subjective mood decreased due to +3Gz. Our data confirm, that motor performance is decreased in hypergravity, whereas an increase in psychophysiological stress markers could be obtained. We conclude that psycho-physiological changes have to be regarded as a possible explanation for deficits in motor performance in hypergravity.

Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice

PubMed Central

Huai, Jisen; Firat, Elke; Nil, Ahmed; Million, Daniele; Gaedicke, Simone; Kanzler, Benoit; Freudenberg, Marina; van Endert, Peter; Kohler, Gabriele; Pahl, Heike L.; Aichele, Peter; Eichmann, Klaus; Niedermann, Gabriele

2008-01-01

The giant cytosolic protease tripeptidyl peptidase II (TPPII) has been implicated in the regulation of proliferation and survival of malignant cells, particularly lymphoma cells. To address its functions in normal cellular and systemic physiology we have generated TPPII-deficient mice. TPPII deficiency activates cell type-specific death programs, including proliferative apoptosis in several T lineage subsets and premature cellular senescence in fibroblasts and CD8+ T cells. This coincides with up-regulation of p53 and dysregulation of NF-κB. Prominent degenerative alterations at the organismic level were a decreased lifespan and symptoms characteristic of immunohematopoietic senescence. These symptoms include accelerated thymic involution, lymphopenia, impaired proliferative T cell responses, extramedullary hematopoiesis, and inflammation. Thus, TPPII is important for maintaining normal cellular and systemic physiology, which may be relevant for potential therapeutic applications of TPPII inhibitors. PMID:18362329

ATM activation in normal human tissues and testicular cancer.

PubMed

Bartkova, Jirina; Bakkenist, Christopher J; Rajpert-De Meyts, Ewa; Skakkebaek, Niels E; Sehested, Maxwell; Lukas, Jiri; Kastan, Michael B; Bartek, Jiri

2005-06-01

The ATM kinase is a tumor suppressor and key regulator of biological responses to DNA damage. Cultured cells respond to genotoxic insults that induce DNA double-strand breaks by prompt activation of ATM through its autophosphorylation on serine 1981. However, whether ATM-S1981 becomes phosphorylated in vivo, for example during physiological processes that generate DSBs, is unknown. Here we produced phospho-specific monoclonal antibodies against S1981-phosphorylated ATM (pS-ATM), and applied them to immunohistochemical analyses of a wide range of normal human tissues and testicular tumors. Our data show that regardless of proliferation and differentiation, most human tissues contain only the S1981-nonphosphorylated, inactive form of ATM. In contrast, nuclear staining for pS-ATM was detected in subsets of bone-marrow lymphocytes and primary spermatocytes in the adult testes, cell types in which DSBs are generated during physiological V(D)J recombination and meiotic recombination, respectively. Among testicular germ-cell tumors, an aberrant constitutive pS-ATM was observed especially in embryonal carcinomas, less in seminomas, and only modestly in teratomas and the pre-invasive carcinoma-in-situ stage. Compared with pS-ATM, phosphorylated histone H2AX (gammaH2AX), another DNA damage marker and ATM substrate, was detected in a higher proportion of cancer cells, and also in normal fetal gonocytes, and a wider range of adult spermatocyte differentiation stages. Collectively, our results strongly support the physiological relevance of the recently proposed model of ATM autoactivation, and provide further evidence for constitutive activation of the DNA damage machinery during cancer development. The new tools characterized here should facilitate monitoring of ATM activation in clinical specimens, and help develop future treatment strategies.

Thermal Stress

DTIC Science & Technology

2011-01-01

can have a significant impact on normal physiological functioning if precipitous increases in core temperature are not adequately controlled with...anterior hypothalamusIntroduction Thermal stress can have a significant impact on normal physiological functioning if precipitous increases in core...fat and skin). The regulation of a relatively constant internal temperature is critical for normal physiological functioning of tissues and cells, as

Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex.

PubMed

Yu, Ki Jun; Kuzum, Duygu; Hwang, Suk-Won; Kim, Bong Hoon; Juul, Halvor; Kim, Nam Heon; Won, Sang Min; Chiang, Ken; Trumpis, Michael; Richardson, Andrew G; Cheng, Huanyu; Fang, Hui; Thomson, Marissa; Bink, Hank; Talos, Delia; Seo, Kyung Jin; Lee, Hee Nam; Kang, Seung-Kyun; Kim, Jae-Hwan; Lee, Jung Yup; Huang, Younggang; Jensen, Frances E; Dichter, Marc A; Lucas, Timothy H; Viventi, Jonathan; Litt, Brian; Rogers, John A

2016-07-01

Bioresorbable silicon electronics technology offers unprecedented opportunities to deploy advanced implantable monitoring systems that eliminate risks, cost and discomfort associated with surgical extraction. Applications include postoperative monitoring and transient physiologic recording after percutaneous or minimally invasive placement of vascular, cardiac, orthopaedic, neural or other devices. We present an embodiment of these materials in both passive and actively addressed arrays of bioresorbable silicon electrodes with multiplexing capabilities, which record in vivo electrophysiological signals from the cortical surface and the subgaleal space. The devices detect normal physiologic and epileptiform activity, both in acute and chronic recordings. Comparative studies show sensor performance comparable to standard clinical systems and reduced tissue reactivity relative to conventional clinical electrocorticography (ECoG) electrodes. This technology offers general applicability in neural interfaces, with additional potential utility in treatment of disorders where transient monitoring and modulation of physiologic function, implant integrity and tissue recovery or regeneration are required.

Membrane lipid-protein interactions modify the regulatory role of adenosine-deaminase complexing protein: a phase fluorometry study of a malignancy marker

NASA Astrophysics Data System (ADS)

Parola, Abraham H.; Porat, Nurith; Caiolfa, Valeria R.; Gill, David; Kiesow, Lutz A.; Weisman, Mathew; Nemschitz, S.; Yaron, Dahlia; Singer, Karen; Solomon, Ethel

1990-05-01

The role of membrane lipid-protein interactions in malignant cell transformation was examined with adenosine deaminase (ADA) as a representative membrane protein. ADA's activity changes dramatically in transformed cells and accordingly it is a malignancy marker. Yet, the mechanisms controlling its variable activity are unknown. We undertook the spectroscopic deciphering of its interactions with its lipidic environment in normal and malignant cells. ADA exists in two interconvertible forms, small (45 KD) and large (21OKD). The large form consists of two small catalytic subunits (55-ADA) and a dimeric complexing protein ADCP. The physiological role of ADCP was not known either. Our studies were carried out at three levels.: 1. Solution enzyme kinetics, 2. The interaction of 55-ADA with ADCP reconstituted in liposomes: Effect of cholesterol and 3. Multifrequency phase modulation spectrofluorometry of pyrene-labeled 55-ADA bound to ADCP on the membranes of normal and RSV or RSV Ts68 transformed chick embryo fibroblasts. We found: 1. ADCP has an allosteric regulatory role on 55-ADA, which may be of physiological relevance: It inhibits 55-ADA activity at low physiological adenosine concentrations but accelerates deamination at high substrate concentration. 2. When reconstituted in DMPC liposomes, it retains 55-ADA activity (in its absence the activity is lost) and upon rigidification with cholesterol, a three fold increase in 55-ADA activity is attained, contrary to ADCP's regulatory activity when free of lipids. 3. The reduced ADA activity in transformed chick embryo fibroblasts is associated with increased membrane lipid fluidity (reduced order parameter), reduced accessibility of ADCP and increase rotational dynamics of the complex. We thus obtained spectroscopic deciphering of the vertical motion of ADCP, controlled by lipid-protein interaction, resulting in variable activity of this malignancy marker.

Combinations of Physiologic Estrogens with Xenoestrogens Alter ERK Phosphorylation Profiles in Rat Pituitary Cells

PubMed Central

Jeng, Yow-Jiun; Watson, Cheryl S.

2011-01-01

Background Estrogens are potent nongenomic phospho-activators of extracellular-signal–regulated kinases (ERKs). A major concern about the toxicity of xenoestrogens (XEs) is potential alteration of responses to physiologic estrogens when XEs are present simultaneously. Objectives We examined estrogen-induced ERK activation, comparing the abilities of structurally related XEs (alkylphenols and bisphenol A) to alter ERK responses induced by physiologic concentrations (1 nM) of estradiol (E2), estrone (E1), and estriol (E3). Methods We quantified hormone/mimetic-induced ERK phosphorylations in the GH3/B6/F10 rat pituitary cell line using a plate immunoassay, comparing effects with those on cell proliferation and by estrogen receptor subtype-selective ligands. Results Alone, these structurally related XEs activate ERKs in an oscillating temporal pattern similar (but not identical) to that with physiologic estrogens. The potency of all estrogens was similar (active between femtomolar and nanomolar concentrations). XEs potently disrupted physiologic estrogen signaling at low, environmentally relevant concentrations. Generally, XEs potentiated (at the lowest, subpicomolar concentrations) and attenuated (at the highest, picomolar to 100 nM concentrations) the actions of the physiologic estrogens. Some XEs showed pronounced nonmonotonic responses/inhibitions. The phosphorylated ERK and proliferative responses to receptor-selective ligands were only partially correlated. Conclusions XEs are both imperfect potent estrogens and endocrine disruptors; the more efficacious an XE, the more it disrupts actions of physiologic estrogens. This ability to disrupt physiologic estrogen signaling suggests that XEs may disturb normal functioning at life stages where actions of particular estrogens are important (e.g., development, reproductive cycling, pregnancy, menopause). PMID:20870566

Dissection of K+ currents in Caenorhabditis elegans muscle cells by genetics and RNA interference

PubMed Central

Santi, C. M.; Yuan, A.; Fawcett, G.; Wang, Z.-W.; Butler, A.; Nonet, M. L.; Wei, A.; Rojas, P.; Salkoff, L.

2003-01-01

GFP-promoter experiments have previously shown that at least nine genes encoding potassium channel subunits are expressed in Caenorhabditis elegans muscle. By using genetic, RNA interference, and physiological techniques we revealed the molecular identity of the major components of the outward K+ currents in body wall muscle cells in culture. We found that under physiological conditions, outward current is dominated by the products of only two genes, Shaker (Kv1) and Shal (Kv4), both expressing voltage-dependent potassium channels. Other channels may be held in reserve to respond to particular circumstances. Because GFP-promoter experiments indicated that slo-2 expression is prominent, we created a deletion mutant to identify the SLO-2 current in vivo. In both whole-cell and single-channel modes, in vivo SLO-2 channels were active only when intracellular Ca2+ and Cl- were raised above normal physiological conditions, as occurs during hypoxia. Under such conditions, SLO-2 is the largest outward current, contributing up to 87% of the total current. Other channels are present in muscle, but our results suggest that they are unlikely to contribute a large outward component under physiological conditions. However, they, too, may contribute currents conditional on other factors. Hence, the picture that emerges is of a complex membrane with a small number of household conductances functioning under normal circumstances, but with additional conductances that are activated during unusual circumstances. PMID:14612577

Quantitative analysis of the Ca2+‐dependent regulation of delayed rectifier K+ current I Ks in rabbit ventricular myocytes

PubMed Central

Bartos, Daniel C.; Morotti, Stefano; Ginsburg, Kenneth S.; Grandi, Eleonora

2017-01-01

Key points [Ca2+]i enhanced rabbit ventricular slowly activating delayed rectifier K+ current (I Ks) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol.Rabbit ventricular rapidly activating delayed rectifier K+ current (I Kr) amplitude and voltage dependence were unaffected by high [Ca2+]i.When measuring or simulating I Ks during an action potential, I Ks was not different during a physiological Ca2+ transient or when [Ca2+]i was buffered to 500 nm. Abstract The slowly activating delayed rectifier K+ current (I Ks) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca2+ ([Ca2+]i) and β‐adrenergic receptor (β‐AR) stimulation modulate I Ks amplitude and kinetics, but details of these important I Ks regulators and their interaction are limited. We assessed the [Ca2+]i dependence of I Ks in steady‐state conditions and with dynamically changing membrane potential and [Ca2+]i during an AP. I Ks was recorded from freshly isolated rabbit ventricular myocytes using whole‐cell patch clamp. With intracellular pipette solutions that controlled free [Ca2+]i, we found that raising [Ca2+]i from 100 to 600 nm produced similar increases in I Ks as did β‐AR activation, and the effects appeared additive. Both β‐AR activation and high [Ca2+]i increased maximally activated tail I Ks, negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well‐established mathematical model of the rabbit myocyte. In both AP‐clamp experiments and simulations, I Ks recorded during a normal physiological Ca2+ transient was similar to I Ks measured with [Ca2+]i clamped at 500–600 nm. Thus, our study provides novel quantitative data as to how physiological [Ca2+]i regulates I Ks amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca2+]i, in the submembrane or junctional cleft space, is not required to maximize [Ca2+]i‐dependent I Ks activation during normal Ca2+ transients. PMID:28008618

Things Don’t Just Go Back to Normal: The Implications of Antenatal and Postpartum Physiology and Morphology for the Resumption of Fitness Testing

DTIC Science & Technology

2015-04-08

September 2014 - April 2015 Things Don’t Just Go Back to Normal: The Implications of Antenatal and Postpartum Physiology and Morphology for the...physiology; morphology Unclassified Unclassified Unclassified UU 56 Marine Corps University/Command a (703) 784-3330 (Admin Office) United States Marine...MASTER OF MILITARY STUDIES Things Don’t Just Go Back to Normal: The Implications of Antenatal and Postpartum Physiology and Morphology for the

Regulation of Chloride Channels by Protein Kinase C in Normal and Cystic Fibrosis Airway Epithelia

NASA Astrophysics Data System (ADS)

Li, Ming; McCann, John D.; Anderson, Matthew P.; Clancy, John P.; Liedtke, Carole M.; Nairn, Angus C.; Greengard, Paul; Welsh, Michael J.

1989-06-01

Apical membrane chloride channels control chloride secretion by airway epithelial cells. Defective regulation of these channels is a prominent characteristic of cystic fibrosis. In normal intact cells, activation of protein kinase C (PKC) by phorbol ester either stimulated or inhibited chloride secretion, depending on the physiological status of the cell. In cell-free membrane patches, PKC also had a dual effect: at a high calcium concentration, PKC inactivated chloride channels; at a low calcium concentration, PKC activated chloride channels. In cystic fibrosis cells, PKC-dependent channel inactivation was normal, but activation was defective. Thus it appears that PKC phosphorylates and regulates two different sites on the channel or on an associated membrane protein, one of which is defective in cystic fibrosis.

Outside of the laboratory: Associations of working-memory performance with psychological and physiological arousal vary with age.

PubMed

Riediger, Michaela; Wrzus, Cornelia; Klipker, Kathrin; Müller, Viktor; Schmiedek, Florian; Wagner, Gert G

2014-03-01

We investigated age differences in associations among self-reported experiences of tense and energetic arousal, physiological activation indicated by heart rate, and working-memory performance in everyday life. The sample comprised 92 participants aged 14-83 years. Data were collected for 24 hr while participants pursued their normal daily routines. Participants wore an ambulatory biomonitoring system that recorded their cardiac and physical activity. Using mobile phones as assessment devices, they also provided an average of 7 assessments of their momentary experiences of tense arousal (feeling nervous) and energetic arousal (feeling wide-awake) and completed 2 trials of a well-practiced working-memory task. Experiences of higher energetic arousal were associated with higher heart rate in participants younger than 50 years of age but not in participants older than that, and energetic arousal was unrelated to within-person fluctuations in working-memory performance. Experiences of tense arousal were associated with higher heart rate independent of participants' age. Tense arousal and physiological activation were accompanied by momentary impairments in working-memory performance in middle-aged and older adults but not in younger individuals. Results suggest that psychological arousal experiences are associated with lower working-memory performance in middle-aged and older adults when they are accompanied by increased physiological activation and that the same is true for physiological activation deriving from other influences. Hence, age differences in cognitive performance may be exaggerated when the assessment situation itself elicits tense arousal or occurs in situations with higher physiological arousal arising from affective experiences, physical activity, or circadian rhythms. (c) 2014 APA, all rights reserved.

Timely Degradation of Wip1 Phosphatase by APC/C Activator Protein Cdh1 is Necessary for Normal Mitotic Progression.

PubMed

Jeong, Ho-Chang; Gil, Na-Yeon; Lee, Ho-Soo; Cho, Seung-Ju; Kim, Kyungtae; Chun, Kwang-Hoon; Cho, Hyeseong; Cha, Hyuk-Jin

2015-08-01

Wip1 belongs to the protein phosphatase C (PP2C) family, of which expression is up-regulated by a number of external stresses, and serves as a stress modulator in normal physiological conditions. When overexpressed, premature dephosphorylation of stress-mediators by Wip1 results in abrogation of tumor surveillance, thus Wip1 acts as an oncogene. Previously, the functional regulation of Wip1 in cell-cycle progression by counteracting cellular G1 and G2/M checkpoint activity in response to DNA damage was reported. However, other than in stress conditions, the function and regulatory mechanism of Wip1 has not been fully determined. Herein, we demonstrated that protein regulation of Wip1 occurs in a cell cycle-dependent manner, which is directly governed by APC/C(Cdh1) at the end of mitosis. In particular, we also showed evidence that Wip1 phosphatase activity is closely associated with its own protein stability, suggesting that reduced phosphatase activity of Wip1 during mitosis could trigger its degradation. Furthermore, to verify the physiological role of its phosphatase activity during mitosis, we established doxycycline-inducible cell models, including a Wip1 wild type (WT) and phosphatase dead mutant (Wip1 DA). When ectopically expressing Wip1 WT, we observed a delay in the transition from metaphase to anaphase. In conclusion, these studies show that mitotic degradation of Wip1 by APC/C(Cdh1) is important for normal mitotic progression. © 2015 Wiley Periodicals, Inc.

[Autonomic regulation at emotional stress under hypoxic conditions in the elderly with physiological and accelerated aging: effect of hypoxic training].

PubMed

Os'mak, E D; Asanov, É O

2014-01-01

The effect of hypoxic training on autonomic regulation in psycho-emotional stress conditions in hypoxic conditions in older people with physiological (25 people) and accelerated (28 people) aging respiratory system. It is shown that hypoxic training leads to an increase in vagal activity indicators (HF) and reduced simpatovagal index (LF/HF), have a normalizing effect on the autonomic balance during stress loads in older people with different types of aging respiratory system.

Modification of cytogenetic and physiological effects of space flight factors by biologically active compounds

NASA Technical Reports Server (NTRS)

Aliyev, A. A.; Mekhti-Zade, E. R.; Mashinskiy, A. L.; Alekperov, U. K.

1986-01-01

Physiological and cytogenetic changes in the Welsh onion plants induced by a short (82 days) and long term (522 days) space flight are expressed in decrease of seed germination, inhibition of stem growth, depression of cell division in root meristem, and increase in the number of structural chromosome rearrangements. The treatment of such plants with solutions of a-tocopherol, auxin, and kinetin decreased the level of chromosome aberrations to the control one and normalized cell divisions and growth partly or completely.

[Clinical interest of fMRI and functional exploration methods of brain activity and interactivity: physical and neurophysiological considerations].

PubMed

de Marco, G; Menuel, C; Guillevin, R; Vallée, J-N; Lehmann, P; Fall, S; Quaglino, V; Bourdin, B; Devauchelle, B; Chiras, J

2008-07-01

After having provided a brief reminder of the principle of the blood oxygen level-dependent (BOLD) contrast effect, the physiological bases of brain activity and the concepts of functional integration and effective connectivity, we describe the most recent approaches, which permit to explore brain activity and putative networks of interconnected active areas in order to examine the normal brain physiology and its dysfunctions. We present various methods and studies of brain activity analysis clinically applicable, and we detail the concepts of functional and effective connectivity, which allow to study the cerebral plasticity which occurs at the child's during the maturation (e.g., dyslexia), at the adult during the ageing (e.g., Alzheimer disease), or still in schizophrenia or Parkinson disease. The study of specific circuits in networks has to allow defining in a more realistic way the dynamic of the central nervous system, which underlies various cerebral functions, both in physiological and pathological conditions. This connectivity approach should improve the diagnostic and facilitate the development of new therapeutic strategies.

Big-conductance Ca2+-activated K+ channels in physiological and pathophysiological urinary bladder smooth muscle cells

PubMed Central

Parajuli, Shankar P.; Zheng, Yun-Min; Levin, Robert; Wang, Yong-Xiao

2016-01-01

ABSTRACT Contraction and relaxation of urinary bladder smooth muscle cells (UBSMCs) represent the important physiological functions of the bladder. Contractile responses in UBSMCs are regulated by a number of ion channels including big-conductance Ca2+- activated K+ (BK) channels. Great progress has been made in studies of BK channels in UBSMCs. The intent of this review is to summarize recent exciting findings with respect to the functional interactions of BK channels with muscarinic receptors, ryanodine receptors (RyRs) and inositol triphosphate receptors (IP3Rs) as well as their functional importance under normal and pathophysiological conditions. BK channels are highly expressed in UBSMCs. Activation of muscarinic M3 receptors inhibits the BK channel activity, facilitates opening of voltage-dependent Ca2+ (CaV) channels, and thereby enhances excitability and contractility of UBSMCs. Signaling molecules and regulatory mechanisms involving RyRs and IP3Rs have a significant effect on functions of BK channels and thereby regulate cellular responses in UBSMCs under normal and pathophysiological conditions including overactive bladders. Moreover, BK channels may represent a novel target for the treatment of bladder dysfunctions. PMID:27101440

Between strain and tissue differences exist in global hydroxymethylation after acute ozone exposure.

EPA Science Inventory

Epigenetics have been increasingly recognized as a mechanism linking environment and gene expression with both normal physiologic function as well as disease states. Demethylation of cysteine residues, generally leading to gene activation, is an oxygen-dependent reaction and crea...

The physiological effects of slow breathing in the healthy human

PubMed Central

Russo, Marc A.; Santarelli, Danielle M.; O’Rourke, Dean

2017-01-01

Slow breathing practices have been adopted in the modern world across the globe due to their claimed health benefits. This has piqued the interest of researchers and clinicians who have initiated investigations into the physiological (and psychological) effects of slow breathing techniques and attempted to uncover the underlying mechanisms. The aim of this article is to provide a comprehensive overview of normal respiratory physiology and the documented physiological effects of slow breathing techniques according to research in healthy humans. The review focuses on the physiological implications to the respiratory, cardiovascular, cardiorespiratory and autonomic nervous systems, with particular focus on diaphragm activity, ventilation efficiency, haemodynamics, heart rate variability, cardiorespiratory coupling, respiratory sinus arrhythmia and sympathovagal balance. The review ends with a brief discussion of the potential clinical implications of slow breathing techniques. This is a topic that warrants further research, understanding and discussion. Key points Slow breathing practices have gained popularity in the western world due to their claimed health benefits, yet remain relatively untouched by the medical community. Investigations into the physiological effects of slow breathing have uncovered significant effects on the respiratory, cardiovascular, cardiorespiratory and autonomic nervous systems. Key findings include effects on respiratory muscle activity, ventilation efficiency, chemoreflex and baroreflex sensitivity, heart rate variability, blood flow dynamics, respiratory sinus arrhythmia, cardiorespiratory coupling, and sympathovagal balance. There appears to be potential for use of controlled slow breathing techniques as a means of optimising physiological parameters that appear to be associated with health and longevity, and that may extend to disease states; however, there is a dire need for further research into the area. Educational aims To provide a comprehensive overview of normal human respiratory physiology and the documented effects of slow breathing in healthy humans. To review and discuss the evidence and hypotheses regarding the mechanisms underlying slow breathing physiological effects in humans. To provide a definition of slow breathing and what may constitute “autonomically optimised respiration”. To open discussion on the potential clinical implications of slow breathing techniques and the need for further research. PMID:29209423

EMG normalization to study muscle activation in cycling.

PubMed

Rouffet, David M; Hautier, Christophe A

2008-10-01

The value of electromyography (EMG) is sensitive to many physiological and non-physiological factors. The purpose of the present study was to determine if the torque-velocity test (T-V) can be used to normalize EMG signals into a framework of biological significance. Peak EMG amplitude of gluteus maximus (GMAX), vastus lateralis (VL), rectus femoris (RF), biceps femoris long head (BF), gastrocnemius medialis (GAS) and soleus (SOL) was calculated for nine subjects during isometric maximal voluntary contractions (IMVC) and torque-velocity bicycling tests (T-V). Then, the reference EMG signals obtained from IMVC and T-V bicycling tests were used to normalize the amplitude of the EMG signals collected for 15 different submaximal pedaling conditions. The results of this study showed that the repeatability of the measurements between IMVC (from 10% to 23%) and T-V (from 8% to 20%) was comparable. The amplitude of the peak EMG of VL was 99+/-43% higher (p<0.001) when measured during T-V. Moreover, the inter-individual variability of the EMG patterns calculated for submaximal cycling exercises differed significantly when using T-V bicycling normalization method (GMAX: 0.33+/-0.16 vs. 1.09+/-0.04, VL: 0.07+/-0.02 vs. 0.64+/-0.14, SOL: 0.07+/-0.03 vs. 1.00+/-0.07, RF: 1.21+/-0.20 vs. 0.92+/-0.13, BF: 1.47+/-0.47 vs. 0.84+/-0.11). It was concluded that T-V bicycling test offers the advantage to be less time and energy-consuming and to be as repeatable as IMVC tests to measure peak EMG amplitude. Furthermore, this normalization method avoids the impact of non-physiological factors on the amplitude of the EMG signals so that it allows quantifying better the activation level of lower limb muscles and the variability of the EMG patterns during submaximal bicycling exercises.

Syndecan-4 Signaling Is Required for Exercise-Induced Cardiac Hypertrophy

PubMed Central

Xie, Jun; He, Guixin; Chen, Qinhua; Sun, Jiayin; Dai, Qin; Lu, Jianrong; Li, Guannan; Wu, Han; Li, Ran; Chen, Jianzhou; Xu, Wei; Xu, Biao

2016-01-01

Cardiac hypertrophy can be broadly classified as either physiological or pathological. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy and normal heart function. Pathological stimuli including hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Syndecan-4 (synd4) is a transmembrane proteoglycan identified as being involved in cardiac adaptation after injury, but whether it takes part in physiological cardiac hypertrophy is unclear. We observed upregulation of synd4 in exercise-induced hypertrophic myocardium. To evaluate the role of synd4 in the physiological form of cardiac hypertrophy, mice lacking synd4 (synd4–/–) were exercised by swimming for 4 wks. Ultrasonic cardiogram (UCG) and histological analysis revealed that swimming induced the hypertrophic phenotype but was blunted in synd4–/– compared with wild-type (WT) mice. The swimming-induced activation of Akt, a key molecule in physiological hypertrophy was also more decreased than in WT controls. In cultured cardiomyocytes, synd4 overexpression could induce cell enlargement, protein synthesis and distinct physiological molecular alternation. Akt activation also was observed in synd4-overexpressed cardiomyocytes. Furthermore, inhibition of protein kinase C (PKC) prevented the synd4-induced hypertrophic phenotype and Akt phosphorylation. This study identified an essential role of synd4 in mediation of physiological cardiac hypertrophy. PMID:26835698

Dependence of normal development of skeletal muscle in neonatal rats on load bearing

NASA Technical Reports Server (NTRS)

Ohira, Y.; Tanaka, T.; Yoshinaga, T.; Kawano, F.; Nomura, T.; Nonaka, I.; Allen, D. L.; Roy, R. R.; Edgerton, V. R.

2000-01-01

Antigravity function plays an important role in determining the morphological and physiological properties of the neuromuscular system. Inhibition of the normal development of the neuromuscular system is induced by hindlimb unloading during the neonatal period in rats. However, the role of gravitational loading on the development of skeletal muscle in rats is not well understood. It could be hypothesized that during the early postnatal period, i.e. when minimal weight-supporting activity occurs, the activity imposed by gravity would be of little consequence in directing the normal development of the skeletal musculature. We have addressed this issue by limiting the amount of postnatal weight-support activity of the hindlimbs of rats during the lactation period. We have focused on the development of three characteristics of the muscle fibers, i.e. size, myonuclear number and myosin heavy chain expression.

Anatomically realistic multiscale models of normal and abnormal gastrointestinal electrical activity

PubMed Central

Cheng, Leo K; Komuro, Rie; Austin, Travis M; Buist, Martin L; Pullan, Andrew J

2007-01-01

One of the major aims of the International Union of Physiological Sciences (IUPS) Physiome Project is to develop multiscale mathematical and computer models that can be used to help understand human health. We present here a small facet of this broad plan that applies to the gastrointestinal system. Specifically, we present an anatomically and physiologically based modelling framework that is capable of simulating normal and pathological electrical activity within the stomach and small intestine. The continuum models used within this framework have been created using anatomical information derived from common medical imaging modalities and data from the Visible Human Project. These models explicitly incorporate the various smooth muscle layers and networks of interstitial cells of Cajal (ICC) that are known to exist within the walls of the stomach and small bowel. Electrical activity within individual ICCs and smooth muscle cells is simulated using a previously published simplified representation of the cell level electrical activity. This simulated cell level activity is incorporated into a bidomain representation of the tissue, allowing electrical activity of the entire stomach or intestine to be simulated in the anatomically derived models. This electrical modelling framework successfully replicates many of the qualitative features of the slow wave activity within the stomach and intestine and has also been used to investigate activity associated with functional uncoupling of the stomach. PMID:17457969

Microgravity Analogues of Herpes Virus Pathogenicity: Human Cytomegalovirus (hCMV) and Varicella Zoster (VZV) Infectivity in Human Tissue Like Assemblies (TLAs)

NASA Technical Reports Server (NTRS)

Goodwin, T. J.; McCarthy, M.; Albrecht, T.; Cohrs, R.

2009-01-01

The old adage we are our own worst enemies may perhaps be the most profound statement ever made when applied to man s desire for extraterrestrial exploration and habitation of Space. Consider the immune system protects the integrity of the entire human physiology and is comprised of two basic elements the adaptive or circulating and the innate immune system. Failure of the components of the adaptive system leads to venerability of the innate system from opportunistic microbes; viral, bacteria, and fungal, which surround us, are transported on our skin, and commonly inhabit the human physiology as normal and imunosuppressed parasites. The fine balance which is maintained for the preponderance of our normal lives, save immune disorders and disease, is deregulated in microgravity. Thus analogue systems to study these potential Risks are essential for our progress in conquering Space exploration and habitation. In this study we employed two known physiological target tissues in which the reactivation of hCMV and VZV occurs, human neural and lung systems created for the study and interaction of these herpes viruses independently and simultaneously on the innate immune system. Normal human neural and lung tissue analogues called tissue like assemblies (TLAs) were infected with low MOIs of approximately 2 x 10(exp -5) pfu hCMV or VZV and established active but prolonged low grade infections which spanned .7-1.5 months in length. These infections were characterized by the ability to continuously produce each of the viruses without expiration of the host cultures. Verification and quantification of viral replication was confirmed via RT_PCR, IHC, and confocal spectral analyses of the respective essential viral genomes. All host TLAs maintained the ability to actively proliferate throughout the entire duration of the experiments as is analogous to normal in vivo physiological conditions. These data represent a significant advance in the ability to study the triggering mechanisms which surround Herpes vial reactivation and proliferation. Additionally, prolonged replication of these viruses will allow the tracking of viral genomic shift.

Role of growth differentiation factor 11 in development, physiology and disease

PubMed Central

Zhang, Yonghui; Wei, Yong; Liu, Dan; Liu, Feng; Li, Xiaoshan; Pan, Lianhong; Pang, Yi; Chen, Dilong

2017-01-01

Growth differentiation factor (GDF11) is a member of TGF-β/BMP superfamily that activates Smad and non-Smad signaling pathways and regulates expression of its target nuclear genes. Since its discovery in 1999, studies have shown the involvement of GDF11 in normal physiological processes, such as embryonic development and erythropoiesis, as well as in the pathophysiology of aging, cardiovascular disease, diabetes mellitus, and cancer. In addition, there are contradictory reports regarding the role of GDF11 in aging, cardiovascular disease, diabetes mellitus, osteogenesis, skeletal muscle development, and neurogenesis. In this review, we describe the GDF11 signaling pathway and its potential role in development, physiology and disease. PMID:29113418

Brain, body, and cognition: Neural, physiological and self-report correlates of phobic and normative fear

PubMed Central

Schaefer, Hillary S.; Larson, Christine L.; Davidson, Richard J.; Coan, James A.

2014-01-01

The phobic fear response appears to resemble an intense form of normal threat responding that can be induced in a nonthreatening situation. However, normative and phobic fear are rarely contrasted directly, thus the degree to which these two types of fear elicit similar neural and bodily responses is not well understood. To examine biological correlates of normal and phobic fear, 21 snake phobic and 21 nonphobic controls saw videos of slithering snakes, attacking snakes and fish in an event-related fMRI design. Simultaneous eletrodermal, pupillary, and self-reported affective responses were collected. Nonphobic fear activated a network of threat-responsive brain regions and involved pupillary dilation, electrodermal response and self-reported affect selective to the attacking snakes. Phobic fear recruited a large array of brain regions including those active in normal fear plus additional structures and also engendered increased pupil dilation, electrodermal and self-reported responses that were greater to any snake versus fish. Importantly, phobics showed greater between- and within-subject concordance among neural, electrodermal, pupillary, and subjective report measures. These results suggest phobic responses recruit overlapping but more strongly activated and more extensive networks of brain activity as compared to normative fear, and are characterized by greater concordance among neural activation, peripheral physiology and self-report. It is yet unclear whether concordance is unique to psychopathology, or rather simply an indicator of the intense fear seen in the phobic response, but these results underscore the importance of synchrony between brain, body, and cognition during the phobic reaction. PMID:24561099

Brain, body, and cognition: neural, physiological and self-report correlates of phobic and normative fear.

PubMed

Schaefer, Hillary S; Larson, Christine L; Davidson, Richard J; Coan, James A

2014-04-01

The phobic fear response appears to resemble an intense form of normal threat responding that can be induced in a nonthreatening situation. However, normative and phobic fear are rarely contrasted directly, thus the degree to which these two types of fear elicit similar neural and bodily responses is not well understood. To examine biological correlates of normal and phobic fear, 21 snake phobic and 21 nonphobic controls saw videos of slithering snakes, attacking snakes and fish in an event-related fMRI design. Simultaneous eletrodermal, pupillary, and self-reported affective responses were collected. Nonphobic fear activated a network of threat-responsive brain regions and involved pupillary dilation, electrodermal response and self-reported affect selective to the attacking snakes. Phobic fear recruited a large array of brain regions including those active in normal fear plus additional structures and also engendered increased pupil dilation, electrodermal and self-reported responses that were greater to any snake versus fish. Importantly, phobics showed greater between- and within-subject concordance among neural, electrodermal, pupillary, and subjective report measures. These results suggest phobic responses recruit overlapping but more strongly activated and more extensive networks of brain activity as compared to normative fear, and are characterized by greater concordance among neural activation, peripheral physiology and self-report. It is yet unclear whether concordance is unique to psychopathology, or rather simply an indicator of the intense fear seen in the phobic response, but these results underscore the importance of synchrony between brain, body, and cognition during the phobic reaction. Copyright © 2014. Published by Elsevier B.V.

Physiological and psychological effects of forest therapy on middle-aged males with high-normal blood pressure.

PubMed

Ochiai, Hiroko; Ikei, Harumi; Song, Chorong; Kobayashi, Maiko; Takamatsu, Ako; Miura, Takashi; Kagawa, Takahide; Li, Qing; Kumeda, Shigeyoshi; Imai, Michiko; Miyazaki, Yoshifumi

2015-02-25

Time spent walking and relaxing in a forest environment ("forest bathing" or "forest therapy") has well demonstrated anti-stress effects in healthy adults, but benefits for ill or at-risk populations have not been reported. The present study assessed the physiological and psychological effects of forest therapy (relaxation and stress management activity in the forest) on middle-aged males with high-normal blood pressure. Blood pressure and several physiological and psychological indices of stress were measured the day before and approximately 2 h following forest therapy. Both pre- and post-treatment measures were conducted at the same time of day to avoid circadian influences. Systolic and diastolic blood pressure (BP), urinary adrenaline, and serum cortisol were all significantly lower than baseline following forest therapy (p<0.05). Subjects reported feeling significantly more "relaxed" and "natural" according to the Semantic Differential (SD) method. Profile of Mood State (POMS) negative mood subscale scores for "tension-anxiety," "confusion," and "anger-hostility," as well as the Total Mood Disturbance (TMD) score were significantly lower following forest therapy. These results highlight that forest is a promising treatment strategy to reduce blood pressure into the optimal range and possibly prevent progression to clinical hypertension in middle-aged males with high-normal blood pressure.

Physiological effects in bovine lymphocytes of inhibiting polyamine synthesis with ethylglyoxal bis(guanylhydrazone).

PubMed

Igarashi, K; Morris, D R

1984-11-01

Previous results have suggested that ethylglyoxal bis(guanylhydrazone) is a more specific inhibitor of polyamine biosynthesis than the widely used methylglyoxal bis(guanylhydrazone). The physiological effects on mitogenically activated lymphocytes of polyamine depletion with ethylglyoxal bis(guanylhydrazone) were examined. In the presence of ethylglyoxal bis(guanylhydrazone) and the ornithine decarboxylase inhibitor alpha-difluoromethylornithine, the cellular contents of putrescine, spermidine, and spermine were decreased by 75 to 90, 65 to 80, and 40 to 60%, respectively, compared with control cultures. Inhibition of DNA synthesis in these polyamine-deficient cells was always greater than that of protein synthesis. Upon addition of spermidine to the deficient cells, the cellular spermidine content was restored within 4 hr, but the complete recovery of macromolecular synthesis took 10 to 20 hr. Thymidine kinase and DNA polymerase alpha activities in polyamine-deficient cells were lower than those in normal cells, whereas RNA polymerase II and leucyl transfer RNA synthase activities were nearly equal to those in normal cells. These results and studies with 2-dimensional gel electrophoresis raise the possibility that polyamines may regulate the synthesis of specific proteins. Decreased synthesis of replication proteins in polyamine-deficient cells may be one reason for the reduced synthesis of DNA.

A prospective randomized trial of two solutions for intrapartum amnioinfusion: effects on fetal electrolytes, osmolality, and acid-base status.

PubMed

Pressman, E K; Blakemore, K J

1996-10-01

Our purpose was to compare the effects of intrapartum amnioinfusion with normal saline solution versus lactated Ringer's solution plus physiologic glucose on neonatal electrolytes and acid-base balance. Patients undergoing amnioinfusion for obstetric indications were randomized to receive normal saline solution or lactated Ringer's solution plus physiologic glucose at standardized amnioinfusion rates. Data were collected prospectively on maternal demographics, course of labor, and maternal and neonatal outcome. Arterial cord blood was obtained for analysis of electrolytes, glucose, osmolality, lactic acid, and blood gases. Control subjects with normal fetal heart rate patterns, and clear amniotic fluid not receiving amnioinfusion were studied concurrently. Data were collected on 59 patients (21 normal saline solution, 18 lactated Ringer's solution plus physiologic glucose, and 20 controls). Maternal demographics, course of labor, and neonatal outcome were similar in all three groups. Cesarean sections were performed more often in the amnioinfusion groups (33.3% for normal saline solution, 38.9% for lactated Ringer's solution plus physiologic glucose) than in the control group (5.0%), p < 0.05. Cord arterial electrolytes, glucose, osmolality, lactic acid, and blood gases were not altered by amnioinfusion with either solution. Intrapartum amnioinfusion with normal saline solution or lactated Ringer's solution plus physiologic glucose has no effect on neonatal electrolytes or acid-base balance.

Near-Infrared Fluorescent Nanoprobes for Revealing the Role of Dopamine in Drug Addiction.

PubMed

Feng, Peijian; Chen, Yulei; Zhang, Lei; Qian, Cheng-Gen; Xiao, Xuanzhong; Han, Xu; Shen, Qun-Dong

2018-02-07

Brain imaging techniques enable visualizing the activity of central nervous system without invasive neurosurgery. Dopamine is an important neurotransmitter. Its fluctuation in brain leads to a wide range of diseases and disorders, like drug addiction, depression, and Parkinson's disease. We designed near-infrared fluorescence dopamine-responsive nanoprobes (DRNs) for brain activity imaging during drug abuse and addiction process. On the basis of light-induced electron transfer between DRNs and dopamine and molecular wire effect of the DRNs, we can track the dynamical change of the neurotransmitter level in the physiological environment and the releasing of the neurotransmitter in living dopaminergic neurons in response to nicotine stimulation. The functional near-infrared fluorescence imaging can dynamically track the dopamine level in the mice midbrain under normal or drug-activated condition and evaluate the long-term effect of addictive substances to the brain. This strategy has the potential for studying neural activity under physiological condition.

A comprehensive prediction and evaluation method of pilot workload

PubMed Central

Feng, Chuanyan; Wanyan, Xiaoru; Yang, Kun; Zhuang, Damin; Wu, Xu

2018-01-01

BACKGROUND: The prediction and evaluation of pilot workload is a key problem in human factor airworthiness of cockpit. OBJECTIVE: A pilot traffic pattern task was designed in a flight simulation environment in order to carry out the pilot workload prediction and improve the evaluation method. METHODS: The prediction of typical flight subtasks and dynamic workloads (cruise, approach, and landing) were built up based on multiple resource theory, and a favorable validity was achieved by the correlation analysis verification between sensitive physiological data and the predicted value. RESULTS: Statistical analysis indicated that eye movement indices (fixation frequency, mean fixation time, saccade frequency, mean saccade time, and mean pupil diameter), Electrocardiogram indices (mean normal-to-normal interval and the ratio between low frequency and sum of low frequency and high frequency), and Electrodermal Activity indices (mean tonic and mean phasic) were all sensitive to typical workloads of subjects. CONCLUSION: A multinominal logistic regression model based on combination of physiological indices (fixation frequency, mean normal-to-normal interval, the ratio between low frequency and sum of low frequency and high frequency, and mean tonic) was constructed, and the discriminate accuracy was comparatively ideal with a rate of 84.85%. PMID:29710742

A comprehensive prediction and evaluation method of pilot workload.

PubMed

Feng, Chuanyan; Wanyan, Xiaoru; Yang, Kun; Zhuang, Damin; Wu, Xu

2018-01-01

The prediction and evaluation of pilot workload is a key problem in human factor airworthiness of cockpit. A pilot traffic pattern task was designed in a flight simulation environment in order to carry out the pilot workload prediction and improve the evaluation method. The prediction of typical flight subtasks and dynamic workloads (cruise, approach, and landing) were built up based on multiple resource theory, and a favorable validity was achieved by the correlation analysis verification between sensitive physiological data and the predicted value. Statistical analysis indicated that eye movement indices (fixation frequency, mean fixation time, saccade frequency, mean saccade time, and mean pupil diameter), Electrocardiogram indices (mean normal-to-normal interval and the ratio between low frequency and sum of low frequency and high frequency), and Electrodermal Activity indices (mean tonic and mean phasic) were all sensitive to typical workloads of subjects. A multinominal logistic regression model based on combination of physiological indices (fixation frequency, mean normal-to-normal interval, the ratio between low frequency and sum of low frequency and high frequency, and mean tonic) was constructed, and the discriminate accuracy was comparatively ideal with a rate of 84.85%.

US experiments flown on the Soviet satellite COSMOS 936

NASA Technical Reports Server (NTRS)

Rosenzweig, S. N.; Souza, K. A.

1978-01-01

Results of spaceborne experiments onboard the Cosmos 936 satellite are reported. Alterations in normal bone chemistry, muscle structure, and general physiology resulting from spaceflight are covered along with measurements of cosmic radiation and its potential hazard to man during prolonged spaceflights. Postflight activities involving the seven U.S. experiments are emphasized.

Genetic and metabolic variability in autotrophic and heterotrophic bacteria

NASA Technical Reports Server (NTRS)

Decicco, B. T.

1972-01-01

The studies to evaluate an organism's ability to maintain normal physiological activities over a long period of time in a bioregenerative system are presented. Studies reviewed include: heat tolerant mutants of Pseudomonas fluoresceins, virulence factors of the Staphylococci, and the effect of mutations on the virulence for man in common and ubiquitous microorganisms.

Plasticity of language-related brain function during recovery from stroke.

PubMed

Thulborn, K R; Carpenter, P A; Just, M A

1999-04-01

This study was undertaken to correlate functional recovery from aphasia after acute stroke with the temporal evolution of the anatomic, physiological, and functional changes as measured by MRI. Blood oxygenation level-dependent contrast and echo-planar MRI were used to map language comprehension in 6 normal adults and in 2 adult patients during recovery from acute stroke presenting with aphasia. Perfusion, diffusion, sodium, and conventional anatomic MRI were used to follow physiological and structural changes. The normal activation pattern for language comprehension showed activation predominately in left-sided Wernicke's and Broca's areas, with laterality ratios of 0.8 and 0.3, respectively. Recovery of the patient confirmed as having a completed stroke affecting Broca's area occurred rapidly with a shift of activation to the homologous region in the right hemisphere within 3 days, with continued rightward lateralization over 6 months. In the second patient, in whom mapping was performed fortuitously before stroke, recovery of a Wernicke's aphasia showed a similar increasing rightward shift in activation recruitment over 9 months after the event. Recovery of aphasia in adults can occur rapidly and is concomitant with an activation pattern that changes from left to a homologous right hemispheric pattern. Such recovery occurs even when the stroke evolves to completion. Such plasticity must be considered when evaluating stroke interventions based on behavioral and neurological measurements.

Let's 'play' with molecular pharmacology.

PubMed

Choudhury, Supriyo; Pradhan, Richeek; Sengupta, Gairik; Das, Manisha; Chatterjee, Manojit; Roy, Ranendra Kumar; Chatterjee, Suparna

2015-01-01

Understanding concepts of molecular mechanisms of drug action involves sequential visualization of physiological processes and drug effects, a task that can be difficult at an undergraduate level. Role-play is a teaching-learning methodology whereby active participation of students as well as clear visualization of the phenomenon is used to convey complex physiological concepts. However, its use in teaching drug action, a process that demands understanding of a second level of complexity over the physiological process, has not been investigated. We hypothesized that role-play can be an effective and well accepted method for teaching molecular pharmacology. In an observational study, students were guided to perform a role-play on a selected topic involving drug activity. Students' gain in knowledge was assessed comparing validated pre- and post-test questionnaires as well as class average normalized gain. The acceptance of role-play among undergraduate medical students was evaluated by Likert scale analysis and thematic analysis of their open-ended written responses. Significant improvement in knowledge (P < 0.001) was noted in the pre- to post-test knowledge scores, while a high gain in class average normalized score was evident. In Likert scale analysis, most students (93%) expressed that role-play was an acceptable way of teaching. In a thematic analysis, themes of both strengths and weaknesses of the session emerged. Role-play can be effectively utilized while teaching selected topics of molecular pharmacology in undergraduate medical curricula.

Central angiotensin modulation of baroreflex control of renal sympathetic nerve activity in the rat: influence of dietary sodium.

PubMed

DiBona, G F

2003-03-01

Administration of angiotensin II (angII) into the cerebral ventricles or specific brain sites impairs arterial baroreflex regulation of renal sympathetic nerve activity (SNA). Further insight into this effect was derived from: (a) using specific non-peptide angII receptor antagonists to assess the role of endogenous angII acting on angII receptor subtypes, (b) microinjection of angII receptor antagonists into brain sites behind an intact blood-brain barrier to assess the role of endogenous angII of brain origin and (c) alterations in dietary sodium intake, a known physiological regulator of activity of the renin-angiotensin system (RAS), to assess the ability to physiologically regulate the activity of the brain RAS. In rats in balance on low, normal or dietary sodium intake, losartan or candesartan was injected into the lateral cerebral ventricle or the rostral ventrolateral medulla (RVLM) and the effects on basal renal SNA and the arterial baroreflex sigmoidal relationship between renal SNA and arterial pressure were determined. With both routes of administration, the effects were proportional to the activity of the RAS as indexed by plasma renin activity (PRA). The magnitude of both the decrease in basal renal SNA and the parallel resetting of arterial baroreflex regulation of renal SNA to a lower arterial pressure was greatest in low-sodium rats with highest PRA and least in high-sodium rats with lowest PRA. Disinhibition of the paraventricular nucleus (PVN) by injection of bicuculline causes pressor, tachycardic and renal sympathoexcitatory responses mediated via an angiotensinergic projection from PVN to RVLM. In comparison with responses in normal sodium rats, these responses were greatly diminished in high-sodium rats and greatly enhanced in low-sodium rats. Physiological changes in the activity of the RAS produced by alterations in dietary sodium intake regulate the contribution of endogenous angII of brain origin in the modulation of arterial baroreflex regulation of renal SNA.

Nonlinear dynamics applied to the study of cardiovascular effects of stress

NASA Astrophysics Data System (ADS)

Anishchenko, T. G.; Igosheva, N. B.

1998-03-01

We study cardiovascular responses to emotional stresses in humans and rats using traditional physiological parameters and methods of nonlinear dynamics. We found that emotional stress results in significant changes of chaos degree of ECG and blood pressure signals, estimated using a normalized entropy. We demonstrate that the normalized entropy is a more sensitive indicator of the stress-induced changes in cardiovascular systems compared with traditional physiological parameters Using the normalized entropy we discovered the significant individual differences in cardiovascular stress-reactivity that was impossible to obtain by traditional physiological methods.

Genetic Analysis of Digestive Physiology Using Fluorescent Phospholipid Reporters

NASA Astrophysics Data System (ADS)

Farber, Steven A.; Pack, Michael; Ho, Shiu-Ying; Johnson, Iain D.; Wagner, Daniel S.; Dosch, Roland; Mullins, Mary C.; Hendrickson, H. Stewart; Hendrickson, Elizabeth K.; Halpern, Marnie E.

2001-05-01

Zebrafish are a valuable model for mammalian lipid metabolism; larvae process lipids similarly through the intestine and hepatobiliary system and respond to drugs that block cholesterol synthesis in humans. After ingestion of fluorescently quenched phospholipids, endogenous lipase activity and rapid transport of cleavage products results in intense gall bladder fluorescence. Genetic screening identifies zebrafish mutants, such as fat free, that show normal digestive organ morphology but severely reduced phospholipid and cholesterol processing. Thus, fluorescent lipids provide a sensitive readout of lipid metabolism and are a powerful tool for identifying genes that mediate vertebrate digestive physiology.

[Influence of physiologic 17 beta-estradiol concentrations on gene E6 expression in HVP type 18 in vitro].

PubMed

Dziubińska-Parol, Izabella; Gasowska, Urszula; Rzymowska, Jolanta; Kwaśniewska, Anna

2003-09-01

Many recent studies indicate that long term use of contraceptives is a strong risk factor in the development of cervical cancer. Steroid hormones, in persistent papilloma virus infection act on various levels, one of them is enhancing transforming activity of the virus. The aim of the study was to estimate if physiological concentrations of 17 beta-estradiol could influence expression of viral transforming genes. HeLa cell lines were incubated with three different physiological concentrations and and on the third day of incubation the level of E6 gene expression was determined. Results show no differences in expression between the control culter, and cultures incubated with physiological concentrations. It indicates that normal levels of 17 beta-estradiol don't play role in transforming process but it also shows need to analyse higher levels of hormones by quantitative analyses in prospective studies.

Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy.

PubMed

Luo, Ji; McMullen, Julie R; Sobkiw, Cassandra L; Zhang, Li; Dorfman, Adam L; Sherwood, Megan C; Logsdon, M Nicole; Horner, James W; DePinho, Ronald A; Izumo, Seigo; Cantley, Lewis C

2005-11-01

Class I(A) phosphoinositide 3-kinases (PI3Ks) are activated by growth factor receptors, and they regulate, among other processes, cell growth and organ size. Studies using transgenic mice overexpressing constitutively active and dominant negative forms of the p110alpha catalytic subunit of class I(A) PI3K have implicated the role of this enzyme in regulating heart size and physiological cardiac hypertrophy. To further understand the role of class I(A) PI3K in controlling heart growth and to circumvent potential complications from the overexpression of dominant negative and constitutively active proteins, we generated mice with muscle-specific deletion of the p85alpha regulatory subunit and germ line deletion of the p85beta regulatory subunit of class I(A) PI3K. Here we show that mice with cardiac deletion of both p85 subunits exhibit attenuated Akt signaling in the heart, reduced heart size, and altered cardiac gene expression. Furthermore, exercise-induced cardiac hypertrophy is also attenuated in the p85 knockout hearts. Despite such defects in postnatal developmental growth and physiological hypertrophy, the p85 knockout hearts exhibit normal contractility and myocardial histology. Our results therefore provide strong genetic evidence that class I(A) PI3Ks are critical regulators for the developmental growth and physiological hypertrophy of the heart.

Monomeric insulins obtained by protein engineering and their medical implications.

PubMed

Brange, J; Ribel, U; Hansen, J F; Dodson, G; Hansen, M T; Havelund, S; Melberg, S G; Norris, F; Norris, K; Snel, L

1988-06-16

The use of insulin as an injected therapeutic agent for the treatment of diabetes has been one of the outstanding successes of modern medicine. The therapy has, however, had its associated problems, not least because injection of insulin does not lead to normal diurnal concentrations of insulin in the blood. This is especially true at meal times when absorption from subcutaneous tissue is too slow to mimic the normal rapid increments of insulin in the blood. In the neutral solutions used for therapy, insulin is mostly assembled as zinc-containing hexamers and this self-association, which under normal physiological circumstances functions to facilitate proinsulin transport, conversion and intracellular storage, may limit the rate of absorption. We now report that it is possible, by single amino-acid substitutions, to make insulins which are essentially monomeric at pharmaceutical concentrations (0.6 mM) and which have largely preserved their biological activity. These monomeric insulins are absorbed two to three times faster after subcutaneous injection than the present rapid-acting insulins. They are therefore capable of giving diabetic patients a more physiological plasma insulin profile at the time of meal consumption.

A Multi-Scale Sampling Strategy for Detecting Physiologically Significant Signals in AVIRIS Imagery

NASA Technical Reports Server (NTRS)

Gamon, John A.; Lee, Lai-Fun; Qiu, Hong-Lie; Davis, Stephen; Roberts, Dar A.; Ustin, Susan L.

1998-01-01

Models of photosynthetic production at ecosystem and global scales require multiple input parameters specifying physical and physiological surface features. While certain physical parameters (e.g., absorbed photosynthetically active radiation) can be derived from current satellite sensors, other physiologically relevant measures (e.g., vegetation type, water status, carboxylation capacity, or photosynthetic light-use efficiency), are not generally directly available from current satellite sensors at the appropriate geographic scale. Consequently, many model parameters must be assumed or derived from independent sources, often at an inappropriate scale. An abundance of ecophysiological studies at the leaf and canopy scales suggests strong physiological control of vegetation-atmosphere CO2 and water vapor fluxes, particularly in evergreen vegetation subjected to diurnal or seasonal stresses. For example hot, dry conditions can lead to stomatal closure, and associated "downregulation" of photosynthetic biochemical processes, a phenomenon often manifested as a "midday photosynthetic depression". A recent study with the revised simple biosphere (SiB2) model demonstrated that photosynthetic downregulation can significantly impact global climate. However, at the global scale, the exact significance of downregulation remains unclear, largely because appropriate physiological measures are generally unavailable at this scale. Clearly, there is a need to develop reliable ways of extracting physiologically relevant information from remote sensing. Narrow-band spectrometers offer many opportunities for deriving physiological parameters needed for ecosystem and global scale photosynthetic models. Experimental studies on the ground at the leaf- to stand-scale have indicated that several narrow-band features can be used to detect plant physiological status. One physiological signal is caused by xanthophyll cycle pigment activity, and is often expressed as the Photochemical Reflectance Index (PRI). Because the xanthophyll cycle pigments are photoregulatory pigments closely linked to photosynthetic function, this index can be used to derive relative photosynthetic rates. An additional signal with physiological significance is the 970 nm water absorption band, which provides a measure of liquid water content. This feature has been quantified both using a simple 2-band ratio (900/970 nm, here referred to as the "Water Band Index" or WBI;), and using the "continuum removal" method. Current atmospheric correction methods for AVIRIS imagery also obtain quantitative expressions of surface liquid water absorption based on the 970 nm water band and may be comparable to ground-based estimates of water content using this feature. However, physiological interpretations of both the PRI and the WBI are best understood at the leaf and canopy scales, where complications of atmospheric interference and complex stand and landscape features can be minimized, and where experimental manipulations can be readily applied. Currently it is not known whether these physiological indices can be used to derive meaningful physiological information from AVIRIS imagery. In addition to the problem of atmospheric interference, another challenge is that any simple physiological index can be confounded by multiple factors unrelated to physiology, and this problem can become more severe at progressively larger spatial scales. For example, previous work has suggested that both the PRI and the WBI, are strongly correlated with other optical measures of canopy structure (e.g., the Normalized Difference Vegetation Index or green vegetation fraction), indicating a confounding effect of structure on physiological signals at the larger, landscape scale. Furthermore, the normal operating mode of most imaging spectrometers does not allow simultaneous, ground truthing at a level of detail needed for physiological sampling. Additionally, manipulative experiments of physiology are difficult to apply at a geographic scale suitable for comparison with remote imagery, which often works at spatial scales that are several orders of magnitude larger than those typically used for physiological studies. These limitations require the consideration of alternative approaches to validating physiological information derived from AVIRIS data. In this report, we present a multi-scale sampling approach to detecting physiologically significant signals in narrow-band spectra. This approach explores the multi-dimensional data space provided by narrow-band spectrometry, and combines AVIRIS imagery at a large scale, with ground spectral sampling at an intermediate scale, and detailed ecophysiological measurements at a fine scale, to examine seasonally and spatially changing relationships between multiple structural and physiological variables. Examples of this approach are provided by simultaneous sampling of the Normalized Difference Vegetation Index (NDVI), an index of fractional PAR interception and green vegetation cover, the Water Band Index (WBI, an index of liquid water absorption, and the Photochemical Reflectance Index (PRI, an index of xanthophyll cycle pigment activity and photosynthetic light-use efficiency. By directly linking changing optical properties sampled on the ground with measurable physiological states, we hope to develop a basis for interpreting similar signals in AVIRIS imagery.

Altered LARK Expression Perturbs Development and Physiology of the Drosophila PDF Clock Neurons

PubMed Central

Huang, Yanmei; Howlett, Eric; Stern, Michael; Jackson, F. Rob

2009-01-01

The LARK RNA-binding protein (RBP) has well documented roles in the circadian systems of Drosophila and mammals. Recent studies have demonstrated that the Drosophila LARK RBP is associated with many mRNA targets, in vivo, including those that regulate either neurophysiology or development of the nervous system. In the present study, we have employed conditional expression techniques to distinguish developmental and physiological functions of LARK for a defined class of neurons: the Pigment Dispersing Factor (PDF)-containing LNv clock neurons. We found that increased LARK expression during development dramatically alters the small LNv class of neurons with no obvious effects on the large LNv cells. Conversely, conditional expression of LARK at the adult stage results in altered clock protein rhythms and circadian locomotor activity, even though neural morphology is normal in such animals. Electrophysiological analyses at the larval neuromuscular junction indicate a role for LARK in regulating neuronal excitability. Altogether, our results demonstrate that LARK activity is critical for neuronal development and physiology. PMID:19303442

Sleep and bodily functions: the physiological interplay between body homeostasis and sleep homeostasis.

PubMed

Amici, R; Bastianini, S; Berteotti, C; Cerri, M; Del Vecchio, F; Lo Martire, V; Luppi, M; Perez, E; Silvani, A; Zamboni, G; Zoccoli, G

2014-01-01

Body homeostasis and sleep homeostasis may both rely on the complex integrative activity carried out by the hypothalamus. Thus, the three main wake-sleep (WS) states (i.e. wakefulness, NREM sleep, and REM sleep) may be better understood if the different cardio-respiratory and metabolic parameters, which are under the integrated control of the autonomic and the endocrine systems, are studied during sleep monitoring. According to this view, many physiological events can be considered as an expression of the activity that physiological regulations should perform in order to cope with the need to fulfill body and sleep homeostasis. This review is aimed at making an assessment of data showing the existence of a physiological interplay between body homeostasis and sleep homeostasis, starting from the spontaneous changes observed in the somatic and autonomic activity during sleep, through evidence showing the deep changes occurring in the central integration of bodily functions during the different WS states, to the changes in the WS states observed when body homeostasis is challenged by the external environment and when the return to normal ambient conditions allows sleep homeo- stasis to run without apparent physiological restrictions. The data summarized in this review suggest that an approach to the dichotomy between NREM and REM sleep based on physiological regulations may offer a framework within which observations that a traditional behavioral approach may overlook can be interpreted. The study of the interplay between body and sleep homeostasis appears, therefore, to be a way to understand the function of complex organisms beyond that of the specific regulations.

Salinity Tolerance Mechanism of Economic Halophytes From Physiological to Molecular Hierarchy for Improving Food Quality

PubMed Central

Xu, Chongzhi; Tang, Xiaoli; Shao, Hongbo; Wang, Hongyan

2016-01-01

Soil salinity is becoming the key constraints factor to agricultural production. Therefore, the plant especially the crops possessing capacities of salt tolerance will be of great economic significance. The adaptation or tolerance of plant to salinity stress involves a series of physiological, metabolic and molecular mechanisms. Halophytes are the kind of organisms which acquire special salt tolerance mechanisms to respond to the salt tress and ensure normal growth and development under saline conditions in their lengthy evolutionary adaptation, so understanding how halophytes respond to salinity stress will provide us with methods and tactics to foster and develop salt resistant varieties of crops. The strategies in physiological and molecular level adopted by halophytes are various including the changes in photosynthetic and transpiration rate, the sequestration of Na+ to extracellular or vacuole, the regulation of stomata aperture and stomatal density, the accumulation and synthesis of the phytohormones as well as the relevant gene expression underlying these physiological traits, such as the stress signal transduction, the regulation of the transcription factors, the activation and expression of the transporter genes, the activation or inhibition of the synthetases and so on. This review focuses on the research advances of the regulating mechanisms in halophytes from physiological to molecular, which render the halophytes tolerance and adaption to salinity stress. PMID:27252587

[18F]-FDG positron emission tomography--an established clinical tool opening a new window into exercise physiology.

PubMed

Rudroff, Thorsten; Kindred, John H; Kalliokoski, Kari K

2015-05-15

Positron emission tomography (PET) with [(18)F]-fluorodeoxyglucose (FDG) is an established clinical tool primarily used to diagnose and evaluate disease status in patients with cancer. PET imaging using FDG can be a highly valuable tool to investigate normal human physiology by providing a noninvasive, quantitative measure of glucose uptake into various cell types. Over the past years it has also been increasingly used in exercise physiology studies to identify changes in glucose uptake, metabolism, and muscle activity during different exercise modalities. Metabolically active cells transport FDG, an (18)fluorine-labeled glucose analog tracer, from the blood into the cells where it is then phosphorylated but not further metabolized. This metabolic trapping process forms the basis of this method's use during exercise. The tracer is given to a participant during an exercise task, and the actual PET imaging is performed immediately after the exercise. Provided the uptake period is of sufficient duration, and the imaging is performed shortly after the exercise; the captured image strongly reflects the metabolic activity of the cells used during the task. When combined with repeated blood sampling to determine tracer blood concentration over time, also known as the input function, glucose uptake rate of the tissues can be quantitatively calculated. This synthesis provides an accounting of studies using FDG-PET to measure acute exercise-induced skeletal muscle activity, describes the advantages and limitations of this imaging technique, and discusses its applications to the field of exercise physiology. Copyright © 2015 the American Physiological Society.

Purification and Properties of Cytidine Deaminase from Normal and Leukemic Granulocytes

PubMed Central

Chabner, Bruce A.; Johns, David G.; Coleman, C. Norman; Drake, James C.; Evans, Warren H.

1974-01-01

Cytidine deaminase, an enzyme that catalyses the deamination of both cytidine and its nucleoside analogues including the antineoplastic agents cytosine arabinoside (ara-C) and 5-azacytidine (5-azaC), has been partially purified from normal and leukemic human granulocytes. The purification procedure included heat precipitation at 70°C, ammonium sulfate precipitation, calcium phosphate gel ion exchange, and Sephadex G-150 gel filtration. The enzyme has mol wt 51,000, isoelectric pH of 4.8, and maximum activity over a broad pH range of 5-9.5. The enzyme is stabilized by the presence of the sulfhydryl reagent, dithiothreitol. Cytidine deaminase from normal human granulocytes has a greater affinity for its physiologic substrate cytidine (Km = 1.1 × 10−5 M) than for ara-C (8.8 × 10−5 M) or 5-azaC (4.3 × 10−4 M). Halogenated analogues such as 5-fluorocytidine and 5-bromo-2′-deoxycytidine also exhibited substrate activity, with maximum velocities greater than that of the physiologic substrates cytidine and deoxycytidine. No activity was observed with nucleotides or deoxynucleotides. The relative maximum velocity of the enzyme for cytidine and its nucleoside analogues remained constant during purification, indicating that a single enzyme was responsible for deamination of these substrates. Tetrahydrouridine (THU) was found to be a strong competitive inhibitor of partially purified deaminase with a Ki of 5.4 × 10−8 M. The biochemical properties of partially purified preparations of cytidine deaminase from normal and leukemic cells were compared with respect to isoelectric pH, molecular weight, and substrate and inhibitor kinetic parameters, and no differences were observed. However, normal circulating granulocytes contained a significantly greater concentration of cytidine deaminase (3.52±1.86 × 103/mg protein) than chronic myelocytic leukemia (CML) cells (1.40±0.70 × 103 U/mg protein) or acute myelocytic leukemia (AML) cells (0.19±0.17 × 103 U/mg protein). To explain these differences in enzyme levels in leukemic versus normal cells, the changes in cytidine deaminase levels associated with maturation of normal granulocytes were studied in normal human bone marrow. Myeloid precursors obtained from bone marrow aspirates were separated into mature and immature fractions by Ficoll density centrifugation. Deaminase activity in lysates of mature granulocytes was 3.55-14.2 times greater than the activity found in the lysates of immature cells. Decreased enzyme activity was also found in immature myeloid cells from a patient with CML as compared to mature granulocytes from the same patient. These observations support the conclusion that the greater specific activity of cytidine deaminase in normal mature granulocytes as compared to leukemic cells is related to the process of granulocyte maturation rather than a specific enzymatic defect in leukemic cells. PMID:4521417

Combined effects of mild-to-moderate obesity and asthma on physiological and sensory responses to exercise.

PubMed

Cortés-Télles, Arturo; Torre-Bouscoulet, Luis; Silva-Cerón, Monica; Mejía-Alfaro, Roberto; Syed, Nafeez; Zavorsky, Gerald S; Guenette, Jordan A

2015-11-01

Despite the close link between asthma and obesity, there are no studies that have evaluated the sensory and physiological responses to exercise in obese asthmatics. We recently demonstrated that normal weight asthmatics with well controlled disease have preserved cardiorespiratory and sensory responses to exercise relative to non-asthmatic controls. However, these similarities may not hold true in patients with combined obesity and asthma. Accordingly, we sought to determine if combined asthma and obesity was associated with deleterious effects on cardiorespiratory fitness, exercise performance, dyspnoea, and physiological responses to exercise. Fourteen well-controlled obese asthmatics and fourteen age-matched normal weight asthmatics performed routine spirometry and underwent an incremental cardiopulmonary cycle test to assess the ventilatory, pulmonary gas exchange, cardiovascular, and sensory responses to exercise. Groups were well matched for age, height, spirometry, and asthma control. Obese asthmatics had a significantly greater body mass index (33 ± 3 vs. 23 ± 1 kg/m(2), p < 0.001) and lower self-reported activity levels by 47 % relative to normal weight asthmatics (p < 0.05). Obese asthmatics had a significantly lower maximal oxygen uptake (VO(2)) (82 ± 14 vs. 92 ± 10 %predicted) and work rate (75 ± 8 vs. 89 ± 13 %predicted) relative to normal weight asthmatics (p < 0.05). The anaerobic threshold occurred at a lower VO(2) in obese asthmatics vs. normal weight asthmatics (54 ± 15 vs. 66 ± 16 %predicted, p < 0.05). Ventilatory responses were superimposed throughout exercise with no evidence of a ventilatory limitation in either group. Cardiovascular responses were normal in both groups. Dyspnoea responses were similar but the obese asthmatics experienced greater leg fatigue ratings at submaximal work rates. In conclusion, obese individuals with well controlled asthma have reduced cardiorespiratory fitness and greater leg fatigue ratings relative to normal weight asthmatics. The relatively reduced cardiorespiratory fitness and exercise performance in obese compared to normal weight asthmatics is most likely driven by their more sedentary lifestyle and resultant deconditioning rather than due to respiratory factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Corticotropin-releasing factor: effect on cerebral blood flow in physiologic and ischaemic conditions.

PubMed

De Michele, Manuela; Touzani, Omar; Foster, Alan C; Fieschi, Cesare; Sette, Giuliano; McCulloch, James

2005-09-01

The expression of corticotrophin-releasing factor (CRF) receptors in cerebral arteries and arterioles suggests that CRF may modulate cerebral blood flow (CBF). In the present study, the effects of CRF, CRF-like peptides and the CRF broad spectrum antagonist DPhe-CRF on CBF have been investigated under normal physiologic conditions and in the margins of focal ischaemic insult. The experiments were carried out in anaesthetised and ventilated rats. Changes in CBF after subarachnoid microapplication of CRF and related peptides were assessed with a laser-Doppler flowmetry (LDF) probe. In the ischaemic animals, agents were injected approximately 60 minutes after permanent middle cerebral artery occlusion (MCAo). Microapplication of CRF and related peptides in normal rats into the subarachnoid space produced sustained concentration-dependent increases in CBF. This effect was attenuated by co-application with DPhe-CRF, which did not alter CBF itself. A second microapplication of CRF 30 min after the first failed to produce increases in CBF in normal animals. Microapplication of CRF in the subarachnoid space overlying the ischaemic cortex effected minor increases in CBF whereas D-Phe-CRF had no significant effect on CBF. Activation of the CRF peptidergic system increases CBF in the rat. Repeated activation of CRF receptors results in tachyphylaxis of the vasodilator response. CRF vasodilator response is still present after MCAo in the ischaemic penumbra, suggesting that the CRF peptidergic system may modulate CBF in ischaemic stroke.

Network recruitment to coherent oscillations in a hippocampal computer model

PubMed Central

Krieger, Abba; Litt, Brian

2011-01-01

Coherent neural oscillations represent transient synchronization of local neuronal populations in both normal and pathological brain activity. These oscillations occur at or above gamma frequencies (>30 Hz) and often are propagated to neighboring tissue under circumstances that are both normal and abnormal, such as gamma binding or seizures. The mechanisms that generate and propagate these oscillations are poorly understood. In the present study we demonstrate, via a detailed computational model, a mechanism whereby physiological noise and coupling initiate oscillations and then recruit neighboring tissue, in a manner well described by a combination of stochastic resonance and coherence resonance. We develop a novel statistical method to quantify recruitment using several measures of network synchrony. This measurement demonstrates that oscillations spread via preexisting network connections such as interneuronal connections, recurrent synapses, and gap junctions, provided that neighboring cells also receive sufficient inputs in the form of random synaptic noise. “Epileptic” high-frequency oscillations (HFOs), produced by pathologies such as increased synaptic activity and recurrent connections, were superior at recruiting neighboring tissue. “Normal” HFOs, associated with fast firing of inhibitory cells and sparse pyramidal cell firing, tended to suppress surrounding cells and showed very limited ability to recruit. These findings point to synaptic noise and physiological coupling as important targets for understanding the generation and propagation of both normal and pathological HFOs, suggesting potential new diagnostic and therapeutic approaches to human disorders such as epilepsy. PMID:21273309

Physiological responses to prolonged bed rest and fluid immersion in humans

NASA Technical Reports Server (NTRS)

Greenleaf, J. E.

1984-01-01

For many centuries, physicians have used prolonged rest in bed and immersion in water in the treatment of ailments and disease. Both treatments have positive remedial effects. However, adverse physiological responses become evident when patients return to their normal daily activities. The present investigation is concerned with an analysis of the physiological changes during bed rest and the effects produced by water immersion. It is found that abrupt changes in body position related to bed rest cause acute changes in fluid compartment volumes. Attention is given to fluid shifts and body composition, renal function and diuresis, calcium and phosphorus metabolism, and orthostatic tolerance. In a discussion of water immersion, fluid shifts are considered along with cardiovascular-respiratory responses, renal function, and natriuretic and diuretic factors.

Bluetooth-based sensor networks for remotely monitoring the physiological signals of a patient.

PubMed

Zhang, Ying; Xiao, Hannan

2009-11-01

Integrating intelligent medical microsensors into a wireless communication network makes it possible to remotely collect physiological signals of a patient, release the patient from being tethered to monitoring medical instrumentations, and facilitate the patient's early hospital discharge. This can further improve life quality by providing continuous observation without the need of disrupting the patient's normal life, thus reducing the risk of infection significantly, and decreasing the cost of the hospital and the patient. This paper discusses the implementation issues, and describes the overall system architecture of our developed Bluetooth sensor network for patient monitoring and the corresponding heart activity sensors. It also presents our approach to developing the intelligent physiological sensor nodes involving integration of Bluetooth radio technology, hardware and software organization, and our solutions for onboard signal processing.

Manipulation of heart rate variability can modify response to anger-inducing stimuli.

PubMed

Francis, Heather M; Penglis, Kathryn M; McDonald, Skye

2016-10-01

Research suggests that heart rate variability (HRV) is a physiological indicator of the flexibility of the autonomic nervous system and can provide an objective measure of an individual's ability to appropriately match emotional responses to environmental demands. The present study investigated whether angry response to emotional stimuli was related to HRV, and whether manipulation of HRV using biofeedback could change the anger response in a healthy adult population. Fifty-eight participants received HRV biofeedback (n = 29) or an active control condition (n = 29). HRV measures included standard deviation of normal-to-normal intervals (SDNN), low-frequency (LF) and high-frequency (HF) power, and was recorded across three sessions: baseline, training, and anger induction. The anger induction procedure resulted in increased subjective experience of anger, as well as physiological changes. The biofeedback group had higher HRV than active controls both during the training session (SDNN and LF HRV) and during anger induction (LF HRV). HRV during anger induction was significantly associated with self-reported emotional response for participants receiving biofeedback but not for active controls. Results provide support for HRV as an index of emotion regulation, specifically anger. Further research is needed to determine whether long-term HRV biofeedback can have a lasting effect on managing anger.

Innate Immune Activation in Obesity

PubMed Central

Lumeng, Carey N.

2014-01-01

The innate immune system is a prewired set of cellular and humoral components that has developed to sense perturbations in normal physiology and trigger responses to restore the system back to baseline. It is now understood that many of these components can also sense the physiologic changes that occur with obesity and be activated. While the exact reasons for this chronic immune response to obesity are unclear, there is strong evidence to suggest that innate inflammatory systems link obesity and disease. Based on this, anti-inflammatory therapies for diseases like type 2 diabetes and metabolic syndrome may form the core of future treatment plans. This review will highlight the components involved in the innate immune response and discuss the evidence that they contribute to the pathogenesis of obesity-associated diseases. PMID:23068074

Local pruning of dendrites and spines by caspase-3-dependent and proteasome-limited mechanisms.

PubMed

Ertürk, Ali; Wang, Yuanyuan; Sheng, Morgan

2014-01-29

Synapse loss occurs normally during development and pathologically during neurodegenerative disease. Long-term depression, a proposed physiological correlate of synapse elimination, requires caspase-3 and the mitochondrial pathway of apoptosis. Here, we show that caspase-3 activity is essential--and can act locally within neurons--for regulation of spine density and dendrite morphology. By photostimulation of Mito-KillerRed, we induced caspase-3 activity in defined dendritic regions of cultured neurons. Within the photostimulated region, local elimination of dendritic spines and dendrite retraction occurred in a caspase-3-dependent manner without inducing cell death. However, pharmacological inhibition of inhibitor of apoptosis proteins or proteasome function led to neuronal death, suggesting that caspase activation is spatially restricted by these "molecular brakes" on apoptosis. Caspase-3 knock-out mice have increased spine density and altered miniature EPSCs, confirming a physiological involvement of caspase-3 in the regulation of spines in vivo.

Influence of Nano-Crystal Metals on Texture and Biological Properties of Water Soluble Polysaccharides of Medicinal Plants

NASA Astrophysics Data System (ADS)

Churilov, G.; Ivanycheva, J.; Kiryshin, V.

2015-11-01

When treating the plants seeds with nano-materials there are some quality and quantity changes of polysaccharides, the molecular mass increase and monosaccharides change that leads to the increase of physiological and pharmacological activity of carbohydrates got from medicinal plants. We have got water soluble polysaccharides and nano-metals combinations containing 0.000165-0.000017 mg/dm3 of the metal. In a case of induced anemia the blood composition has practically restored on the 10th day of the treatment with nanocomposites. The use of pectin polysaccharides (that are attributed to modifiers of biological respond) to get nano-structured materials seems to be actual relative to their physiological activity (radio nuclides persorption, heavy metals ions, bacteria cells and their toxins; lipids metabolism normalization; bowels secreting and motor functions activation and modulation of the endocrine system.

Mannan oligosaccharide requires functional ETC and TLR for biological radiation protection to normal cells.

PubMed

Sanguri, Sweta; Gupta, Damodar

2018-06-27

Low LET Ionizing radiation is known to alter intracellular redox balance by inducing free radical generation, which may cause oxidative modification of various cellular biomolecules. The extent of biomolecule-modifications/ damages and changes in vital processes (viz. cellular homeostasis, inter-/intra-cellular signaling, mitochondrial physiology/dynamics antioxidant defence systems) are crucial which in turn determine fate of cells. In the present study, we expended TLR expressing (normal/ transformed) and TLR null cells; and we have shown that mannan pretreatment in TLR expressing normal cells offers survival advantage against lethal doses of ionizing radiation. On the contrary, mannan pretreatment does not offer any protection against radiation to TLR null cells, NKE ρ° cells and transformed cells. In normal cells, abrupt decrease in mitochondrial membrane potential and endogenous ROS levels occurs following treatment with mannan. We intend to irradiate mannan-pretreated cells at a specific stage of perturbed mitochondrial functioning and ROS levels to comprehend if mannan pretreatment offers any survival advantage against radiation exposure to cells. Interestingly, pre-irradiation treatment of cells with mannan activates NFκB, p38 and JNK, alters mitochondrial physiology, increases expression of Cu/ZnSOD and MnSOD, minimizes oxidation of mitochondrial phospholipids and offers survival advantage in comparison to irradiated group, in TLR expressing normal cells. The study demonstrates that TLR and mitochondrial ETC functions are inevitable in radio-protective efficacy exhibited by mannan.

GSNOR Deficiency Enhances In Situ Skeletal Muscle Strength, Fatigue Resistance, and RyR1 S-Nitrosylation Without Impacting Mitochondrial Content and Activity

PubMed Central

Moon, Younghye; Cao, Yenong; Zhu, Jingjing; Xu, Yuanyuan; Balkan, Wayne; Buys, Emmanuel S.; Diaz, Francisca; Kerrick, W. Glenn; Hare, Joshua M.

2017-01-01

Abstract Aim: Nitric oxide (NO) plays important, but incompletely defined roles in skeletal muscle. NO exerts its regulatory effects partly though S-nitrosylation, which is balanced by denitrosylation by enzymes such as S-nitrosoglutathione reductase (GSNOR), whose functions in skeletal muscle remain to be fully deciphered. Results: GSNOR null (GSNOR−/−) tibialis anterior (TA) muscles showed normal growth and were stronger and more fatigue resistant than controls in situ. However, GSNOR−/− lumbrical muscles showed normal contractility and Ca2+ handling in vitro, suggesting important differences in GSNOR function between muscles or between in vitro and in situ environments. GSNOR−/− TA muscles exhibited normal mitochondrial content, and capillary densities, but reduced type IIA fiber content. GSNOR inhibition did not impact mitochondrial respiratory complex I, III, or IV activities. These findings argue that enhanced GSNOR−/− TA contractility is not driven by changes in mitochondrial content or activity, fiber type, or blood vessel density. However, loss of GSNOR led to RyR1 hypernitrosylation, which is believed to increase muscle force output under physiological conditions. cGMP synthesis by soluble guanylate cyclase (sGC) was decreased in resting GSNOR−/− muscle and was more responsive to agonist (DETANO, BAY 41, and BAY 58) stimulation, suggesting that GSNOR modulates cGMP production in skeletal muscle. Innovation: GSNOR may act as a “brake” on skeletal muscle contractile performance under physiological conditions by modulating nitrosylation/denitrosylation balance. Conclusions: GSNOR may play important roles in skeletal muscle contractility, RyR1 S-nitrosylation, fiber type specification, and sGC activity. Antioxid. Redox Signal. 26, 165–181. PMID:27412893

CO2/HCO3−- and Calcium-regulated Soluble Adenylyl Cyclase as a Physiological ATP Sensor*

PubMed Central

Zippin, Jonathan H.; Chen, Yanqiu; Straub, Susanne G.; Hess, Kenneth C.; Diaz, Ana; Lee, Dana; Tso, Patrick; Holz, George G.; Sharp, Geoffrey W. G.; Levin, Lonny R.; Buck, Jochen

2013-01-01

The second messenger molecule cAMP is integral for many physiological processes. In mammalian cells, cAMP can be generated from hormone- and G protein-regulated transmembrane adenylyl cyclases or via the widely expressed and structurally and biochemically distinct enzyme soluble adenylyl cyclase (sAC). sAC activity is uniquely stimulated by bicarbonate ions, and in cells, sAC functions as a physiological carbon dioxide, bicarbonate, and pH sensor. sAC activity is also stimulated by calcium, and its affinity for its substrate ATP suggests that it may be sensitive to physiologically relevant fluctuations in intracellular ATP. We demonstrate here that sAC can function as a cellular ATP sensor. In cells, sAC-generated cAMP reflects alterations in intracellular ATP that do not affect transmembrane AC-generated cAMP. In β cells of the pancreas, glucose metabolism generates ATP, which corresponds to an increase in cAMP, and we show here that sAC is responsible for an ATP-dependent cAMP increase. Glucose metabolism also elicits insulin secretion, and we further show that sAC is necessary for normal glucose-stimulated insulin secretion in vitro and in vivo. PMID:24100033

What goes on behind closed doors: physiological vs. pharmacological steroid hormone actions

PubMed Central

Simons, S. Stoney

2009-01-01

Summary Steroid hormone-activated receptor proteins are among the best understood class of factors for altering gene transcription in cells. Steroid receptors are of major importance in maintaining normal human physiology by responding to circulating concentrations of steroid in the nM range. Nonetheless, most studies of steroid receptor action have been conducted using the supra-physiological conditions of saturating concentrations (≥100 nM) of potent synthetic steroid agonists. Here we summarize the recent developments arising from experiments using two clinically relevant conditions: subsaturating concentrations of agonist (to mimic the circulating concentrations in mammals) and saturating concentrations of antagonists (which are employed in endocrine therapies to block the actions of endogenous steroids). These studies have revealed new facets of steroid hormone action that could not be uncovered by conventional experiments with saturating concentrations of agonist steroids, such as a plethora of factors/conditions for the differential control of gene expression by physiological levels of steroid, a rational approach for examining the gene-specific variations in partial agonist activity of antisteroids, and a dissociation of steroid potency and efficacy that implies the existence of separate, and possibly novel, mechanistic steps and cofactors. PMID:18623071

Synaptic up-scaling preserves motor circuit output after chronic, natural inactivity

PubMed Central

Vallejo, Mauricio; Hartzler, Lynn K

2017-01-01

Neural systems use homeostatic plasticity to maintain normal brain functions and to prevent abnormal activity. Surprisingly, homeostatic mechanisms that regulate circuit output have mainly been demonstrated during artificial and/or pathological perturbations. Natural, physiological scenarios that activate these stabilizing mechanisms in neural networks of mature animals remain elusive. To establish the extent to which a naturally inactive circuit engages mechanisms of homeostatic plasticity, we utilized the respiratory motor circuit in bullfrogs that normally remains inactive for several months during the winter. We found that inactive respiratory motoneurons exhibit a classic form of homeostatic plasticity, up-scaling of AMPA-glutamate receptors. Up-scaling increased the synaptic strength of respiratory motoneurons and acted to boost motor amplitude from the respiratory network following months of inactivity. Our results show that synaptic scaling sustains strength of the respiratory motor output following months of inactivity, thereby supporting a major neuroscience hypothesis in a normal context for an adult animal. PMID:28914603

Computerized mapping of fibrillation in normal ventricular myocardium

NASA Astrophysics Data System (ADS)

Chen, Peng-Sheng; Garfinkel, Alan; Weiss, James N.; Karagueuzian, Hrayr S.

1998-03-01

It is well known that the ability to fibrillate is intrinsic to a normal ventricle that exceeds a critical mass. The questions we address are how is ventricular fibrillation (VF) initiated and perpetuated in normal myocardium, and why is VF not seen more often in the general population if all ventricles have the ability to fibrillate. To study the mechanisms of VF, we used computerized mapping techniques with up to 512 channels of simultaneous multisite recordings for data acquisition. The data were then processed for dynamic display of the activation patterns and for mathematical analyses of the activation intervals. The results show that in normal ventricles, VF can be initiated by a single strong premature stimulus given during the vulnerable period of the cardiac cycle. The initial activations form a figure-eight pattern. Afterward, VF will perpetuate itself without any outside help. The self-perpetuation itself is due to at least two factors. One is that single wave fronts spontaneously break up into two or more wavelets. The second is that when two wavelets intersect perpendicular to each other, the second wavelet is broken by the residual refractoriness left over from the first wavelet. Mathematical analyses of the patterns of activation during VF revealed that VF is a form of chaos, and that transition from ventricular tachycardia (VT) to VF occurs via the quasiperiodic route. In separate experiments, we found that we can convert VF to VT by tissue size reduction. The physiological mechanism associated with the latter transition appears to be the reduction of the number of reentrant wave fronts and wandering wavelets. Based on these findings, we propose that the reentrant wave fronts and the wandering wavelets serve as the physiological equivalent of coupled oscillators. A minimal number of oscillators is needed for VF to perpetuate itself, and to generate chaotic dynamics; hence a critical mass is required to perpetuate VF. We conclude that VF in normal myocardium is a form of reentrant cardiac arrhythmia. A strong electrical stimulus initiates single or dual reentrant wave fronts that break up into multiple wavelets. Sometimes short-lived reentry is also generated during the course of VF. These organized reentrant and broken wavelets serve as coupled oscillators that perpetuate VF and maintain chaos. Although the ability to support these oscillators exists in a normal ventricle, the triggers required to generate them are nonexistent in the normal heart. Therefore, VF and sudden death do not happen to most people with normal ventricular myocardium.

Evidence for vestibular regulation of autonomic functions in a mouse genetic model

NASA Technical Reports Server (NTRS)

Murakami, Dean M.; Erkman, Linda; Hermanson, Ola; Rosenfeld, Michael G.; Fuller, Charles A.

2002-01-01

Physiological responses to changes in the gravitational field and body position, as well as symptoms of patients with anxiety-related disorders, have indicated an interrelationship between vestibular function and stress responses. However, the relative significance of cochlear and vestibular information in autonomic regulation remains unresolved because of the difficulties in distinguishing the relative contributions of other proprioceptive and interoceptive inputs, including vagal and somatic information. To investigate the role of cochlear and vestibular function in central and physiological responses, we have examined the effects of increased gravity in wild-type mice and mice lacking the POU homeodomain transcription factor Brn-3.1 (Brn-3bPou4f3). The only known phenotype of the Brn-3.1(-/-) mouse is related to hearing and balance functions, owing to the failure of cochlear and vestibular hair cells to differentiate properly. Here, we show that normal physiological responses to increased gravity (2G exposure), such as a dramatic drop in body temperature and concomitant circadian adjustment, were completely absent in Brn-3.1(-/-) mice. In line with the lack of autonomic responses, the massive increase in neuronal activity after 2G exposure normally detected in wild-type mice was virtually abolished in Brn-3.1(-/-) mice. Our results suggest that cochlear and vestibular hair cells are the primary regulators of autonomic responses to altered gravity and provide genetic evidence that these cells are sufficient to alter neural activity in regions involved in autonomic and neuroendocrine control.

Orexins and appetite regulation.

PubMed

Rodgers, R J; Ishii, Y; Halford, J C G; Blundell, J E

2002-10-01

Initial research on the functional significance of two novel hypothalamic neuropeptides, orexin-A and orexin-B, suggested an important role in appetite regulation. Since then, however, these peptides have also been shown to influence a wide range of other physiological and behavioural processes. In this paper, we review the now quite extensive literature on orexins and appetite control, and consider their additional effects within this context. Although the evidence for orexin (particularly orexin-A and the orexin-1 receptor) involvement in many aspects of ingestive physiology and behaviour is incontrovertible, central administration of orexins is also associated with increased EEG arousal and wakefulness, locomotor activity and grooming, sympathetic and HPA activity, and pain thresholds. Since the orexin system is selectively activated by signals indicating severe nutritional depletion, it would be highly adaptive for a hungry animal not only to seek sustenance but also to remain fully alert to dangers in the environment. Crucial evidence indicates that orexin-A increases food intake by delaying the onset of a behaviourally normal satiety sequence. In contrast, a selective orexin-1 receptor antagonist (SB-334867) suppresses food intake and advances the onset of a normal satiety sequence. These data suggest that orexin-1 receptors mediate the episodic signalling of satiety and appear to bridge the transition from eating to resting in the rats' feeding-sleep cycle. The argument is developed that the diverse physiological and behavioural effects of orexins can best be understood in terms of an integrated set of reactions which function to rectify nutritional status without compromising personal survival. Indeed, many of the non-ingestive effects of orexin administration are identical to the cluster of active defences mediated via the lateral and dorsolateral columns of the midbrain periaqueductal gray matter, i.e., somatomotor activation, vigilance, tachycardia, hypertension and non-opioid analgesia. In our view, therefore, the LH orexin system is very well placed to orchestrate the diverse subsystems involved in foraging under potentially dangerous circumstances, i.e., finding and ingesting food without oneself becoming a meal for someone else.

Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man.

PubMed

Kalafatakis, K; Russell, G M; Harmer, C J; Munafo, M R; Marchant, N; Wilson, A; Brooks, J C; Durant, C; Thakrar, J; Murphy, P; Thai, N J; Lightman, S L

2018-04-24

Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.

Status of research on MMPs in India.

PubMed

Saravanan, Chinnadurai; Singh, Sushil Kumar

2011-06-01

MMPs are metal-dependant endopeptidases capable of degrading any one of the components of the extracellular matrix. In normal physiological conditions it is regulated by tissue inhibitors of metalloproteinases, and any alteration in this regulatory process leads to pathological conditions. This review discusses the status of MMP research in India. The first research paper was published in 1998; the subsequent developments in this field led to an increase in the number of publications. This review highlights the growth of MMP research in India based on the research papers published from 1998 to 2010. We identify four major subject areas: cancer, arthritis, ulcer and quantitative structure-activity relationship. The diseases involved are discussed along with the required steps for improving treatments. Indian researchers need to work on new molecules with specific MMP inhibitory activity for cancer and communicable and geriatric diseases. Although several publications on natural products have appeared from India, they are very few considering the number of medicinal plants available in the country. Inhibiting MMPs could be both beneficial and detrimental to cells, owing to the inter-relationship between normal physiology and pathology; thus, targeting MMPs with broad MMP inhibitors can have mixed blessings.

Metal ions potentiate microglia responsiveness to endotoxin.

PubMed

Rachmawati, Dessy; Peferoen, Laura A N; Vogel, Daphne Y S; Alsalem, Inás W A; Amor, Sandra; Bontkes, Hetty J; von Blomberg, B Mary E; Scheper, Rik J; van Hoogstraten, Ingrid M W

2016-02-15

Oral metal exposure has been associated with diverse adverse reactions, including neurotoxicity. We showed previously that dentally applied metals activate dendritic cells (MoDC) via TLR4 (Ni, Co, Pd) and TLR3 (Au). It is still unknown whether the low levels of dental metals reaching the brain can trigger local innate cells or prime them to become more responsive. Here we tested whether dentally applied metals (Cr, Fe, Co, Ni, Cu, Zn, Au, Hg) activate primary human microglia in vitro and, as a model, monocytic THP-1-cells, in high non-toxic as well as near-physiological concentrations. In addition the effects of 'near-physiological' metal exposure on endotoxin (LPS) responsiveness of these cells were evaluated. IL-8 and IL-6 production after 24h was used as read out. In high, non-toxic concentrations all transition metals except Cr induced IL-8 and IL-6 production in microglia, with Ni and Co providing the strongest stimulation. When using near-physiological doses (up to 10× the normal plasma concentration), only Zn and Cu induced significant IL-8 production. Of note, the latter metals also markedly potentiated LPS responsiveness of microglia and THP-1 cells. In conclusion, transition metals activate microglia similar to MoDCs. In near-physiological concentrations Zn and Cu are the most effective mediators of innate immune activation. A clear synergism between innate responses to Zn/Cu and LPS was observed, shedding new light on the possible relation between oral metal exposure and neurotoxicity. Copyright © 2015. Published by Elsevier B.V.

Modulating kidney transplant interstitial fibrosis and tubular atrophy: is the RAAS an important target?

PubMed

Amer, Hatem; Griffin, Matthew D

2014-02-01

In follow-up to a recently published randomized controlled clinical trial, Issa et al. provide evidence that systemic activity and physiological responsiveness of the renin aldosterone angiotensin system (RAAS) are well within normal limits in most kidney recipients during the first 5 years post-transplant. Implications of the results include the need to better understand intra-renal RAAS activity in transplanted kidneys and to identify patients in which the graft-protective effects of RAAS blockade are most relevant.

Visual and psychological stress during computer work in healthy, young females-physiological responses.

PubMed

Mork, Randi; Falkenberg, Helle K; Fostervold, Knut Inge; Thorud, Hanne Mari S

2018-05-30

Among computer workers, visual complaints, and neck pain are highly prevalent. This study explores how occupational simulated stressors during computer work, like glare and psychosocial stress, affect physiological responses in young females with normal vision. The study was a within-subject laboratory experiment with a counterbalanced, repeated design. Forty-three females performed four 10-min computer-work sessions with different stress exposures: (1) minimal stress; (2) visual stress (direct glare); (3) psychological stress; and (4) combined visual and psychological stress. Muscle activity and muscle blood flow in trapezius, muscle blood flow in orbicularis oculi, heart rate, blood pressure, blink rate and postural angles were continuously recorded. Immediately after each computer-work session, fixation disparity was measured and a questionnaire regarding perceived workstation lighting and stress was completed. Exposure to direct glare resulted in increased trapezius muscle blood flow, increased blink rate, and forward bending of the head. Psychological stress induced a transient increase in trapezius muscle activity and a more forward-bent posture. Bending forward towards the computer screen was correlated with higher productivity (reading speed), indicating a concentration or stress response. Forward bent posture was also associated with changes in fixation disparity. Furthermore, during computer work per se, trapezius muscle activity and blood flow, orbicularis oculi muscle blood flow, and heart rate were increased compared to rest. Exposure to glare and psychological stress during computer work were shown to influence the trapezius muscle, posture, and blink rate in young, healthy females with normal binocular vision, but in different ways. Accordingly, both visual and psychological factors must be taken into account when optimizing computer workstations to reduce physiological responses that may cause excessive eyestrain and musculoskeletal load.

Pulmonary arterial distension and vagal afferent nerve activity in anaesthetized dogs.

PubMed

Moore, Jonathan P; Hainsworth, Roger; Drinkhill, Mark J

2004-03-16

Distension of the main pulmonary artery and its bifurcation are known to result in a reflex vasoconstriction and increased respiratory drive; however, these responses are observed at abnormally high distending pressures. In this study we recorded afferent activity from pulmonary arterial baroreceptors to investigate their stimulus-response characteristics and to determine whether they are influenced by physiological changes in intrathoracic pressure. In chloralose-anaesthetized dogs, a cardiopulmonary bypass was established, the pulmonary trunk and its main branches were vascularly isolated and perfused with venous blood at pulsatile pressures designed to simulate the normal pulmonary arterial pressure waveform. Afferent slips of a cervical vagus were dissected and nerve fibres identified that displayed discharge patterns with characteristics expected from pulmonary arterial baroreceptors. Recordings were obtained with (a) chest open (b) chest closed and resealed, and (c) with phasic negative intrathoracic pressures in the resealed chest. Pressure-discharge characteristics obtained in the open-chest animals indicated that the threshold pulmonary pressure (corresponding to 5% of the overall response) was 17.1 +/- 2.9 and the inflexion point of the curve was 29.2 +/- 3.3 mmHg (mean +/-S.E.M). In closed-chest animals the threshold and inflexion pressures were reduced to 12.0 +/- 1.7 and 20.7 +/- 1.8 mmHg. Application of phasic negative intrathoracic pressures further reduced the threshold and inflexion pressures to 9.5 +/- 1.2 mmHg (P < 0.05 vs. open) and 14.7 +/- 0.8 mmHg (P < 0.003 vs. open and P < 0.02 vs. atmospheric). These results indicate that under physiological conditions, with closed-chest and phasic negative intrathoracic pressure changes similar to those associated with normal breathing, activity from pulmonary baroreceptors is obtained at physiological pulmonary arterial pressures in intact animals.

Variable stoichiometry in active ion transport: theoretical analysis of physiological consequences.

PubMed

Johnson, E A; Tanford, C; Reynolds, J A

1985-08-01

Active ion transport systems with fixed stoichiometry are subject to a thermodynamic limit on the ion concentration gradients that they can generate and maintain, and their net rates of transport must inevitably decrease as this limit is approached. The capability to vary stoichiometry might thus be physiologically advantageous: a shift to lower stoichiometry (fewer ions pumped per reaction cycle) at increasing thermodynamic load could increase the limit on the supportable concentration gradient and could accelerate the rate of transport under high-load conditions. Here we present a theoretical and numerical analysis of this possibility, using the sarcoplasmic reticulum ATP-driven Ca pump as the example. It is easy to introduce alternate pathways into the reaction cycle for this system to shift the stoichiometry (Ca2+/ATP) from the normal value of 2:1 to 1:1, but it cannot be done without simultaneous generation of a pathway for uncoupled leak of Ca2+ across the membrane. This counteracts the advantageous effect of the change in transport stoichiometry and a physiologically useful rate acceleration cannot be obtained. This result is likely to be generally applicable to most active transport systems.

Variable stoichiometry in active ion transport: theoretical analysis of physiological consequences.

PubMed Central

Johnson, E A; Tanford, C; Reynolds, J A

1985-01-01

Active ion transport systems with fixed stoichiometry are subject to a thermodynamic limit on the ion concentration gradients that they can generate and maintain, and their net rates of transport must inevitably decrease as this limit is approached. The capability to vary stoichiometry might thus be physiologically advantageous: a shift to lower stoichiometry (fewer ions pumped per reaction cycle) at increasing thermodynamic load could increase the limit on the supportable concentration gradient and could accelerate the rate of transport under high-load conditions. Here we present a theoretical and numerical analysis of this possibility, using the sarcoplasmic reticulum ATP-driven Ca pump as the example. It is easy to introduce alternate pathways into the reaction cycle for this system to shift the stoichiometry (Ca2+/ATP) from the normal value of 2:1 to 1:1, but it cannot be done without simultaneous generation of a pathway for uncoupled leak of Ca2+ across the membrane. This counteracts the advantageous effect of the change in transport stoichiometry and a physiologically useful rate acceleration cannot be obtained. This result is likely to be generally applicable to most active transport systems. PMID:3860866

Endurance Exercise: Normal Physiology and Limitations Imposed by Pathological Processes (Part 1).

ERIC Educational Resources Information Center

Frontera, Walter R.; Adams, Richard P.

1986-01-01

The physiologic and metabolic adjustments of the body to a single endurance exercise session are analyzed in terms of the respiratory system, the cardiovascular system, and oxygen delivery to the muscles. Patients with cardiorespiratory and neuromuscular diseases are compared to normal individuals. (Author/MT)

Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta

PubMed Central

Labarrere, Carlos A.; DiCarlo, Hector L.; Bammerlin, Elaine; Hardin, James W.; Kim, Yeon Mee; Chaemsaithong, Piya; Haas, David M.; Kassab, Ghassan S.; Romero, Roberto

2018-01-01

Background Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 expression, is present in atherosclerotic-like lesions of heart transplantation and considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Intercellular adhesion molecule-1-overexpressing-activated endothelial cells are more resistant to trophoblast displacement than nonactivated endothelium and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation. Objective To determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate. Study Design A cross-sectional study of 123 placentas (19-42 weeks’ gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10) was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of intercellular adhesion molecule-1 (ICAM-1). Investigators examining microscopic sections were blinded to clinical diagnosis. Pairwise comparisons among placenta groups were performed with the Fisher’s exact and Wilcoxon rank sum tests using a Bonferroni-adjusted level of significance (.025). Results 87% (94/108) of placentas having spiral arteries with failure of physiologic transformation (actin-positive and cytokeratin-negative) in the basal plate, and 0% (0/15) of placentas having only spiral arteries with complete physiologic transformation (cytokeratin-positive and actin-negative), had arterial endothelial and/or interstitial extravillous trophoblasts reactive with the ICAM-1 activation marker (P < .001). A significant correlation (R2 = 0.84) was found between expression of spiral artery endothelial and interstitial extravillous trophoblast ICAM-1 (P < .001) in activated placentas. Lesions of atherosis were found in 31.9% (30/94) of placentas with complete and/or partial failure of physiologic transformation of spiral arteries that were ICAM-1-positive, in none of the 14 placentas with failure of physiologic transformation that were ICAM-1-negative, and in none of the 15 placentas with complete spiral artery physiologic transformation without failure (P = .001). All placentas (30/30, 100%) with atherosis were identified in placentas having concomitant spiral artery endothelial and interstitial extravillous trophoblast activation. Conclusion Failure of spiral artery physiologic transformation in the placental basal plate is associated with interstitial extravillous trophoblast and arterial endothelial activation along with increased frequency of spiral artery atherosis. These findings may be used to improve the characterization of different disorders of the placental bed such as in refining the existing tools for the early prediction of risk for preterm, preeclamptic, and other abnormal pregnancies. PMID:28034657

Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.

PubMed

Labarrere, Carlos A; DiCarlo, Hector L; Bammerlin, Elaine; Hardin, James W; Kim, Yeon M; Chaemsaithong, Piya; Haas, David M; Kassab, Ghassan S; Romero, Roberto

2017-03-01

Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 expression, is present in atherosclerotic-like lesions of heart transplantation, and is considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Intercellular adhesion molecule-1-overexpressing-activated endothelial cells are more resistant to trophoblast displacement than nonactivated endothelium, and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation. We sought to determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate. A cross-sectional study of 123 placentas (19-42 weeks' gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10) was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of intercellular adhesion molecule-1. Investigators examining microscopic sections were blinded to clinical diagnosis. Pairwise comparisons among placenta groups were performed with Fisher exact test and Wilcoxon rank sum test using a Bonferroni-adjusted level of significance (.025). We found that 87% (94/108) of placentas having spiral arteries with failure of physiologic transformation (actin-positive and cytokeratin-negative) in the basal plate, and 0% (0/15) of placentas having only spiral arteries with complete physiologic transformation (cytokeratin-positive and actin-negative), had arterial endothelial and/or interstitial extravillous trophoblasts reactive with the intercellular adhesion molecule-1 activation marker (P < .001). A significant correlation (R 2  = 0.84) was found between expression of spiral artery endothelial and interstitial extravillous trophoblast intercellular adhesion molecule-1 (P < .001) in activated placentas. Lesions of atherosis were found in 31.9% (30/94) of placentas with complete and/or partial failure of physiologic transformation of spiral arteries that were intercellular adhesion molecule-1-positive, in none of the 14 placentas with failure of physiologic transformation that were intercellular adhesion molecule-1-negative, and in none of the 15 placentas with complete spiral artery physiologic transformation without failure (P = .001). All placentas (30/30, 100%) with atherosis were identified in placentas having concomitant spiral artery endothelial and interstitial extravillous trophoblast activation. Failure of spiral artery physiologic transformation in the placental basal plate is associated with interstitial extravillous trophoblast and arterial endothelial activation along with increased frequency of spiral artery atherosis. These findings may be used to improve the characterization of different disorders of the placental bed such as in refining the existing tools for the early prediction of risk for preterm, preeclamptic, and other abnormal pregnancies. Copyright © 2016 Elsevier Inc. All rights reserved.

Heavy Metal Pollution from Gold Mines: Environmental Effects and Bacterial Strategies for Resistance.

PubMed

Fashola, Muibat Omotola; Ngole-Jeme, Veronica Mpode; Babalola, Olubukola Oluranti

2016-10-26

Mining activities can lead to the generation of large quantities of heavy metal laden wastes which are released in an uncontrolled manner, causing widespread contamination of the ecosystem. Though some heavy metals classified as essential are important for normal life physiological processes, higher concentrations above stipulated levels have deleterious effects on human health and biota. Bacteria able to withstand high concentrations of these heavy metals are found in the environment as a result of various inherent biochemical, physiological, and/or genetic mechanisms. These mechanisms can serve as potential tools for bioremediation of heavy metal polluted sites. This review focuses on the effects of heavy metal wastes generated from gold mining activities on the environment and the various mechanisms used by bacteria to counteract the effect of these heavy metals in their immediate environment.

Heavy Metal Pollution from Gold Mines: Environmental Effects and Bacterial Strategies for Resistance

PubMed Central

Fashola, Muibat Omotola; Ngole-Jeme, Veronica Mpode; Babalola, Olubukola Oluranti

2016-01-01

Mining activities can lead to the generation of large quantities of heavy metal laden wastes which are released in an uncontrolled manner, causing widespread contamination of the ecosystem. Though some heavy metals classified as essential are important for normal life physiological processes, higher concentrations above stipulated levels have deleterious effects on human health and biota. Bacteria able to withstand high concentrations of these heavy metals are found in the environment as a result of various inherent biochemical, physiological, and/or genetic mechanisms. These mechanisms can serve as potential tools for bioremediation of heavy metal polluted sites. This review focuses on the effects of heavy metal wastes generated from gold mining activities on the environment and the various mechanisms used by bacteria to counteract the effect of these heavy metals in their immediate environment. PMID:27792205

Effect of incorporating low intensity exercise into the recovery period after a rugby match.

PubMed

Suzuki, M; Umeda, T; Nakaji, S; Shimoyama, T; Mashiko, T; Sugawara, K

2004-08-01

The psychological and physiological condition of athletes affect both their performance in competitions and their health. Rugby is an intense sport which appears to impose psychological and physiological stress on players. However, there have been few studies of the most appropriate resting techniques to deliver effective recovery from a match. To compare the difference in recovery after a match using resting techniques with or without exercise. Fifteen Japanese college rugby football players were studied. Seven performed only normal daily activities and eight performed additional low intensity exercise during the post-match rest period. Players were examined just before and immediately after the match and one and two days after the match. Blood biochemistry and two neutrophil functions, phagocytic activity and oxidative burst, were measured to assess physiological condition, and the profile of mood states (POMS) scores were examined to evaluate psychological condition. Immediately after the match, muscle damage, decreases in neutrophil functions, and mental fatigue were observed in both groups. Muscle damage and neutrophil functions recovered with time almost equally in the two groups, but the POMS scores were significantly decreased only in subjects in the low intensity exercise group. Rugby matches impose both physiological and psychological stress on players. The addition of low intensity exercise to the rest period did not adversely affect physiological recovery and had a significantly beneficial effect on psychological recovery by enhancing relaxation.

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides

PubMed Central

Schuchardt, Christiane; Kulkarni, Harshad R.; Shahinfar, Mostafa; Singh, Aviral; Glatting, Gerhard; Baum, Richard P.; Beer, Ambros J.

2016-01-01

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25−29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1–3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably. PMID:27611841

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.

PubMed

Kletting, Peter; Schuchardt, Christiane; Kulkarni, Harshad R; Shahinfar, Mostafa; Singh, Aviral; Glatting, Gerhard; Baum, Richard P; Beer, Ambros J

2016-01-01

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25-29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1-3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably.

Devices for noninvasive transcranial electrostimulation of the brain endorphinergic system: application for improvement of human psycho-physiological status.

PubMed

Lebedev, Valery P; Malygin, A V; Kovalevski, A V; Rychkova, S V; Sisoev, V N; Kropotov, S P; Krupitski, E M; Gerasimova, L I; Glukhov, D V; Kozlowski, G P

2002-03-01

It is well known that deficit of endorphins plays an important role in disturbances of human psycho-physiological status. Previously, we revealed that brain endorphinergic structures have quasiresonance characteristics. On the basis of these data, a method of activation of the brain endorphinergic structures by means of noninvasive and rather selective transcranial electrostimulation (TES) as a kind of functional electrical stimulation (FES) was elaborated. New models of TES devices (TRANSAIR) were developed for indoor and outdoor usage. To increase the efficacy of TES, the frequency modulation according to normal distribution in the limits of the quasiresonance characteristics was put into operation. The blind and placebo-controlled (passive and active placebo) study was produced to estimate the TES effects on stress events and accompanied psycho-physiological and autonomic disturbances of different intensities on volunteers and patients in the following groups: everyday stress and fatigue; stress in regular military service and in field conditions; stress in the relatives of those lost in mass disaster; posttraumatic stress (thermal burns); and affective disorders in a postabstinence period. Some subjective verbal and nonverbal tests and objective tests (including heart rate variability) were used for estimation of the initial level of psycho-physiological status, which changes after TES sessions. It was demonstrated that fatigue, stress, and other accompanied psycho-physiological disturbances were significantly improved or abolished after 2-5 TES sessions. The TES effects were more pronounced in cases of heavier disturbances. In conclusion, activation of the brain endorphinergic structures by TES is an effective homeostatic method of FES that sufficiently improves quality of life.

Olfactory behavior and physiology are disrupted in prion protein knockout mice.

PubMed

Le Pichon, Claire E; Valley, Matthew T; Polymenidou, Magdalini; Chesler, Alexander T; Sagdullaev, Botir T; Aguzzi, Adriano; Firestein, Stuart

2009-01-01

The prion protein PrP(C) is infamous for its role in disease, but its normal physiological function remains unknown. Here we found a previously unknown behavioral phenotype of Prnp(-/-) mice in an odor-guided task. This phenotype was manifest in three Prnp knockout lines on different genetic backgrounds, which provides strong evidence that the phenotype is caused by a lack of PrP(C) rather than by other genetic factors. Prnp(-/-) mice also showed altered behavior in a second olfactory task, suggesting that the phenotype is olfactory specific. Furthermore, PrP(C) deficiency affected oscillatory activity in the deep layers of the main olfactory bulb, as well as dendrodendritic synaptic transmission between olfactory bulb granule and mitral cells. Notably, both the behavioral and electrophysiological alterations found in Prnp(-/-) mice were rescued by transgenic neuronal-specific expression of PrP(C). These data suggest that PrP(C) is important in the normal processing of sensory information by the olfactory system.

Dopamine and anorexia nervosa.

PubMed

Södersten, P; Bergh, C; Leon, M; Zandian, M

2016-01-01

We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sexual activity and aging.

PubMed

Ni Lochlainn, Mary; Kenny, Rose Anne

2013-08-01

Sexuality is an important component of emotional and physical intimacy that men and women experience throughout their lives. Research suggesting that a high proportion of men and women remain sexually active well into later life refutes the prevailing myth that aging and sexual dysfunction are inexorably linked. Age-related physiological changes do not render a meaningful sexual relationship impossible or even necessarily difficult. Many of these physiological changes are modifiable. There are various therapeutic options available to patients to achieve maximum sexual capacity in old age. This article reviews the prevalence of sexual activity among older adults, the problems these adults encounter with sexual activity, and the role of the health care professional in addressing these problems. The physiological sex-related changes that occur as part of the normal aging process in men and women are reviewed, as well as the effect of age-related physical and psychological illness on sexual function. The attitudes and perceptions of the media and general public toward sexual activity and aging are summarized. An understanding of the sexual changes that accompany the aging process may help general practitioners and other doctors to give practical and useful advice on sexuality as well as refute the misconception that aging equates to celibacy. A thorough awareness of this aspect of older people's quality of life can raise meaningful expectations for aging patients. Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.

Tissue Physiology and Pathology of Aromatase

PubMed Central

Stocco, Carlos

2011-01-01

Summary Aromatase is expressed in multiple tissues, indicating a crucial role for locally produced oestrogens in the differentiation, regulation and normal function of several organs and processes. This review is an overview of the role of aromatase in different tissues under normal physiological conditions and its contribution to the development of some oestrogen-related pathologies. PMID:22108547

F response and H reflex analysis of physiological unity of gravity and antigravity muscles in man.

PubMed

García, H A; Fisher, M A

1977-01-01

Observational differences between reflex (H reflex) and antidromic (F response) activation of segmental motoneurons by a peripheral electrical stimulus are described. In contrast to H reflexes, the percentage of F responses found after a series of stimuli is directly related to the pick-up field of the recording electrode consistent with this response being due to the variable activation of a small fraction of the available motoneuron pool. Despite the differing physiological mechanisms, both F responses and H reflexes can be used to demonstrate similar relative "central excitatory states" for antigravity muscles (i.e. extensors in the lower extremity and flexors in the upper extremity) and their antagonist gravity muscles. H reflexes were elicited not only in their usual location in certain antigravity muscles but also in unusual locations by length/tension changes in agonist and antagonist groups as well as by passive stretch. The data argue for the physiological unity of similarly acting gravity and antigravity muscles as well as supporting a meaningful role of group II afferents in normal segmental motoneuron pool excitability.

High-Moisture Diet for Laboratory Rats: Complete Blood Counts, Serum Biochemical Values, and Intestinal Enzyme Activity

NASA Technical Reports Server (NTRS)

Battles, August H.; Knapka, Joseph T.; Stevens, Bruce R.; Lewis, Laura; Lang, Marie T.; Gruendel, Douglas J.

1991-01-01

Rats were fed an irradiated high-moisture diet (KSC-25) with or without access to a water bottle. Physiologic values were compared between these two groups and a group of rats fed a purified diet. Hematologic and serum biochemical values, urine specific gravity, and intestinal enzyme activities were determined from samples collected from the three groups of rats. Sprague Dawley rats (n=32) fed the irradiated high-moisture diet with or without a water bottle were the test animals. Rats (n=16) fed an irradiated purified diet and water provided via a water bottle were the control group. The purified diet formulation, modified AIN-76A, is a commonly used purified diet for laboratory rodents. All rats remained alert and healthy throughout the study. A comparison of the physiologic values of rats in this study with reported normal values indicated that all of the rats in the study were in good health. Significant differences (P less than 0.05) of the physiologic values from each rat group are reported.

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

Vasuri, Francesco; Capizzi, Elisa; Bellavista, Elena

Despite the central role of proteasomes in relevant physiological pathways and pathological processes, this topic is unexpectedly largely unexplored in human liver. Here we present data on the presence of proteasome and immunoproteasome in human livers from normal adults, fetuses and patients affected by major hepatic diseases such as cirrhosis and chronic active hepatitis. Immunohistochemistry for constitutive ({alpha}4 and {beta}1) and inducible (LMP2 and LMP7) proteasome subunits, and for the PA28{alpha}{beta} regulator, was performed in liver samples from 38 normal subjects, 6 fetuses, 2 pediatric cases, and 19 pathological cases (10 chronic active hepatitis and 9 cirrhosis). The immunohistochemical datamore » have been validated and quantified by Western blotting analysis. The most striking result we found was the concomitant presence in hepatocyte cytoplasm of all healthy subjects, including the pediatric cases, of constitutive proteasome and immunoproteasome subunits, as well as PA28{alpha}{beta}. At variance, immunoproteasome was not present in hepatocytes from fetuses, while a strong cytoplasmic and nuclear positivity for LMP2 and LMP7 was found in pathological samples, directly correlated to the histopathological grade of inflammation. At variance from other organs such as the brain, immunoproteasome is present in livers from normal adult and pediatric cases, in apparent absence of pathological processes, suggesting the presence of a peculiar regulation of the proteasome/immunoproteasome system, likely related to the physiological stimuli derived from the gut microbiota after birth. Other inflammatory stimuli contribute in inducing high levels of immunoproteasome in pathological conditions, where its role deserve further attention.« less

Distinguishing hyperhidrosis and normal physiological sweat production: new data and review of hyperhidrosis data for 1980-2013.

PubMed

Thorlacius, Linnea; Gyldenløve, Mette; Zachariae, Claus; Carlsen, Berit C

2015-10-01

Hyperhidrosis is a condition in which the production of sweat is abnormally increased. No objective criteria for the diagnosis of hyperhidrosis exist, mainly because reference intervals for normal physiological sweat production at rest are unknown. The main objective of this study was to establish reference intervals for normal physiological axillary and palmar sweat production. Gravimetric testing was performed in 75 healthy control subjects. Subsequently, these results were compared with findings in a cohort of patients with hyperhidrosis and with the results derived from a review of data on hyperhidrosis published between 1980 and 2013. Approximately 90% of the controls had axillary and palmar sweat production rates of below 100 mg/5 min. In all except one of the axillary and palmar hyperhidrosis studies reviewed, average sweat production exceeded 100 mg/5 min. A sweat production rate of 100 mg/5 min as measured by gravimetric testing may be a reasonable cut-off value for distinguishing axillary and palmar hyperhidrosis from normal physiological sweat production. © 2015 The International Society of Dermatology.

Thyroid Hormone, Cancer, and Apoptosis.

PubMed

Lin, Hung-Yun; Chin, Yu-Tan; Yang, Yu-Chen S H; Lai, Husan-Yu; Wang-Peng, Jacqueline; Liu, Leory F; Tang, Heng-Yuan; Davis, Paul J

2016-06-13

Thyroid hormones play important roles in regulating normal metabolism, development, and growth. They also stimulate cancer cell proliferation. Their metabolic and developmental effects and growth effects in normal tissues are mediated primarily by nuclear hormone receptors. A cell surface receptor for the hormone on integrin [alpha]vβ3 is the initiation site for effects on tumor cells. Clinical hypothyroidism may retard cancer growth, and hyperthyroidism was recently linked to the prevalence of certain cancers. Local levels of thyroid hormones are controlled through activation and deactivation of iodothyronine deiodinases in different organs. The relative activities of different deiodinases that exist in tissues or organs also affect the progression and development of specific types of cancers. In this review, the effects of thyroid hormone on signaling pathways in breast, brain, liver, thyroid, and colon cancers are discussed. The importance of nuclear thyroid hormone receptor isoforms and of the hormone receptor on the extracellular domain of integrin [alpha]vβ3 as potential cancer risk factors and therapeutic targets are addressed. We analyze the intracellular signaling pathways activated by thyroid hormones in cancer progression in hyperthyroidism or at physiological concentrations in the euthyroid state. Determining how to utilize the deaminated thyroid hormone analog (tetrac), and its nanoparticulate derivative to reduce risks of cancer progression, enhance therapeutic outcomes, and prevent cancer recurrence is also deliberated. © 2016 American Physiological Society. Compr Physiol 6:1221-1237, 2016. Copyright © 2016 John Wiley & Sons, Inc.

TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis.

PubMed

Yadav, Hariom; Devalaraja, Samir; Chung, Stephanie T; Rane, Sushil G

2017-02-24

Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis*

PubMed Central

Yadav, Hariom; Devalaraja, Samir; Chung, Stephanie T.; Rane, Sushil G.

2017-01-01

Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance. PMID:28069811

Eccentric activation and muscle damage: biomechanical and physiological considerations during downhill running.

PubMed Central

Eston, R G; Mickleborough, J; Baltzopoulos, V

1995-01-01

An eccentric muscle activation is the controlled lengthening of the muscle under tension. Functionally, most leg muscles work eccentrically for some part of a normal gait cycle, to support the weight of the body against gravity and to absorb shock. During downhill running the role of eccentric work of the 'anti-gravity' muscles--knee extensors, muscles of the anterior and posterior tibial compartments and hip extensors--is accentuated. The purpose of this paper is to review the relationship between eccentric muscle activation and muscle damage, particularly as it relates to running, and specifically, downhill running. PMID:7551767

Mechanisms of intracellular defense and activity of free radical oxidation in rat myocardium in the dynamics of chronic fluorine intoxication.

PubMed

Zhukova, A G; Alekhina, D A; Sazontova, T G; Prokop'ev, Yu A; Gorokhova, L G; Stryapko, N V; Mikhailova, N N

2013-12-01

The mechanisms of intracellular defense and activity of free radical oxidation in the myocardium were studied in the dynamics of chronic fluorine intoxication. At the early stages of fluorine intoxication (day 3-week 3), the concentrations of defense proteins HIF-1α, HSC73, and HOx-2 and activity of the main metabolic enzymes increased, which promoted maintenance of cardiomyocyte structure and function at the normal physiological level. At late stages of fluorine intoxication (weeks 6 and 9), metabolic changes in the myocardium attest to high strain of the adaptive mechanisms.

Attenuation of smoke induced neuronal and physiological changes by bacoside rich extract in Wistar rats via down regulation of HO-1 and iNOS.

PubMed

Pandareesh, M D; Anand, T

2014-01-01

Bacopa monniera is well known herbal medicine for its neuropharmacological effects. It alleviates variety of disorders including neuronal and physiological changes. Crackers smoke is a potent risk factor that leads to free radical mediated oxidative stress in vivo. The aim of the current study is to evaluate the protective efficacy of B. monniera extract (BME) against crackers smoke induced neuronal and physiological changes via modulating inducible nitric oxide synthase (iNOS) and hemeoxygenase-1 (HO-1) expression in rats. Rats were exposed to smoke for 1h for a period of 3 weeks and consecutively treated with BME at three different dosages (i.e., 10, 20 and 40 mg/kg b.wt.). Our results elucidate that BME treatment ameliorates histopathalogical changes, reactive oxygen species levels, lipid peroxidation, acetylcholine esterase activity and brain neurotransmitter levels to normal. BME supplementation efficiently inhibited HO-1 expression and nitric oxide generation by down-regulating iNOS expression. Smoke induced depletion of antioxidant enzyme status, monoamine oxidase activity was also replenished by BME supplementation. Thus the present study indicates that BME ameliorates various impairments associated with neuronal and physiological changes in rats exposed to crackers smoke by its potent neuromodulatory, antioxidant and adaptogenic propensity. Copyright © 2013 Elsevier Inc. All rights reserved.

Evaluating acoustic speaker normalization algorithms: evidence from longitudinal child data.

PubMed

Kohn, Mary Elizabeth; Farrington, Charlie

2012-03-01

Speaker vowel formant normalization, a technique that controls for variation introduced by physical differences between speakers, is necessary in variationist studies to compare speakers of different ages, genders, and physiological makeup in order to understand non-physiological variation patterns within populations. Many algorithms have been established to reduce variation introduced into vocalic data from physiological sources. The lack of real-time studies tracking the effectiveness of these normalization algorithms from childhood through adolescence inhibits exploration of child participation in vowel shifts. This analysis compares normalization techniques applied to data collected from ten African American children across five time points. Linear regressions compare the reduction in variation attributable to age and gender for each speaker for the vowels BEET, BAT, BOT, BUT, and BOAR. A normalization technique is successful if it maintains variation attributable to a reference sociolinguistic variable, while reducing variation attributable to age. Results indicate that normalization techniques which rely on both a measure of central tendency and range of the vowel space perform best at reducing variation attributable to age, although some variation attributable to age persists after normalization for some sections of the vowel space. © 2012 Acoustical Society of America

First-Year Medical Students' Naïve Beliefs about Respiratory Physiology

ERIC Educational Resources Information Center

Badenhorst, Elmi; Mamede, Silvia; Abrahams, Amaal; Bugarith, Kishor; Friedling, Jacqui; Gunston, Geney; Kelly-Laubscher, Roisin; Schmidt, Henk G.

2016-01-01

The present study explored the nature and frequency of physiology naïve beliefs by investigating novices' understanding of the respiratory system. Previous studies have shown considerable misconceptions related to physiology but focused mostly on specific physiological processes of normal respiration. Little is known about novices' broader…

Reduced G tolerance associated with supplement use.

PubMed

Barker, Patrick D

2011-02-01

High G forces encountered in tactical military aviation and aerobatic flight produce a host of physiologic responses aimed at preserving cerebral perfusion. The military has instituted measures to augment the physiologic response in order to avoid G-induced loss of consciousness (G-LOC) because of its potential to cause a catastrophic mishap. The case presented here details a Naval Aviator who experienced reduced G tolerance over two successive flights with a temporal relationship of starting a new supplement. Two components of the supplement, coenzyme Q10 and niacin, are highlighted here for their hemodynamic effects. After stopping the supplement the aviator regained his normal G tolerance and had no further issues in flight. There are several factors that can reduce G tolerance and supplement use has to be considered here because of the potential for altering the normal physiological response to increased G force. Our discussion reviews the physiological effects of increased G force, the spectrum of signs of decompensation under the stress of G force, and the potential effects this supplement had on the normal physiological response to increased G force, thus reducing the aviator's G tolerance.

Tissue-specific expression of transgenic secreted ACE in vasculature can restore normal kidney functions, but not blood pressure, of Ace-/- mice.

PubMed

Chattopadhyay, Saurabh; Kessler, Sean P; Colucci, Juliana Almada; Yamashita, Michifumi; Senanayake, Preenie deS; Sen, Ganes C

2014-01-01

Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE.

Tissue-Specific Expression of Transgenic Secreted ACE in Vasculature Can Restore Normal Kidney Functions, but Not Blood Pressure, of Ace-/- Mice

PubMed Central

Chattopadhyay, Saurabh; Kessler, Sean P.; Colucci, Juliana Almada; Yamashita, Michifumi; Senanayake, Preenie deS; Sen, Ganes C.

2014-01-01

Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE. PMID:24475296

Expression and activity of multidrug resistance protein 1 in a murine thymoma cell line

PubMed Central

Echevarria-Lima, Juliana; Kyle-Cezar, Fernanda; Leite, Daniela F P; Capella, Luiz; Capella, Márcia A M; Rumjanek, Vivian M

2005-01-01

Multidrug resistance proteins [MRPs and P-glycoprotein (Pgp)] are members of the family of ATP-binding cassette (ABC) transport proteins, originally described as being involved in the resistance against anti-cancer agents in tumour cells. These proteins act as ATP-dependent efflux pumps and have now been described in normal cells where they exert physiological roles. The aim of this work was to investigate the expression and activity of MRP and Pgp in the thymoma cell line, EL4. It was observed that EL4 cells expressed mRNA for MRP1, but not for MRP2, MRP3 or Pgp. The activity of ABC transport proteins was evaluated by using the efflux of the fluorescent probes carboxy-2′-7′-dichlorofluorescein diacetate (CFDA) and rhodamine 123 (Rho 123). EL4 cells did not retain CFDA intracellularly, and MRP inhibitors (probenecid, indomethacin and MK 571) decreased MRP1 activity in a concentration-dependent manner. As expected, EL4 cells accumulated Rho 123, and the presence of cyclosporin A and verapamil did not modify this accumulation. Most importantly, when EL4 cells were incubated in the presence of the MRP1 inhibitors indomethacin and MK 571 for 6 days, they started to express CD4 and CD8 molecules on their surface, producing double-positive cells and CD8 single-positive cells. Our results suggest that MRP activity is important for the maintenance of the undifferentiated state in this cell type. This finding might have implications in the physiological process of normal thymocyte maturation. PMID:15804283

Homeostasis 5: nurses as external agents of control in breast cancer.

PubMed

Clancy, John; McVicar, Andrew

Breast cancer is caused by a homeostatic imbalance of cell division. Healthcare practitioners need to understand cellular activities to appreciate the physiological basis of health (homeostasis), the pathophysiological basis of illness and the physiological rationale of healthcare. Cells are the 'basic unit of life' (Clancy and McVicar, 2011a). This article describes normal cell division and the anatomy and physiology of the breast and, using a case study, will show how breast cancer is a homeostatic imbalance of cell division. There are analogies between the components of homeostasis and the components of the nursing (healthcare) process (Clancy and McVicar, 2011b) in the condition of breast cancer. After reading this article, nurses should be able to: understand that breast cancer is a cellular hence chemical imbalance that causes uncontrollable mitotic division of breast cells; understand how the cell cycle of cancer cells differs from that of normal cells; identify nature-nurture interactions involved in the aetiology of breast cancer; understand that when caring for people with breast cancer, health professionals including oncology nurses are acting as external agents of homeostatic control as the patient 'recovers' from breast cancer, and also to some extent when reducing signs and symptoms, hence quality of life, by providing palliative care.

Synthetic lipids and their role in defining macromolecular assemblies.

PubMed

Parrill, Abby L

2015-10-01

Lipids have a variety of physiological roles, ranging from structural and biophysical contributions to membrane functions to signaling contributions in normal and abnormal physiology. This review highlights some of the contributions made by Robert Bittman to our understanding of lipid assemblies through the production of synthetic lipid analogs in the sterol, sphingolipid, and glycolipid classes. His contributions have included the development of a fluorescent cholesterol analog that shows strong functional analogies to cholesterol that has allowed live imaging of cholesterol distribution in living systems, to stereospecific synthetic approaches to both sphingolipid and glycolipid analogs crucial in defining the structure-activity relationships of lipid biological targets. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Recent neuroimaging techniques in mild traumatic brain injury.

PubMed

Belanger, Heather G; Vanderploeg, Rodney D; Curtiss, Glenn; Warden, Deborah L

2007-01-01

Mild traumatic brain injury (TBI) is characterized by acute physiological changes that result in at least some acute cognitive difficulties and typically resolve by 3 months postinjury. Because the majority of mild TBI patients have normal structural magnetic resonance imaging (MRI)/computed tomography (CT) scans, there is increasing attention directed at finding objective physiological correlates of persistent cognitive and neuropsychiatric symptoms through experimental neuroimaging techniques. The authors review studies utilizing these techniques in patients with mild TBI; these techniques may provide more sensitive assessment of structural and functional abnormalities following mild TBI. Particular promise is evident with fMRI, PET, and SPECT scanning, as demonstrated by associations between brain activation and clinical outcomes.

The anatomy and physiology of normal and abnormal swallowing in oropharyngeal dysphagia.

PubMed

Sasegbon, A; Hamdy, S

2017-11-01

Eating and drinking are enjoyable activities that positively impact on an individual's quality of life. The ability to swallow food and fluid is integral to the process of eating. Swallowing occupies a dual role being both part of the enjoyment of eating and being a critically important utilitarian activity to enable adequate nutrition and hydration. Any impairment to the process of swallowing can negatively affect a person's perception of their quality of life. The process of swallowing is highly complex and involves muscles in the mouth, pharynx, larynx, and esophagus. The oropharynx is the anatomical region encompassing the oral cavity and the pharynx. Food must be masticated, formed into a bolus and transported to the pharynx by the tongue whereas fluids are usually held within the mouth before being transported ab-orally. The bolus must then be transported through the pharynx to the esophagus without any matter entering the larynx. The muscles needed for all these steps are coordinated by swallowing centers within the brainstem which are supplied with sensory information by afferent nerve fibers from several cranial nerves. The swallowing centers also receive modulatory input from higher centers within the brain. Hence, a swallow has both voluntary and involuntary physiologic components and the term dysphagia is given to difficult swallowing while oropharyngeal dysphagia is difficult swallowing due to pathology within the oropharynx. Problems affecting any point along the complex swallowing pathway can result in dysphagia. This review focuses on the anatomy and physiology behind normal and abnormal oropharyngeal swallowing. It also details the common diseases and pathology causing oropharyngeal dysphagia. © 2017 John Wiley & Sons Ltd.

Mechanical stress activates NMDA receptors in the absence of agonists.

PubMed

Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K; Sachs, Frederick; Hua, Susan Z

2017-01-03

While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca 2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca 2+ influx. Extracellular Mg 2+ at 2 mM did not significantly affect the shear induced Ca 2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.

Mechanical stress activates NMDA receptors in the absence of agonists

PubMed Central

Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

2017-01-01

While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca2+ influx. Extracellular Mg2+ at 2 mM did not significantly affect the shear induced Ca2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI. PMID:28045032

Endocrine effects of the herbicide linuron on the American Goldfinch (Carduelis tristis)

USGS Publications Warehouse

Sughrue, K.M.; Brittingham, M.C.; French, J.B.

2008-01-01

Certain contaminants alter normal physiological function, morphology, and behavior of exposed organisms through an endocrine mechanism. We evaluated how the herbicide linuron, an endocrine-active compound, affects physiological parameters and secondary sex characteristics of the American Goldfinch (Carduelis tristis). When administered at relatively low doses (control, 1.0, 4.0, and 16.0 μg linuron per gram of body mass per day), linuron delayed prealternate molt progression in a dose-dependent manner. At the high dose level, linuron exposure lowered hematocrit and female plasma thyroxine concentrations and increased body mass. Neither plasma testosterone concentrations nor the color of plumage or integument of birds in the treatment groups were different from those of the control group. Overall, the physiological effects that were measured suggested disruption of thyroid function. These results highlight the importance of continual monitoring of avian populations for potential effects of exposure to pesticides and other chemicals at sublethal concentrations.

Iron-mediated redox modulation in neural plasticity

PubMed Central

Muñoz, Pablo

2012-01-01

The role of iron in brain physiology has focused on the neuropathological, effects due to iron-induced oxidative stress. However, our recent work has established a physiological relationship between the iron-mediated oxidative modification and normal neuronal function. Our results obtained from hippocampal neurons, suggest that iron-generated reactive species oxygen (ROS) are involved in calcium signaling initiated by stimulation of NMDA receptors. This signal is amplified by ryanodine receptors (RyR), a redox- sensitive calcium channel, allowing the phosphorylation and nuclear translocation of ERK1/2. Furthermore, using electrophysiological approaches, we showed that iron is required for basal synaptic transmission and full expression of long-term potentiation, a type of synaptic plasticity. Our data combined suggest that the oxidative effect of iron is critical to activate processes that are downstream of NMDAR activation. Finally, due to the high reactivity of DNA with iron-generated ROS, we hypothesize an additional function of iron in gene regulation. PMID:22808323

Pre-gravid physical activity and reduced risk of glucose intolerance in pregnancy: the role of insulin sensitivity.

PubMed

Retnakaran, Ravi; Qi, Ying; Sermer, Mathew; Connelly, Philip W; Zinman, Bernard; Hanley, Anthony J G

2009-04-01

Pre-gravid physical activity has been associated with a reduced risk of gestational diabetes mellitus (GDM), although neither the types of exercise nor the physiologic mechanisms underlying this protective effect have been well-studied. Thus, we sought to study the relationships between types of pre-gravid physical activity and metabolic parameters in pregnancy, including glucose tolerance, insulin sensitivity and beta-cell function. A total of 851 women underwent a glucose challenge test (GCT) and a 3-h oral glucose tolerance test (OGTT) in late pregnancy, yielding four glucose tolerance groups: (i) GDM; (ii) gestational impaired glucose tolerance (GIGT); (iii) abnormal GCT with normal glucose tolerance on OGTT (abnormal GCT NGT); and (iv) normal GCT with NGT on OGTT (normal GCT NGT). Pre-gravid physical activity was assessed using the Baecke questionnaire, which measures (i) total physical activity and (ii) its three component domains: work, nonsport leisure-time, and vigorous/sports activity. Glucose tolerance status improved across increasing quartiles of pre-gravid total physical activity (P = 0.0244). Whereas neither work nor nonsport leisure-time activity differed between glucose tolerance groups, pre-gravid vigorous/sports activity was significantly higher in women with normal GCT NGT compared to women with (i) abnormal GCT NGT (P = 0.0018) (ii) GIGT (P = 0.0025), and (iii) GDM (P = 0.0044). In particular, vigorous/sports activity correlated with insulin sensitivity (measured by IS(OGTT)) (r = 0.21, P < 0.0001). Furthermore, on multiple linear regression analysis, pre-gravid vigorous/sports activity emerged as a significant independent predictor of IS(OGTT) in pregnancy (t = 4.97, P < 0.0001). Pre-gravid vigorous/sports activity is associated with a reduced risk of glucose intolerance in pregnancy, an effect likely mediated by enhanced insulin sensitivity.

The Role of Dopamine in Normal Rodent Motor Cortex: Physiological Effects and Structural Correlates

DTIC Science & Technology

1999-04-05

things she does on a daily basis made the lab a great place to do research. Susan’s expertise in molecular techniques was evident from day one , and I...applied OA on the spontaneous activity (SA) of PTNs. the receptors that mediate these effects, and DA’s effects on glutamate induced excitation of PTNs...numerous neurons in the motor cortex and may have profound effects on motor cortex activity, through its influence on PTNs. iv The Role of Dopamine in

Lactational ectopic breast tissue of the vulva: case report and brief historical review.

PubMed

Pieh-Holder, Kelly L

2013-04-01

Ectopic breast tissue is defined as glands of breast tissue located outside of the normal anatomic breasts. Historically, ectopic breast tissue has been thought to arise from a remnant of the embryonic mammary ridge along the "milk line" or the midaxillary line from the axilla to the groin, including the vulvar region. Extramammary tissue displays the same pathologic and physiologic changes as normal breast tissue and is often discovered in multiparous women as the result of swelling from lactational activity. We present a case report of a gravid patient with lactating vulvar mass and a brief historical perspective of vulvar ectopic breast tissue.

Quantitative rest activity in ambulatory monitoring as a physiological marker of restless legs syndrome: a controlled study.

PubMed

Tuisku, Katinka; Holi, Matti Mikael; Wahlbeck, Kristian; Ahlgren, Aulikki Johanna; Lauerma, Hannu

2003-04-01

An objective marker of restless legs syndrome (RLS) is needed for developing diagnostic tools and monitoring symptoms. Actometric ambulatory monitoring of 15 RLS patients and 15 healthy controls was undertaken in order to differentiate between RLS-related motor symptoms and normal motor activity. Nocturnal lower-limb activity per minute differentiated and discriminated between groups with no overlap, whereas the periodic limb movement index and the controlled rest activity during sitting showed less discriminative power. The naturalistic recording of nocturnal activity by actometry may prove useful for assessing the severity of RLS and for finding an objective marker to support the diagnosis of RLS. Copyright 2002 Movement Disorder Society

Replicating Physiological Patterns of Activity with Prosthetic Stimulation

DTIC Science & Technology

2008-07-01

from retinitis pigmentosa : Arch Ophthalmol, v. 122, p. 460-9. 8 Dacey, D. M., B. B. Peterson, F. R. Robinson, and P. D. Gamlin, 2003, Fireworks in...with DTL electrodes: a study in patients with retinitis pigmentosa , glaucoma, and homonymous visual field loss and normal subjects: Invest Ophthalmol...outcomes associated with retinal prosthetics. To accomplish this, we are investigating the mechanism(s) by which different types of retinal neurons

Hematite enhances the removal of Cr(VI) by Bacillus subtilis BSn5 from aquatic environment.

PubMed

Ma, Shuai; Song, Chang-Shun; Chen, Yuefang; Wang, Fei; Chen, Hui-Lun

2018-06-05

In the present study, we investigated the removal of Cr(VI) and the associated bacterial activity in the systems containing Bacillus subtilis BSn5 (B. subtilis BSn5) and hematite. The microcalorimetry was used to study the effect of hematite on the normal physiological functions of B. subtilis BSn5 towards the removal of Cr(VI) for the first time. The results of the heat flux and the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed that hematite does not affect the normal physiological functions of B. subtilis BSn5, and can help the strains maintain their activity in the presence of Cr(VI). More importantly, the relative capacity and intensity of Cr(VI) and total Cr removal by B. subtilis BSn5 in the presence of hematite were higher than that in the absence of hematite. The enhancement effect could be associated with their mineral adsorption, biosorption, Fe(II) reduction, bioreduction and immobilization functions. This study demonstrates the possibility of reducing the toxicity of Cr(VI) and enhancing the Cr(VI) removal efficiency in contaminated environments using a combination of hematite and B. subtilis BSn5. Copyright © 2018 Elsevier Ltd. All rights reserved.

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

PubMed Central

Gentric, Géraldine; Maillet, Vanessa; Paradis, Valérie; Couton, Dominique; L’Hermitte, Antoine; Panasyuk, Ganna; Fromenty, Bernard; Celton-Morizur, Séverine; Desdouets, Chantal

2015-01-01

Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development. PMID:25621497

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease.

PubMed

Gentric, Géraldine; Maillet, Vanessa; Paradis, Valérie; Couton, Dominique; L'Hermitte, Antoine; Panasyuk, Ganna; Fromenty, Bernard; Celton-Morizur, Séverine; Desdouets, Chantal

2015-03-02

Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development.

Sex-Based Differences in Physiology: What Should We Teach in the Medical Curriculum?

ERIC Educational Resources Information Center

Blair, Martha L.

2007-01-01

An abundance of recent research indicates that there are multiple differences between males and females both in normal physiology and in the pathophysiology of disease. The Refresher Course on Gender Differences in Physiology, sponsored by the American Physiological Society Education Committee at the 2006 Experimental Biology Meeting in San…

Relationship between seminal plasma levels of anandamide congeners palmitoylethanolamide and oleoylethanolamide and semen quality.

PubMed

Amoako, Akwasi Atakora; Marczylo, Timothy Hywel; Elson, Janine; Taylor, Anthony Henry; Willets, Jonathon M; Konje, Justin Chi

2014-11-01

To determine whether changes in seminal plasma concentrations of the endogenous lipid signaling molecules palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) have significant effects on sperm quality. Biochemical and physiological studies of human seminal plasma and spermatozoa. Academic tertiary care medical center. Ninety men attending an infertility clinic for semen analysis. Palmitoylethanolamide and OEA extracted from seminal plasma were quantified by ultra high-performance liquid chromatography (HPLC)-tandem mass spectrometry. Patient sperm from semen with normal parameters were exposed in vitro to PEA or OEA to determine effects on sperm motility, viability, and mitochondrial activity. The relationship between seminal plasma concentrations of PEA and OEA and sperm quality and the effect of these compounds on sperm motility, viability, and mitochondria activity in vitro. Palmitoylethanolamide and OEA concentrations in seminal plasma were lower in men with asthenozoospermia and oligoasthenoteratozospermia compared with men with normal semen parameters. Palmitoylethanolamide and OEA rapidly and significantly improved sperm motility and maintained viability without affecting mitochondria activity in vitro. Maintenance of normal PEA and OEA tone in human seminal plasma may be necessary for the preservation of normal sperm function and male fertility. Exocannabinoids found in Cannabis, such as delta-9-tetrahydrocannabinol and cannabidiol, could compete with these endocannabinoids upsetting their finely balanced, normal functioning and resulting in male reproductive failure. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Tunable cytotoxicity of rhodamine 6G via anion variations.

PubMed

Magut, Paul K S; Das, Susmita; Fernand, Vivian E; Losso, Jack; McDonough, Karen; Naylor, Brittni M; Aggarwal, Sita; Warner, Isiah M

2013-10-23

Chemotherapeutic agents with low toxicity to normal tissues are a major goal in cancer research. In this regard, the therapeutic activities of cationic dyes, such as rhodamine 6G, toward cancer cells have been studied for decades with observed toxicities toward normal and cancer cells. Herein, we report rhodamine 6G-based organic salts with varying counteranions that are stable under physiological conditions, display excellent fluorescence photostability, and more importantly have tunable chemotherapeutic properties. Our in vitro studies indicate that the hydrophobic compounds of this series allow production of nanoparticles which are nontoxic to normal cells and toxic to cancer cells. Furthermore, the anions, in combination with cations such as sodium, were observed to be nontoxic to both normal and cancer cells. To the best of our knowledge, this is the first demonstration that both the cation and anion play an extremely important and cooperative role in the antitumor properties of these compounds.

Prognosis of physiological disorders in physic nut to N, P, and K deficiency during initial growth.

PubMed

Santos, Elcio Ferreira; Macedo, Fernando Giovannetti; Zanchim, Bruno José; Lima, Giuseppina Pace Pereira; Lavres, José

2017-06-01

The description of physiological disorders in physic nut plants deficient in nitrogen (N), phosphorus (P) and potassium (K) may help to predict nutritional imbalances before the appearance of visual symptoms and to guide strategies for early nutrient supply. The aim of this study was to evaluate the growth of physic nuts (Jatropha curcas L.) during initial development by analyzing the gas exchange parameters, nutrient uptake and use efficiency, as well as the nitrate reductase and acid phosphatase activities and polyamine content. Plants were grown in a complete nutrient solution and solutions from which N, P or K was omitted. The nitrate reductase activity, phosphatase acid activity, polyamine content and gas exchange parameters from leaves of N, P and K-deficient plants indicates earlier imbalances before the appearance of visual symptoms. Nutrient deficiencies resulted in reduced plant growth, although P- and K-deficient plants retained normal net photosynthesis (A), stomatal conductance (g s ) and instantaneous carboxylation efficiency (k) during the first evaluation periods, as modulated by the P and K use efficiencies. Increased phosphatase acid activity in P-deficient plants may also contribute to the P use efficiency and to A and gs during the first evaluations. Early physiological and biochemical evaluations of N-, P- and K-starved plants may rely on reliable, useful methods to predict early nutritional imbalances. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Interactions between Artificial Gravity, the Affected Physiological Systems, and Nutrition

NASA Technical Reports Server (NTRS)

Heer, Martina; Baecker, Nathalie; Zwart, Sara; Smith, Scott

2006-01-01

Malnutrition, either by insufficient supply of some nutrients or by overfeeding, has a profound effect on the health of an organism. Therefore, optimal nutrition is a necessity in normal gravity on Earth, in microgravity, and when applying artificial gravity to the human system. Reduced physical activity, such as observed in microgravity or bed rest, has an effect on many physiological systems, such as the cardiovascular, musculoskeletal, immune, and body fluids regulation systems. There is currently no countermeasure that is effective to counteract both the cardiovascular and musculoskeletal deconditioning when applied for a short duration (see Chapter 1). Artificial gravity therefore seems the simplest physiological approach to keep these systems intact. The application of intermittent daily dose of artificial gravity by means of centrifugation has often been proposed as a potential countermeasure against the physiological deconditioning induced by spaceflight. However, neither the optimal gravity level, nor its optimal duration of exposure have been enough studied to recommend a validated, effective, and efficient artificial gravity application. As discussed in previous chapters, artificial gravity has a very high potential to counteract any changes caused by reduced physical activity. The nutrient supply, which ideally should match the actual needs, will interact with these changes and therefore has also to be taken into account. This chapter reviews the potential interactions between these nutrients (energy intake, vitamins, minerals) and the other physiological systems affected by artificial gravity generated by an on-board short-radius centrifuge.

Effects of body temperature on post-anoxic oxidative stress from the perspective of postnatal physiological adaptive processes in rats.

PubMed

Kletkiewicz, H; Rogalska, J; Nowakowska, A; Wozniak, A; Mila-Kierzenkowska, C; Caputa, M

2016-04-01

It is well known that decrease in body temperature provides protection to newborns subjected to anoxia/ischemia. We hypothesized that the normal body temperature of 33°C in neonatal rats (4°C below normal body temperature in adults) is in fact a preadaptation to protect CNS from anoxia and further reductions as well as elevations in temperature may be counterproductive. Our experiments aimed to examine the effect of changes in body temperature on oxidative stress development in newborn rats exposed to anoxia. Two-day-old Wistar rats were divided into 4 temperature groups: i. hypothermic at body temperature of 31°C, ii. maintaining physiological neonatal body temperature of 33°C, iii. forced to maintain hyperthermic temperature of 37°C, and i.v. forced to maintain hyperthermic temperature of 39°C. The temperature was controlled starting 15 minutes before and afterword during 10 minutes of anoxia as well as for 2 hours post-anoxia. Cerebral concentrations of lipid peroxidation products malondialdehyde (MDA) and conjugated dienes (CD) and the activities of antioxidant enzymes had been determined post mortem: immediately after anoxia was finished and 3, 7, and 14 days later. There were no post-anoxic changes in the concentration of MDA, CD and in antioxidant enzymes activity in newborn rats kept at their physiological body temperature of 33°C. In contrast, perinatal anoxia at body temperature elevated to 37°C or 39°C as well as under hypothermic conditions (31°C) intensified post-anoxic oxidative stress and depleted the antioxidant pool. Overall, these findings suggest that elevated body temperature (hyperthermia or fever), as well as exceeding cooling beyond the physiological level of body temperature of newborn rats, may extend perinatal anoxia-induced brain lesions. Our findings provide new insights into the role of body temperature in anoxic insult in vivo.

Gut feedback mechanisms and food intake: a physiological approach to slow carbohydrate bioavailability.

PubMed

Zhang, Genyi; Hasek, Like Y; Lee, Byung-Hoo; Hamaker, Bruce R

2015-04-01

Glycemic carbohydrates in foods are an important macronutrient providing the biological fuel of glucose for a variety of physiological processes. A classification of glycemic carbohydrates into rapidly digestible carbohydrate (RDC) and slowly digestible carbohydrate (SDC) has been used to specify their nutritional quality related to glucose homeostasis that is essential to normal functioning of the brain and critical to life. Although there have been many studies and reviews on slowly digestible starch (SDS) and SDC, the mechanisms of their slow digestion and absorption were mostly investigated from the material side without considering the physiological processes of their in vivo digestion, absorption, and most importantly interactions with other food components and the gastrointestinal tract. In this article, the physiological processes modulating the bioavailability of carbohydrates, specifically the rate and extent of their digestion and absorption as well as the related locations, in a whole food context, will be discussed by focusing on the activities of the gastrointestinal tract including glycolytic enzymes and glucose release, sugar sensing, gut hormones, and neurohormonal negative feedback mechanisms. It is hoped that a deep understanding of these physiological processes will facilitate the development of innovative dietary approaches to achieve desired carbohydrate or glucose bioavailability for improved health.

Voluntary physical activity prevents insulin resistance in a tissue specific manner.

PubMed

Sarvas, Jessica L; Otis, Jeffrey S; Khaper, Neelam; Lees, Simon J

2015-02-01

Physical inactivity and a sedentary lifestyle are risk factors for the development of type 2 diabetes. Here, we identified the effects 8 weeks of voluntary physical activity had on the prevention of insulin resistance in mouse skeletal muscles and liver (a hallmark of T2D). To do this, 8 week old C57BL/6J mice with (RUN) and without (SED) voluntary access to running wheels were fed a standard rodent chow ad libitum for 8 weeks. In the liver, there was a 2.5-fold increase in insulin stimulated Akt(SER) (473) phosphorylation, and a threefold increase in insulin-stimulated (0.5 U/kg) GSK3β(SER) (9) phosphorylation in RUN compared to SED mice. Although not induced in skeletal muscles, there was a twofold increase in SOCS3 expression in SED compared to RUN mice in the liver. There was no difference in the glucose tolerance test between groups. This study was the first to show differences in liver insulin sensitivity after 8 weeks of voluntary physical activity, and increased SOCS3 expression in the liver of sedentary mice compared to active mice. These findings demonstrate that even in young mice that would normally be considered healthy, the lack of physical activity leads to insulin resistance representing the initial pathogenesis of impaired glucose metabolism leading to type 2 diabetes. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Ca(2+) signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca(2+) channel blockade.

PubMed

Gryshchenko, Oleksiy; Gerasimenko, Julia V; Gerasimenko, Oleg V; Petersen, Ole H

2016-01-15

Bradykinin may play a role in the autodigestive disease acute pancreatitis, but little is known about its pancreatic actions. In this study, we have investigated bradykinin-elicited Ca(2+) signal generation in normal mouse pancreatic lobules. We found complete separation of Ca(2+) signalling between pancreatic acinar (PACs) and stellate cells (PSCs). Pathophysiologically relevant bradykinin concentrations consistently evoked Ca(2+) signals, via B2 receptors, in PSCs but never in neighbouring PACs, whereas cholecystokinin, consistently evoking Ca(2+) signals in PACs, never elicited Ca(2+) signals in PSCs. The bradykinin-elicited Ca(2+) signals were due to initial Ca(2+) release from inositol trisphosphate-sensitive stores followed by Ca(2+) entry through Ca(2+) release-activated channels (CRACs). The Ca(2+) entry phase was effectively inhibited by a CRAC blocker. B2 receptor blockade reduced the extent of PAC necrosis evoked by pancreatitis-promoting agents and we therefore conclude that bradykinin plays a role in acute pancreatitis via specific actions on PSCs. Normal pancreatic stellate cells (PSCs) are regarded as quiescent, only to become activated in chronic pancreatitis and pancreatic cancer. However, we now report that these cells in their normal microenvironment are far from quiescent, but are capable of generating substantial Ca(2+) signals. We have compared Ca(2+) signalling in PSCs and their better studied neighbouring acinar cells (PACs) and found complete separation of Ca(2+) signalling in even closely neighbouring PACs and PSCs. Bradykinin (BK), at concentrations corresponding to the slightly elevated plasma BK levels that have been shown to occur in the auto-digestive disease acute pancreatitis in vivo, consistently elicited substantial Ca(2+) signals in PSCs, but never in neighbouring PACs, whereas the physiological PAC stimulant cholecystokinin failed to evoke Ca(2+) signals in PSCs. The BK-induced Ca(2+) signals were mediated by B2 receptors and B2 receptor blockade protected against PAC necrosis evoked by agents causing acute pancreatitis. The initial Ca(2+) rise in PSCs was due to inositol trisphosphate receptor-mediated release from internal stores, whereas the sustained phase depended on external Ca(2+) entry through Ca(2+) release-activated Ca(2+) (CRAC) channels. CRAC channel inhibitors, which have been shown to protect PACs against damage caused by agents inducing pancreatitis, therefore also inhibit Ca(2+) signal generation in PSCs and this may be helpful in treating acute pancreatitis. © 2015 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

24-Hour colonic manometry in pediatric slow transit constipation shows significant reductions in antegrade propagation.

PubMed

King, Sebastian K; Catto-Smith, Anthony G; Stanton, Michael P; Sutcliffe, Jonathan R; Simpson, Dianne; Cook, Ian; Dinning, Phil; Hutson, John M; Southwell, Bridget R

2008-08-01

The physiological basis of slow transit constipation (STC) in children remains poorly understood. We wished to examine pan-colonic motility in a group of children with severe chronic constipation refractory to conservative therapy. We performed 24 h pan-colonic manometry in 18 children (13 boys, 11.6 +/- 0.9 yr, range 6.6-18.7 yr) with scintigraphically proven STC. A water-perfused, balloon tipped, 8-channel, silicone catheter with a 7.5 cm intersidehole distance was introduced through a previously formed appendicostomy. Comparison data were obtained from nasocolonic motility studies in 16 healthy young adult controls and per-appendicostomy motility studies in eight constipated children with anorectal retention and/or normal transit on scintigraphy (non-STC). Antegrade propagating sequences (PS) were significantly less frequent (P < 0.01) in subjects with STC (29 +/- 4 per 24 h) compared to adult (53 +/- 4 per 24 h) and non-STC (70 +/- 14 per 24 h) subjects. High amplitude propagating sequences (HAPS) were of a normal frequency in STC subjects. Retrograde propagating sequences were significantly more frequent (P < 0.05) in non-STC subjects compared to STC and adult subjects. High amplitude retrograde propagating sequences were only identified in the STC and non-STC pediatric groups. The normal increase in motility index associated with waking and ingestion of a meal was absent in STC subjects. Prolonged pancolonic manometry in children with STC showed significant impairment in antegrade propagating motor activity and failure to respond to normal physiological stimuli. Despite this, HAPS occurred with normal frequency. These findings suggest significant clinical differences between STC in children and adults.

Effect of vitamin C on male fertility in rats subjected to forced swimming stress.

PubMed

Vijayprasad, Sanghishetti; Bb, Ghongane; Bb, Nayak

2014-07-01

Stress is defined as a general body response to initially threatening external or internal demands, involving the mobilization of physiological and psychological resources to deal with them. Recently, oxidative stress has become the focus of interest as a potential cause of male infertility. Normally, equilibrium exists between reactive oxygen species (ROS) production and antioxidant scavenging activities in the male reproductive organs. The ascorbic acid is a known antioxidant present in the testis with the precise role of protecting the latter from the oxidative damage. It also contributes to the support of spermatogensis at least in part through its capacity to maintain antioxidant in an active state. Group1: Normal Control animal received Distilled water, Group 2: Positive control (Only Stress), Group 3: Normal rats received an intermediate dose of Vitamin C (20mg/kg/day), Group 4: Stress + Low dose Vitamin C (10mg/kg/day), Group 5: Stress+ Intermediate dose Vitamin C (20mg/kg/day), Group 6: High dose Vitamin C (30mg/kg/day). On 16(th) day effect of stress on body weight, Reproductive organ weight, sperm parameters, and hormonal assay was studied. In the present context, in stress group the sperm count, motility, testicular weight declined significantly. The intermediate dose and high dose of vitamin C showed significantly increased effect on the sperm count and motility. Various physiological changes produced force swimming indicates that swimming is an effective model for producing stress in albino rats. The results suggest that Vitamin C supplementation improves the stress induced reproductive infertility due to both their testosterone increase effect and their antioxidant effect.

Physiological Ranges of Matrix Rigidity Modulate Primary Mouse Hepatocyte Function In Part Through Hepatocyte Nuclear Factor 4 Alpha

PubMed Central

Desai, Seema S.; Tung, Jason C.; Zhou, Vivian X.; Grenert, James P.; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M.; Chang, Tammy T.

2016-01-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of hepatic-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150Pa and increased to 1–6kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α) whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase (FAK). In addition, blockade of the Rho/Rho-associated protein kinase (ROCK) pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Conclusion Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/ROCK pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. PMID:26755329

Sodium intake influences hemodynamic and neural responses to angiotensin receptor blockade in rostral ventrolateral medulla.

PubMed

DiBona, G F; Jones, S Y

2001-04-01

To determine the effects of physiological alterations in endogenous angiotensin II activity on basal renal sympathetic nerve activity (RSNA) and its arterial baroreflex regulation, angiotensin II type 1 receptor antagonists were microinjected into the rostral ventrolateral medulla of anesthetized rats consuming a low, normal, or high sodium diet that were instrumented for simultaneous measurement of arterial pressure and RSNA. Plasma renin activity was increased in rats fed a low sodium diet and decreased in those fed a high sodium diet. Losartan (50, 100, and 200 pmol) decreased heart rate and RSNA (but not mean arterial pressure) dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a high sodium diet. Candesartan (1, 2, and 10 pmol) decreased mean arterial pressure, heart rate, and RSNA dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a normal or high sodium diet. [D-Ala(7)]Angiotensin-(1-7) (100, 200, and 1000 pmol) did not affect mean arterial pressure, heart rate, or RSNA in rats fed either a low or a high sodium diet. In rats fed a low sodium diet, candesartan reset the arterial baroreflex control of RSNA to a lower level of arterial pressure, and in rats with congestive heart failure, candesartan increased the arterial baroreflex gain of RSNA. Physiological alterations in the endogenous activity of the renin-angiotensin system influence the bradycardic, vasodepressor, and renal sympathoinhibitory responses to rostral ventrolateral medulla injection of antagonists to angiotensin II type 1 receptors but not to angiotensin-(1-7) receptors.

A primer on clothing systems for cold-weather field work

USGS Publications Warehouse

Denner, Jon

1990-01-01

Conducting field work in cold weather is a demanding task. The most important safety consideration for field personnel is to maintain normal body temperature and avoid hypothermia.The human body adjusts to cold temperatures through different physiological processes. Heat production is enhanced by increases in the rates of basal metabolism, specific dynamic action, and physical exercise, and heat loss is reduced by vasoconstriction.Physiological adaptations alone are inadequate to stop rapid heat loss in cold temperatures. Additional insulation in the form of cold-weather clothing is necessary to retain heat.The most practical method of dressing for winter conditions is the layering system. Wearing multiple thin layers allows one to fine tune the insulation needed for different temperatures and activity levels.

Cardiorespiratory coupling in health and disease.

PubMed

Garcia, Alfredo J; Koschnitzky, Jenna E; Dashevskiy, Tatiana; Ramirez, Jan-Marino

2013-04-01

Cardiac and respiratory activities are intricately linked both functionally as well as anatomically through highly overlapping brainstem networks controlling these autonomic physiologies that are essential for survival. Cardiorespiratory coupling (CRC) has many potential benefits creating synergies that promote healthy physiology. However, when such coupling deteriorates autonomic dysautonomia may ensue. Unfortunately there is still an incomplete mechanistic understanding of both normal and pathophysiological interactions that respectively give rise to CRC and cardiorespiratory dysautonomia. Moreover, there is also a need for better quantitative methods to assess CRC. This review addresses the current understanding of CRC by discussing: (1) the neurobiological basis of respiratory sinus arrhythmia (RSA); (2) various disease states involving cardiorespiratory dysautonomia; and (3) methodologies measuring heart rate variability and RSA. Copyright © 2013 Elsevier B.V. All rights reserved.

Cardiorespiratory Coupling in Health and Disease

PubMed Central

Garcia, Alfredo J.; Koschnitzky, Jenna E.; Dashevskiy, Tatiana; Ramirez, Jan-Marino

2013-01-01

Cardiac and respiratory activities are intricately linked both functionally as well as anatomically through highly overlapping brainstem networks controlling these autonomic physiologies that are essential for survival. Cardiorespiratory coupling (CRC) has many potential benefits creating synergies that promote healthy physiology. However, when such coupling deteriorates autonomic dysautonomia may ensue. Unfortunately there is still an incomplete mechanistic understanding of both normal and pathophysiological interactions that respectively give rise to CRC and cardiorespiratory dysautonomia. Moreover, there is also a need for better quantitative methods to assess CRC. This review addresses the current understanding of CRC by discussing: (1) the neurobiological basis of respiratory sinus arrhythmia (RSA); (2) various disease states involving cardiorespiratory dysautonomia; and (3) methodologies measuring heart rate variability and RSA. PMID:23497744

Lowering the milk lactose content in vivo: potential interests, strategies and physiological consequences.

PubMed

Vilotte, Jean-Luc

2002-01-01

Lactose is the major sugar present in milk and an important osmotic regulator of lactation. It is digested by intestinal lactase, an enzyme expressed in new-borns. Its activity declines following weaning. As a result, adult mammals are normally lactose-intolerant and more than 75% of the human adult population suffers from lactase deficiency. A reduction in milk lactose content could be beneficial for nutritional but also agricultural and industrial purposes (less volume to transport, better milk coagulation, less effluent production). Several attempts to create transgenic mice producing milk with modified carbohydrate compositions have recently been described. Depending on whether these modifications resulted from an alteration of lactose synthesis or from lactose hydrolysis, striking physiological differences are observed.

What have we learned about GPER function in physiology and disease from knockout mice?

PubMed Central

Prossnitz, Eric R.; Hathaway, Helen J.

2015-01-01

Estrogens, predominantly 17β-estradiol, exert diverse effects throughout the body in both normal and patho-physiology, during development and in reproductive, metabolic, endocrine, cardiovascular, nervous, musculoskeletal and immune systems. Estrogen and its receptors also play important roles in carcinogenesis and therapy, particularly for breast cancer. In addition to the classical nuclear estrogen receptors (ERα and ERβ) that traditionally mediate predominantly genomic signaling, the G protein-coupled estrogen receptor GPER has become recognized as a critical mediator of rapid signaling in response to estrogen. Mouse models, and in particular knockout (KO) mice, represent an important approach to understand the functions of receptors in normal physiology and disease. Whereas ERα KO mice display multiple significant defects in reproduction and mammary gland development, ERβ KO phenotypes are more limited, and GPER KO exhibit no reproductive deficits. However, the study of GPER KO mice over the last six years has revealed that GPER deficiency results in multiple physiological alterations including obesity, cardiovascular dysfunction, insulin resistance and glucose intolerance. In addition, the lack of estrogen-mediated effects in numerous tissues of GPER KO mice, studied in vivo or ex vivo, including those of the cardiovascular, endocrine, nervous and immune systems, reveals GPER as a genuine mediator of estrogen action. Importantly, GPER KO mice have also revealed roles for GPER in breast carcinogenesis and metastasis. In combination with the supporting effects of GPER-selective ligands and GPER knockdown approaches, GPER KO mice demonstrate the therapeutic potential of targeting GPER activity in diseases as diverse as obesity, diabetes, multiple sclerosis, hypertension, atherosclerosis, myocardial infarction, stroke and cancer. PMID:26189910

Insulin-producing cells could not mimic the physiological regulation of insulin secretion performed by pancreatic beta cells

PubMed Central

2013-01-01

Objective The aim of this study was to compare the difference between insulin-producing cells (IPCs) and normal human pancreatic beta cells both in physiological function and morphological features in cellular level. Methods The levels of insulin secretion were measured by enzyme-linked immunosorbent assay. The insulin gene expression was determined by real-time quantitative polymerase chain reaction. The morphological features were detected by atomic force microscopy (AFM) and laser confocal scanning microscopy. Results IPCs and normal human pancreatic beta cells were similar to each other under the observation in AFM with the porous structure features in the cytoplasm. Both number of membrane particle size and average roughness of normal human beta cells were higher than those of IPCs. Conclusions Our results firstly revealed that the cellular ultrastructure of IPCs was closer to that of normal human pancreatic beta cells, but they still could not mimic the physiological regulation of insulin secretion performed by pancreatic beta cells. PMID:23421382

Analgesic and Antineuropathic Drugs Acting Through Central Cholinergic Mechanisms

PubMed Central

Bartolini, Alessandro; Cesare Mannelli, Lorenzo Di; Ghelardini, Carla

2011-01-01

The role of muscarinic and nicotinic cholinergic receptors in analgesia and neuropathic pain relief is relatively unknown. This review describes how such drugs induce analgesia or alleviate neuropathic pain by acting on the central cholinergic system. Several pharmacological strategies are discussed which increase synthesis and release of acetylcholine (ACh) from cholinergic neurons. The effects of their acute and chronic administration are described. The pharmacological strategies which facilitate the physiological functions of the cholinergic system without altering the normal modulation of cholinergic signals are highlighted. It is proposed that full agonists of muscarinic or nicotinic receptors should be avoided. Their activation is too intense and un-physiological because neuronal signals are distorted when these receptors are constantly activated. Good results can be achieved by using agents that are able to a) increase ACh synthesis, b) partially inhibit cholinesterase activity c) selectively block the autoreceptor or heteroreceptor feedback mechanisms. Activation of M1 subtype muscarinic receptors induces analgesia. Chronic stimulation of nicotinic (N1) receptors has neuronal protective effects. Recent experimental results indicate a relationship between repeated cholinergic stimulation and neurotrophic activation of the glial derived neurotrophic factor (GDNF) family. At least 9 patents covering novel chemicals for cholinergic system modulation and pain control are discussed. PMID:21585331

Physiological changes, sleep, and morning mood in an isolated environment

NASA Technical Reports Server (NTRS)

Kraft, Norbert O.; Inoue, Natsuhiko; Mizuno, Koh; Ohshima, Hiroshi; Murai, Tadashi; Sekiguchi, Chiharu; Orasanu, J. M. (Principal Investigator)

2002-01-01

BACKGROUND: Previous isolation studies have shown increased 24-h urine volumes and body weight gains in subjects. This project examined those and other physiological variables in relationship to sleep motor activity, subjective sleep quality, mood, and complaints during confinement. METHODS: Six male and two female subjects lived for 7 d in the National Space Development Agency of Japan's isolation chamber, which simulates the interior of the Japanese Experiment Module. Each 24-h period included 6 h of sleep, 3 meals, and 20 min of exercise. Each morning, subjects completed Sleep Sensation and Complaint Index questionnaires. Catecholamine and creatinine excretion, urine volume, and body weight were measured on the 2 d before and 2 d after confinement, and sleep motor activity was measured during confinement. RESULTS: Confinement produced no significant change in body weight, urine volume, or questionnaire results. In contrast, epinephrine, norepinephrine, and sleep motor activity exhibited significant differences during confinement (p < 0.05). Higher nocturnal norepinephrine excretion correlated with higher sleep motor activity. CONCLUSION: The 24-h epinephrine values were slightly higher than normal throughout the experiment, but lower than for subjects working under time-stress. High sympathetic activity (as indicated by norepinephrine) may have interfered with sleep.

Matrix metalloproteinases: their biological functions and clinical implications.

PubMed

Hijova, E

2005-01-01

Matrix metalloproteinases (MMPs), which are also known as matrixins, are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, at that of activation of the pro-MMP precursor zymogenes as well as at that of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs). Alterations in the regulation of MMP activity are implicated in diseases such as cancer, fibrosis, arthritis and atherosclerosis. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and cardiac remodelling in congestive heart failure or after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinases activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention aimed at the modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. Recent findings suggest that MMPs are also involved in cancer initiation, invasion and metastasis; MMP inhibitors could be considered for evaluation as cancer chemopreventive molecules. This review describes the members of MMP and TIMP families and discusses the structure, function and regulation of MMP activity. (Tab. 1, Ref: 45.)

Changes in Physiological Parameters Induced by Indoor Simulated Driving: Effect of Lower Body Exercise at Mid-Term Break

PubMed Central

Liang, Wen Chieh; Yuan, John; Sun, Deh Chuan; Lin, Ming Han

2009-01-01

The study monitored physiological parameter changes after 120-min of simulated driving. Blood pressures, heart rate (HR), heart rate variability (HRV) and palm temperatures were measured using an ANSWatch® monitor. Subjects were divided into two groups (A & B). Both groups performed 2-hour driving, but group B additionally took a 15-min exercise break. Heart rate, systolic pressure, LF/HF, and palm temperature decreased for group A after driving; for group B only HR and palm temperatures decreased. HRV and parasympathetic indices HF(AU) and HF(NU) increased for group A, while HRV and sympathetic index LF(AU) increased in group B. Group A had higher fatigue scores than group B. ANS activation may overcome some fatigue symptoms, but the recovery is nonetheless incomplete. Exercise break is proven to be an effective remedy, especially if accompanied by the ANS actions. The normalized parasympathetic index HF(NU), the normalized sympathetic index LF(NU), and the sympatho-vagal balance index LF/HF are three most promising parameters that could be further developed to monitor driver fatigue. PMID:22399979

Effectiveness of the Flipped Classroom Model in Anatomy and Physiology Laboratory Courses at a Hispanic Serving Institution

NASA Astrophysics Data System (ADS)

Sanchez, Gerardo

A flipped laboratory model involves significant preparation by the students on lab material prior to entry to the laboratory. This allows laboratory time to be focused on active learning through experiments. The aim of this study was to observe changes in student performance through the transition from a traditional laboratory format, to a flipped format. The data showed that for both Anatomy and Physiology (I and II) laboratories a more normal distribution of grades was observed once labs were flipped and lecture grade averages increased. Chi square and analysis of variance tests showed grade changes to a statistically significant degree, with a p value of less than 0.05 on both analyses. Regression analyses gave decreasing numbers after the flipped labs were introduced with an r. 2 value of .485 for A&P I, and .564 for A&P II. Results indicate improved scores for the lecture part of the A&P course, decreased outlying scores above 100, and all score distributions approached a more normal distribution.

Stress and physiological, behavioral and performance patterns of children under varied air ion levels

NASA Astrophysics Data System (ADS)

Fornof, K. T.; Gilbert, G. O.

1988-12-01

The possibility that individual differences in reactivity to stressors are a major factor underlying discordant results reported for air ion studies prompted an investigation of response patterns in school children under both normal indoor air ion levels and moderately increased negative air ion levels (4000±500/cm3). It was hypothesized that the impact of stressors is reduced with high negative air ionization, and that resultant changes in stress effects would be differentially exhibited according to the children's normal degree of stimulus reactivity. A counter-balanced, replicative, withinssubject design was selected, and the subjects were 12 environmentally sensitive, 1st 4th grade school children. In addition to monitoring stress effects on activity level, attention span, concentration to task and conceptual performance, measures were also made of urinary 5-hydroxyindole acetic acid levels and skin resistance response (SRR) to determine if changes extended to the physiological state. The cold water test was used to add physical stress and enable calculations of Lacey's autonomic lability scores (ALS) as indicators of individual reactivity. The results show main effects for air ions on both physiological parameters, with 48% less change in %SRR ( P<0.01) and 46% less change in urinary 5-HIAA levels ( P<0.055) during negative air ions, indicating increased stress tolerance. Strong interactive effects for ALS x air ion condition appeared, with high and low ALS children reacting oppositely to negative air ions in measures of skin resistance level ( P<0.01), wrist activity ( P<0.01) and digit span backwards ( P<0.004). Thus individual differences in autonomic reactivity and the presence or absence of stressors appear as critical elements for internal validity, and in preventing consequent skewed results from obscuring progress in air ion research.

Heat shock modulates the subcellular localization, stability, and activity of HIPK2

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

Upadhyay, Mamta; Bhadauriya, Pratibha; Ganesh, Subramaniam, E-mail: sganesh@iitk.ac.in

2016-04-15

The homeodomain-interacting protein kinase-2 (HIPK2) is a highly conserved serine/threonine kinase and is involved in transcriptional regulation. HIPK2 is a highly unstable protein, and is kept at a low level under normal physiological conditions. However, exposure of cells to physiological stress – such as hypoxia, oxidative stress, or UV damage – is known to stabilize HIPK2, leading to the HIPK2-dependent activation of p53 and the cell death pathway. Therefore HIPK2 is also known as a stress kinase and as a stress-activated pro-apoptotic factor. We demonstrate here that exposure of cells to heat shock results in the stabilization of HIPK2 andmore » the stabilization is mediated via K63-linked ubiquitination. Intriguingly, a sub-lethal heat shock (42 °C, 1 h) results in the cytoplasmic localization of HIPK2, while a lethal heat shock (45 °C, 1 h) results in its nuclear localization. Cells exposed to the lethal heat shock showed significantly higher levels of the p53 activity than those exposed to the sub-lethal thermal stress, suggesting that both the level and the nuclear localization are essential for the pro-apoptotic activity of HIPK2 and that the lethal heat shock could retain the HIPK2 in the nucleus to promote the cell death. Taken together our study underscores the importance of HIPK2 in stress mediated cell death, and that the HIPK2 is a generic stress kinase that gets activated by diverse set of physiological stressors.« less

A Physiologically Based Model of Orexinergic Stabilization of Sleep and Wake

PubMed Central

Fulcher, Ben D.; Phillips, Andrew J. K.; Postnova, Svetlana; Robinson, Peter A.

2014-01-01

The orexinergic neurons of the lateral hypothalamus (Orx) are essential for regulating sleep-wake dynamics, and their loss causes narcolepsy, a disorder characterized by severe instability of sleep and wake states. However, the mechanisms through which Orx stabilize sleep and wake are not well understood. In this work, an explanation of the stabilizing effects of Orx is presented using a quantitative model of important physiological connections between Orx and the sleep-wake switch. In addition to Orx and the sleep-wake switch, which is composed of mutually inhibitory wake-active monoaminergic neurons in brainstem and hypothalamus (MA) and the sleep-active ventrolateral preoptic neurons of the hypothalamus (VLPO), the model also includes the circadian and homeostatic sleep drives. It is shown that Orx stabilizes prolonged waking episodes via its excitatory input to MA and by relaying a circadian input to MA, thus sustaining MA firing activity during the circadian day. During sleep, both Orx and MA are inhibited by the VLPO, and the subsequent reduction in Orx input to the MA indirectly stabilizes sustained sleep episodes. Simulating a loss of Orx, the model produces dynamics resembling narcolepsy, including frequent transitions between states, reduced waking arousal levels, and a normal daily amount of total sleep. The model predicts a change in sleep timing with differences in orexin levels, with higher orexin levels delaying the normal sleep episode, suggesting that individual differences in Orx signaling may contribute to chronotype. Dynamics resembling sleep inertia also emerge from the model as a gradual sleep-to-wake transition on a timescale that varies with that of Orx dynamics. The quantitative, physiologically based model developed in this work thus provides a new explanation of how Orx stabilizes prolonged episodes of sleep and wake, and makes a range of experimentally testable predictions, including a role for Orx in chronotype and sleep inertia. PMID:24651580

Abnormal pulmonary function in adults with sickle cell anemia.

PubMed

Klings, Elizabeth S; Wyszynski, Diego F; Nolan, Vikki G; Steinberg, Martin H

2006-06-01

Pulmonary complications of sickle cell anemia (Hb-SS) commonly cause morbidity, yet few large studies of pulmonary function tests (PFTs) in this population have been reported. PFTs (spirometry, lung volumes, and diffusion capacity for carbon monoxide [DLCO]) from 310 adults with Hb-SS were analyzed to determine the pattern of pulmonary dysfunction and their association with other systemic complications of sickle cell disease. Raw PFT data were compared with predicted values. Each subject was subclassified into one of five groups: obstructive physiology, restrictive physiology, mixed obstructive/restrictive physiology, isolated low DLCO, or normal. The association between laboratory data of patients with decreased DLCO or restrictive physiology and those of normal subjects was assessed by multivariate linear regression. Normal PFTs were present in only 31 of 310 (10%) patients. Overall, adults with Hb-SS were characterized by decreased total lung capacities (70.2 +/- 14.7% predicted) and DLCO (64.5 +/- 19.9%). The most common PFT patterns were restrictive physiology (74%) and isolated low DLCO (13%). Decreased DLCO was associated with thrombocytosis (p = 0.05), with hepatic dysfunction (elevated alanine aminotransferase; p = 0.07), and a trend toward renal dysfunction (elevated blood urea nitrogen and creatinine; p = 0.05 and 0.07, respectively). Pulmonary function is abnormal in 90% of adult patients with Hb-SS. Common abnormalities include restrictive physiology and decreased DLCO. Decreased DLCO may indicate more severe sickle vasculopathy characterized by impaired hepatic and renal function.

Sex-comparative study of mouse cerebellum physiology under adult-onset hypothyroidism: The significance of GC-MS metabolomic data normalization in meta-analysis.

PubMed

Maga-Nteve, Christoniki; Vasilopoulou, Catherine G; Constantinou, Caterina; Margarity, Marigoula; Klapa, Maria I

2017-01-15

A systematic data quality validation and normalization strategy is an important component of the omic profile meta-analysis, ensuring comparability of the profiles and exclusion of experimental biases from the derived biological conclusions. In this study, we present the normalization methodology applied on the sets of cerebellum gas chromatography-mass spectrometry metabolic profiles of 124days old male and female animals in an adult-onset-hypothyroidism (AOH) mouse model before combining them into a sex-comparative analysis. The employed AOH model concerns the monitoring of the brain physiology of Balb/cJ mice after eight-week administration of 1%w/v KClO 4 in the drinking water, initiated on the 60th day of their life. While originating from the same animal study, the tissues of the two sexes were processed and their profiles acquired and analyzed at different time periods. Hence, the previously published profile set of male mice was first re-annotated based on the presently available resources. Then, after being validated as acquired under the same analytical conditions, both profiles sets were corrected for derivatization biases and filtered for low-confidence measurements based on the same criteria. The final normalized 73-metabolite profiles contribute to the currently few available omic datasets of the AOH effect on brain molecular physiology, especially with respect to sex differentiation. Multivariate statistical analysis indicated one (unknown) and three (succinate, benzoate, myristate) metabolites with significantly higher and lower, respectively, cerebellum concentration in the hypothyroid compared to the euthyroid female mice. The respective numbers for the males were two and 24. Comparison of the euthyroid cerebellum metabolic profiles between the two sexes indicated 36 metabolites, including glucose, myo- and scyllo-inositol, with significantly lower concentration in the females versus the males. This implies that the female mouse cerebellum has been conditioned to smaller changes in its metabolic activity with respect to the pathways involving these metabolites compared to the male animals. In conclusion, our study indicated a much subtler AOH effect on the cerebellum metabolic activity of the female compared to the male mice. The leaner metabolic profile of the female mouse cerebellum was suggested as a potential factor contributing to this phenomenon. Copyright © 2016 Elsevier B.V. All rights reserved.

Dietary sodium influences the effect of mental stress on heart rate variability: a randomized trial in healthy adults.

PubMed

Allen, Alexander R; Gullixson, Leah R; Wolhart, Sarah C; Kost, Susan L; Schroeder, Darrell R; Eisenach, John H

2014-02-01

Dietary sodium influences intermediate physiological traits in healthy adults independent of changes in blood pressure. The purpose of this study was to test the hypothesis that dietary sodium affects cardiac autonomic modulation during mental stress. In a prospective, randomized cross-over design separated by 1 month between diets, 70 normotensive healthy young adults (F/M: 44/26, aged 18-38 years) consumed a 5-day low (10 mmol/day), normal (150 mmol), and high (400 mmol) sodium diet followed by heart rate variability (HRV) recordings at rest and during 5-min computerized mental arithmetic. Women were studied in the low hormone phase of the menstrual cycle following each diet. Diet did not affect resting blood pressure, but heart rate (HR) (mean ± SE) was 66 ± 1, 64 ± 1, and 63 ± 1 bpm in low, normal, and high sodium conditions, respectively (analysis of variance P = 0.02). For HRV, there was a main effect of sodium on resting SD of normalized RR intervals (SDNN), square root of the mean squared difference of successive normalized RR intervals (RMSSD), high frequency, low-frequency normalized units (LFnu), and high-frequency normalized units (HFnu) (P < 0.01 for all). The response to low sodium was most marked and consistent with sympathetic activation and reduced vagal activity, with increased LFnu and decreased SDNN, RMSSD, and HFnu compared to both normal and high sodium conditions (P ≤0.05 for all). Dietary sodium-by-mental stress interactions were significant for mean NN, RMSSD, high-frequency power, LFnu, and low frequency/high frequency ratio (P < 0.05 for all). The interactions signify that sodium restriction evoked an increase in resting sympathetic activity and reduced vagal activity to the extent that mental stress caused modest additional disruptions in autonomic balance. Conversely, normal and high sodium evoked a reduction in resting sympathetic activity and incremental increase in resting vagal activity, which were disrupted to a greater extent during mental stress compared to low sodium. We conclude that autonomic control of HRV at rest and during mental stress is altered by dietary sodium in healthy normotensive young adult men and women.

Divergent effects of postmortem ambient temperature on organophosphorus- and carbamate-inhibited brain cholinesterase activity in birds

USGS Publications Warehouse

Hill, E.F.

1989-01-01

Time- and temperature-dependent postmortem changes in inhibited brain cholinesterase (ChE) activity may confound diagnosis of field poisoning of wildlife by anticholinesterase pesticide. Carbamate-inhibited ChE activity may return to normal within 1 to 2 days of exposure of intact carcass to moderate ambient temperature (18-32C). Organophosphorus-inhibited ChE activity becomes more depressed over the same time. Uninhibited ChE activity was resilient to above freezing temperature to 32C for 1 day and 25C for 3 days. Carbamate- and organophosphorus-inhibited ChE can be separated by incubation of homogenate for 1 hour at physiological temperatures; carbamylated ChE can be readily reactivated while phosphorylated ChE cannot.

Aberrant activation of the human sex-determining gene in early embryonic development results in postnatal growth retardation and lethality in mice.

PubMed

Kido, Tatsuo; Sun, Zhaoyu; Lau, Yun-Fai Chris

2017-06-23

Sexual dimorphisms are prevalent in development, physiology and diseases in humans. Currently, the contributions of the genes on the male-specific region of the Y chromosome (MSY) in these processes are uncertain. Using a transgene activation system, the human sex-determining gene hSRY is activated in the single-cell embryos of the mouse. Pups with hSRY activated (hSRY ON ) are born of similar sizes as those of non-activated controls. However, they retard significantly in postnatal growth and development and all die of multi-organ failure before two weeks of age. Pathological and molecular analyses indicate that hSRY ON pups lack innate suckling activities, and develop fatty liver disease, arrested alveologenesis in the lung, impaired neurogenesis in the brain and occasional myocardial fibrosis and minimized thymus development. Transcriptome analysis shows that, in addition to those unique to the respective organs, various cell growth and survival pathways and functions are differentially affected in the transgenic mice. These observations suggest that ectopic activation of a Y-located SRY gene could exert male-specific effects in development and physiology of multiple organs, thereby contributing to sexual dimorphisms in normal biological functions and disease processes in affected individuals.

Hemodynamic Functions of Fenestrated Stent Graft under Resting, Hypertension, and Exercise Conditions

PubMed Central

Kandail, Harkamaljot Singh; Hamady, Mohamad; Xu, Xiao Yun

2016-01-01

The aim of this study was to assess the hemodynamic performance of a patient-specific fenestrated stent graft (FSG) under different physiological conditions, including normal resting, hypertension, and hypertension with moderate lower limb exercise. A patient-specific FSG model was constructed from computed tomography images and was discretized into a fine unstructured mesh comprising tetrahedral and prism elements. Blood flow was simulated using Navier–Stokes equations, and physiologically realistic boundary conditions were utilized to yield clinically relevant results. For a given cycle-averaged inflow of 2.08 L/min at normal resting and hypertension conditions, approximately 25% of flow was channeled into each renal artery. When hypertension was combined with exercise, the cycle-averaged inflow increased to 6.39 L/min but only 6.29% of this was channeled into each renal artery, which led to a 438.46% increase in the iliac flow. For all the simulated scenarios and throughout the cardiac cycle, the instantaneous flow streamlines in the FSG were well organized without any notable flow recirculation. This well-organized flow led to low values of endothelial cell activation potential, which is a hemodynamic metric used to identify regions at risk of thrombosis. The displacement forces acting on the FSG varied with the physiological conditions, and the cycle-averaged displacement force at normal rest, hypertension, and hypertension with exercise was 6.46, 8.77, and 8.99 N, respectively. The numerical results from this study suggest that the analyzed FSG can maintain sufficient blood perfusion to the end organs at all the simulated conditions. Even though the FSG was found to have a low risk of thrombosis at rest and hypertension, this risk can be reduced even further with moderate lower limb exercise. PMID:27379242

Autonomic nervous system profile in fibromyalgia patients and its modulation by exercise: a mini review.

PubMed

Kulshreshtha, Poorvi; Deepak, Kishore K

2013-03-01

This review imparts an impressionistic tone to our current understanding of autonomic nervous system abnormalities in fibromyalgia. In the wake of symptoms present in patients with fibromyalgia (FM), autonomic dysfunction seems plausible in fibromyalgia. A popular notion is that of a relentless sympathetic hyperactivity and hyporeactivity based on heart rate variability (HRV) analyses and responses to various physiological stimuli. However, some exactly opposite findings suggesting normal/hypersympathetic reactivity in patients with fibromyalgia do exist. This heterogeneous picture along with multiple comorbidities accounts for the quantitative and qualitative differences in the degree of dysautonomia present in patients with FM. We contend that HRV changes in fibromyalgia may not actually represent increased cardiac sympathetic tone. Normal muscle sympathetic nerve activity (MSNA) and normal autonomic reactivity tests in patients with fibromyalgia suggest defective vascular end organ in fibromyalgia. Previously, we proposed a model linking deconditioning with physical inactivity resulting from widespread pain in patients with fibromyalgia. Deconditioning also modulates the autonomic nervous system (high sympathetic tone and a low parasympathetic tone). A high peripheral sympathetic tone causes regional ischaemia, which in turn results in widespread pain. Thus, vascular dysregulation and hypoperfusion in patients with FM give rise to ischaemic pain leading to physical inactivity. Microvascular abnormalities are also found in patients with FM. Therapeutic interventions (e.g. exercise) that result in vasodilatation and favourable autonomic alterations have proven to be effective. In this review, we focus on the vascular end organ in patients with fibromyalgia in particular and its modulation by exercise in general. © 2012 The Authors Clinical Physiology and Functional Imaging © 2012 Scandinavian Society of Clinical Physiology and Nuclear Medicine.

Luminal glucose concentrations in the gut under normal conditions.

PubMed

Ferraris, R P; Yasharpour, S; Lloyd, K C; Mirzayan, R; Diamond, J M

1990-11-01

Luminal glucose (Glc) concentrations in the small intestine (SI) are widely assumed to be 50-500 mM. These values have posed problems for interpreting SI luminal osmolality and absorptive capacity, Glc transporter Michaelis-Menten constants (Km), and the physiological role of active Glc transport and its regulation. Hence we measured luminal contents, osmolality, and Glc, Na+, and K+ concentrations in normally feeding rats, rabbits, and dogs. Measured Glc concentrations were compatible with the portion of measured osmolality not accounted for by Na+ and K+ salts, amino acids, and peptides. Mean SI luminal osmolalities were less than or equal to 100 mosmol/kg hypertonic. For animals on the most nearly physiological diets, SI Glc concentrations averaged 0.4-24 mM and ranged with time and SI region from 0.2 to a maximum of 48 mM. The older published very high values are artifacts of direct infusion of concentrated Glc solutions into the gut, nonspecific Glc assays, and failure to test for quantitative recovery or to centrifuge samples in the cold. By storing food after meals and releasing it between meals, rat stomach greatly damps diurnal fluctuations in quantity and osmolality of food reaching the SI and hence also damps fluctuations in absorption rates. These new values for luminal Glc have five important physiological implications: the problem of accounting for apparently very hypertonic SI contents in the face of high osmotic water permeability disappears; the effective Km of the SI Glc transporter is now comparable to prevailing Glc concentrations; the SI no longer appears to have enormous excess absorptive capacity for Glc; regulation of Glc transport by dietary intake now makes functional sense; and the claim that high luminal Glc concentrations permit solvent drag to become the major mode of Glc absorption under normal conditions is undermined.

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology.

PubMed

Suchyna, Thomas M

2017-11-01

Discovery of Piezo channels and the reporting of their sensitivity to the inhibitor GsMTx4 were important milestones in the study of non-selective cationic mechanosensitive channels (MSCs) in normal physiology and pathogenesis. GsMTx4 had been used for years to investigate the functional role of cationic MSCs, especially in muscle tissue, but with little understanding of its target or inhibitory mechanism. The sensitivity of Piezo channels to bilayer stress and its robust mechanosensitivity when expressed in heterologous systems were keys to determining GsMTx4's mechanism of action. However, questions remain regarding Piezo's role in muscle function due to the non-selective nature of GsMTx4 inhibition toward membrane mechanoenzymes and the implication of MCS channel types by genetic knockdown. Evidence supporting Piezo like activity, at least in the developmental stages of muscle, is presented. While the MSC targets of GsMTx4 in muscle pathology are unclear, its muscle protective effects are clearly demonstrated in two recent in situ studies on normal cardiomyocytes and dystrophic skeletal muscle. The muscle protective function may be due to the combined effect of GsMTx4's inhibitory action on cationic MSCs like Piezo and TRP, and its potentiation of repolarizing K + selective MSCs like K2P and SAKCa. Paradoxically, the potent in vitro action of GsMTx4 on many physiological functions seems to conflict with its lack of in situ side-effects on normal animal physiology. Future investigations into cytoskeletal control of sarcolemma mechanics and the suspected inclusion of MSCs in membrane micro/nano sized domains with distinct mechanical properties will aide our understanding of this dichotomy. Published by Elsevier Ltd.

The control of calcium metabolism by parathyroid hormone, calcitonin and vitamin D

NASA Technical Reports Server (NTRS)

Potts, J. T., Jr.

1976-01-01

Advances in analysis of chemistry and physiology of parathyroid hormone, calcitonin, and Vitamin D are described along with development of techniques in radioassay methods. Emphasis is placed on assessment of normal and abnormal patterns of secretion of these hormones in specific relation to the physiological adaptations of weightlessness and space flight. Related diseases that involve perturbations in normal skeletal and calcium homeostasis are also considered.

Inhibition of intracellular proteolysis in muscle cultures by multiplication-stimulating activity

NASA Technical Reports Server (NTRS)

Janeczko, Richard A.; Etlinger, Joseph D.

1984-01-01

The effects of the insulin-like growth factor, multiplication-stimulating activity (MSA), on chick myotube cultures are studied. The results indicate that MSA is an effective anabolic agent regulating protein metabolism and amino acid uptake, but not sugar transport. Similar size effects on protein metabolism and amino acid uptake in serum-free media were observed in parallel studies with insulin, although insulin levels well in excess of the normal physiological range are required to produce significant effects. It is suggested that there is a generally low insulin sensitivity in cultured chick myotubes relative to adult tissues.

Deregulated activation of oncoprotein kinase Tpl2/Cot in HTLV-I-transformed T cells.

PubMed

Babu, Geetha; Waterfield, Michael; Chang, Mikyoung; Wu, Xuefeng; Sun, Shao-Cong

2006-05-19

Protein kinase Tpl2/Cot is encoded by a protooncogene that is cis-activated by retroviral insertion in murine T cell lymphomas. It has remained unclear whether this oncoprotein kinase is mutated or post-translationally activated in human cancer cells. We have shown here that Tpl2/Cot is constitutively activated in human leukemia cell lines transformed by the human T cell leukemia virus type I (HTLV-I). The kinase activity of Tpl2/Cot is normally suppressed through its physical interaction with an inhibitor, the NF-kappaB1 precursor protein p105. Interestingly, a large pool of Tpl2/Cot is liberated from p105 and exhibits constitutive kinase activity in HTLV-I-transformed T cells. In contrast to its labile property in normal cells, the pathologically activated Tpl2/Cot is remarkably stable. Further, whereas the physiological activation of Tpl2/Cot involves its long isoform, the HTLV-activated Tpl2/Cot is predominantly the short isoform. We have also shown that the HTLV-I-encoded Tax protein is able to activate Tpl2/Cot in transfected cells. Finally, Tpl2/Cot participates in the activation of NF-kappaB by Tax. These findings indicate that deregulated activation of Tpl2/Cot may occur in human cancer cells.

Effect of environmental parameters on habitat structural weight and cost

NASA Technical Reports Server (NTRS)

Bock, E.; Lambrou, F., Jr.; Simon, M.

1979-01-01

Space-settlement conceptual designs were previously accomplished using earth-normal physiological conditions. The habitat weight and cost penalties associated with this conservative design approach are quantified. These penalties are identified by comparison of conservative earth-normal designs with habitats designed to less than earth-normal conditions. Physiological research areas are also recommended as a necessary prerequisite to realizing these potential weight and cost savings. Major habitat structural elements, that is, pressure shell and radiation shielding, for populations of 100, 10,000, and 1,000,000, are evaluated for effects of atmospheric pressure, pseudogravity level, radiation shielding thickness, and habitat configuration.

Neutropenia - infants

MedlinePlus

... Bliss JM, Mariscalco MM. Normal and abnormal neutrophil physiology in the newborn. In: Polin RA, Abman SH, ... Benitz WE, Fox WW, eds. Fetal and Neonatal Physiology . 5th ed. Philadelphia, PA: Elsevier; 2017:chap 126. ...

Orchestrating brain-cell renewal: the role of immune cells in adult neurogenesis in health and disease.

PubMed

Ziv, Yaniv; Schwartz, Michal

2008-11-01

Immune cells and immune molecules have recently been shown to support neurogenesis from neural stem and progenitor cells in the adult brain. This non-classical immune activity takes place constantly under normal physiological conditions and is extended under acute pathological conditions to include the attraction of progenitor cells and induction of neurogenesis in regions of the adult central nervous system (CNS) in which formation of new neurons does not normally occur. We suggest that the immune system should be viewed as a novel player in the adult neural stem cell niche and a coordinator of cell renewal processes after injury. We discuss these notions in light of the well-known facts that both immune-cell activity and cell renewal are inherently limited in the adult CNS and that immune and stem cells provide the body's mechanisms of repair.

Cannabinoid mitigation of neuronal morphological change important to development and learning: insight from a zebra finch model of psychopharmacology.

PubMed

Soderstrom, Ken; Gilbert, Marcoita T

2013-03-19

Normal CNS development proceeds through late-postnatal stages of adolescent development. The activity-dependence of this development underscores the significance of CNS-active drug exposure prior to completion of brain maturation. Exogenous modulation of signaling important in regulating normal development is of particular concern. This mini-review presents a summary of the accumulated behavioral, physiological and biochemical evidence supporting such a key regulatory role for endocannabinoid signaling during late-postnatal CNS development. Our focus is on the data obtained using a unique zebra finch model of developmental psychopharmacology. This animal has allowed investigation of neuronal morphological effects essential to establishment and maintenance of neural circuitry, including processes related to synaptogenesis and dendritic spine dynamics. Altered neurophysiology that follows exogenous cannabinoid exposure during adolescent development has the potential to persistently alter cognition, learning and memory. Copyright © 2012 Elsevier Inc. All rights reserved.

IGFBP-4 and PAPP-A in normal physiology and disease.

PubMed

Hjortebjerg, Rikke

2018-05-30

Insulin-like growth factor (IGF) binding protein-4 (IGFBP-4) is a modulator of the IGF system, exerting both inhibitory and stimulatory effects on IGF-induced cellular growth. IGFBP-4 is the principal substrate for the enzyme pregnancy-associated plasma protein-A (PAPP-A). Through IGF-dependent cleavage of IGFBP-4 in the vicinity of the IGF receptor, PAPP-A is able to increase IGF bioavailability and stimulate IGF-mediated growth. Recently, the stanniocalcins (STCs) were identified as novel inhibitors of PAPP-A proteolytic activity, hereby adding additional members to the seemingly endless list of proteins belonging to the IGF family. Our understanding of these proteins has advanced throughout recent years, and there is evidence to suggest that the role of IGFBP-4 and PAPP-A in defining the relationship between total IGF and IGF bioactivity can be linked to a number of pathological conditions. This review provides an overview of the experimental and clinical findings on the IGFBP-4/PAPP-A/STC axis as a regulator of IGF activity and examines the conundrum surrounding extrapolation of circulating concentrations to tissue action of these proteins. The primary focus will be on the biological significance of IGFBP-4 and PAPP-A in normal physiology and in pathophysiology with emphasis on metabolic disorders, cardiovascular diseases, and cancer. Finally, the review assesses current new trajectories of IGFBP-4 and PAPP-A research. Copyright © 2018. Published by Elsevier Ltd.

Physiology of ejaculation: emphasis on serotonergic control.

PubMed

Giuliano, François; Clément, Pierre

2005-09-01

Ejaculation is constituted by two distinct phases, emission and expulsion. Orgasm, a feature perhaps unique in humans, is a cerebral process that occurs, in normal conditions, concomitantly to expulsion of semen. Normal antegrade ejaculation is a highly coordinated physiological process with emission and expulsion phases being under the control of autonomic and somatic nervous systems respectively. The central command of ejaculation is located at the thoracolumbar and lumbosacral levels of the spinal cord and is activated by stimuli from genital, mainly penile, origin although cerebral descending pathways exert both inhibitory and excitatory regulatory roles. Cerebral structures specifically activated during ejaculation form a tightly interconnected network comprising hypothalamic, diencephalic and pontine areas. A rational neurobiological approach has led to identify several neurotransmitters contributing to the ejaculatory process. Amongst them, serotonin (5-HT) has received strong experimental evidences indicating its inhibitory role in the central control of ejaculation. In particular, 5-HT1A cerebral autoreceptors but also spinal 5-HT1B and, in a lesser extent, 5-HT2C receptors have been shown to mediate the effects of 5-HT on ejaculation. Pharmacological strategies, especially those targeting serotonergic system, for the treatment of ejaculatory disorders in human will undoubtedly benefit from the application of basic and clinical research findings. In this perspective, the use of selective serotonin reuptake inhibitors (SSRIs) which basically increase the amount of central 5-HT and delay ejaculation in humans seems promising.

Physiologic correlates to background noise acceptance

NASA Astrophysics Data System (ADS)

Tampas, Joanna; Harkrider, Ashley; Nabelek, Anna

2004-05-01

Acceptance of background noise can be evaluated by having listeners indicate the highest background noise level (BNL) they are willing to accept while following the words of a story presented at their most comfortable listening level (MCL). The difference between the selected MCL and BNL is termed the acceptable noise level (ANL). One of the consistent findings in previous studies of ANL is large intersubject variability in acceptance of background noise. This variability is not related to age, gender, hearing sensitivity, personality, type of background noise, or speech perception in noise performance. The purpose of the current experiment was to determine if individual differences in physiological activity measured from the peripheral and central auditory systems of young female adults with normal hearing can account for the variability observed in ANL. Correlations between ANL and various physiological responses, including spontaneous, click-evoked, and distortion-product otoacoustic emissions, auditory brainstem and middle latency evoked potentials, and electroencephalography will be presented. Results may increase understanding of the regions of the auditory system that contribute to individual noise acceptance.

Interictal epileptiform discharges induce hippocampal-cortical coupling in temporal lobe epilepsy

PubMed Central

Gelinas, Jennifer N.; Khodagholy, Dion; Thesen, Thomas; Devinsky, Orrin; Buzsáki, György

2016-01-01

Interactions between the hippocampus and cortex are critical for memory. Interictal epileptiform discharges (IEDs) identify epileptic brain regions and can impair memory, but how they interact with physiological patterns of network activity is mostly undefined. We show in a rat model of temporal lobe epilepsy that spontaneous hippocampal IEDs correlate with impaired memory consolidation and are precisely coordinated with spindle oscillations in the prefrontal cortex during NREM sleep. This coordination surpasses the normal physiological ripple-spindle coupling and is accompanied by decreased ripple occurrence. IEDs also induce spindles during REM sleep and wakefulness, behavioral states that do not naturally express these oscillations, by generating a cortical ‘DOWN’ state. We confirm a similar correlation of temporofrontal IEDs with spindles over anatomically restricted cortical regions in a pilot clinical examination of four subjects with focal epilepsy. These findings imply that IEDs may impair memory via misappropriation of physiological mechanisms for hippocampal-cortical coupling, suggesting a target to treat memory impairment in epilepsy. PMID:27111281

Constitutive properties of adult mammalian cardiac muscle cells

NASA Technical Reports Server (NTRS)

Zile, M. R.; Richardson, K.; Cowles, M. K.; Buckley, J. M.; Koide, M.; Cowles, B. A.; Gharpuray, V.; Cooper, G. 4th

1998-01-01

BACKGROUND: The purpose of this study was to determine whether changes in the constitutive properties of the cardiac muscle cell play a causative role in the development of diastolic dysfunction. METHODS AND RESULTS: Cardiocytes from normal and pressure-hypertrophied cats were embedded in an agarose gel, placed on a stretching device, and subjected to a change in stress (sigma), and resultant changes in cell strain (epsilon) were measured. These measurements were used to examine the passive elastic spring, viscous damping, and myofilament activation. The passive elastic spring was assessed in protocol A by increasing the sigma on the agarose gel at a constant rate to define the cardiocyte sigma-versus-epsilon relationship. Viscous damping was assessed in protocol B from the loop area between the cardiocyte sigma-versus-epsilon relationship during an increase and then a decrease in sigma. In both protocols, myofilament activation was minimized by a reduction in [Ca2+]i. Myofilament activation effects were assessed in protocol C by defining cardiocyte sigma versus epsilon during an increase in sigma with physiological [Ca2+]i. In protocol A, the cardiocyte sigma-versus-epsilon relationship was similar in normal and hypertrophied cells. In protocol B, the loop area was greater in hypertrophied than normal cardiocytes. In protocol C, the sigma-versus-epsilon relation in hypertrophied cardiocytes was shifted to the left compared with normal cells. CONCLUSIONS: Changes in viscous damping and myofilament activation in combination may cause pressure-hypertrophied cardiocytes to resist changes in shape during diastole and contribute to diastolic dysfunction.

Cortisol as a Biomarker of Stress in Term Human Labor: Physiological and Methodological Issues

PubMed Central

Newton, Edward R.; Tanner, Charles J.; Heitkemper, Margaret M.

2013-01-01

Literature on the use of plasma cortisol to quantify psychophysiological stress in humans is extensive. However, in parturition at term gestation the use of cortisol as a biomarker of stress is particularly complex. Plasma cortisol levels increase as labor progresses. This increase seems to be important for maintenance of maternal/fetal wellbeing and facilitation of normal labor progress. Unique physiological and methodological issues involved in the use of cortisol as a biomarker of stress in labor present challenges for researchers. This review examines these issues, suggests mixed methods and within-subject repeated measures designs, and offers recommendations for assay procedures for parturient sampling. Documentation of clinical interventions and delivery outcomes may elucidate relationships among psychophysiological stressors, cortisol and normal labor progress. With attention to these methodological issues, analysis of plasma cortisol may lead to clinical interventions that support normal labor physiology. PMID:23338011

Consequences of inhibiting amyloid precursor protein processing enzymes on synaptic function and plasticity.

PubMed

Wang, Hui; Megill, Andrea; He, Kaiwen; Kirkwood, Alfredo; Lee, Hey-Kyoung

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregated β-amyloid (Aβ) peptides. It is now recognized that soluble Aβ oligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. Aβ is produced by a sequential cleavage of amyloid precursor protein (APP) by the activity of β- and γ-secretases, which have been identified as major candidate therapeutic targets of AD. This paper focuses on how Aβ alters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for Aβ generation. Abnormalities in synaptic function resulting from the absence or inhibition of the Aβ-producing enzymes suggest that Aβ itself may have normal physiological functions which are disrupted by abnormal accumulation of Aβ during AD pathology. This interpretation suggests that AD therapeutics targeting the β- and γ-secretases should be developed to restore normal levels of Aβ or combined with measures to circumvent the associated synaptic dysfunction(s) in order to have minimal impact on normal synaptic function.

Dynamical complexity detection in geomagnetic activity indices using wavelet transforms and Tsallis entropy

NASA Astrophysics Data System (ADS)

Balasis, G.; Daglis, I. A.; Papadimitriou, C.; Kalimeri, M.; Anastasiadis, A.; Eftaxias, K.

2008-12-01

Dynamical complexity detection for output time series of complex systems is one of the foremost problems in physics, biology, engineering, and economic sciences. Especially in magnetospheric physics, accurate detection of the dissimilarity between normal and abnormal states (e.g. pre-storm activity and magnetic storms) can vastly improve space weather diagnosis and, consequently, the mitigation of space weather hazards. Herein, we examine the fractal spectral properties of the Dst data using a wavelet analysis technique. We show that distinct changes in associated scaling parameters occur (i.e., transition from anti- persistent to persistent behavior) as an intense magnetic storm approaches. We then analyze Dst time series by introducing the non-extensive Tsallis entropy, Sq, as an appropriate complexity measure. The Tsallis entropy sensitively shows the complexity dissimilarity among different "physiological" (normal) and "pathological" states (intense magnetic storms). The Tsallis entropy implies the emergence of two distinct patterns: (i) a pattern associated with the intense magnetic storms, which is characterized by a higher degree of organization, and (ii) a pattern associated with normal periods, which is characterized by a lower degree of organization.

[Acute and remote biochemical and physiological effects of exhaustive weightlifting exercise].

PubMed

Minigalin, A D; Shumakov, A R; Baranova, T I; Danilova, M A; Kalinskiĭ, M I; Morozov, V I

2011-01-01

The goal of the work was a study of exhaustive weightlifting exercise effect on prolonged changes in physiological and biochemical variables characterized functional status of skeletal muscles. An exercise gave rise to significant blood lactate concentration increase that was indicative of an anaerobic metabolism to be a predominant mechanism of muscle contraction energy supply. A reduction of m. rectus femoris EMG activity (amplitude and frequency), tonus of tension and an increase in tonus of relaxation were found immediately after exercise. Both EMG amplitude and frequency were increased 1 day post-exercise. However, after 3 days of recovery, EMG amplitude and frequency were decreased again and, in parallel, blood serum creatine kinase (CK) activity was significantly increased. After 9 recovery days, all measured variables with the exception of CK were normalized. A significant reverse correlation was found between blood serum lactate concentration and m. rectus femoris EMG activity at the same time points. Blood serum CK activity and m. rectus femoris EMG and tonus variables were observed to be significantly reversely correlated on the 3rd post-exercise day. Presented data demonstrate that exhaustive exercise-induced muscle injury resulted in phase alterations in electrical activity and tonus which correlated with lactate concentration and CK activity in blood serum.

Multiplexed profiling of GPCR activities by combining split TEV assays and EXT-based barcoded readouts.

PubMed

Galinski, Sabrina; Wichert, Sven P; Rossner, Moritz J; Wehr, Michael C

2018-05-25

G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors and are implicated in the physiological regulation of many biological processes. The high diversity of GPCRs and their physiological functions make them primary targets for therapeutic drugs. For the generation of novel compounds, however, selectivity towards a given target is a critical issue in drug development as structural similarities between members of GPCR subfamilies exist. Therefore, the activities of multiple GPCRs that are both closely and distantly related to assess compound selectivity need to be tested simultaneously. Here, we present a cell-based multiplexed GPCR activity assay, termed GPCRprofiler, which uses a β-arrestin recruitment strategy and combines split TEV protein-protein interaction and EXT-based barcode technologies. This approach enables simultaneous measurements of receptor activities of multiple GPCR-ligand combinations by applying massively parallelized reporter assays. In proof-of-principle experiments covering 19 different GPCRs, both the specificity of endogenous agonists and the polypharmacological effects of two known antipsychotics on GPCR activities were demonstrated. Technically, normalization of barcode reporters across individual assays allows quantitative pharmacological assays in a parallelized manner. In summary, the GPCRprofiler technique constitutes a flexible and scalable approach, which enables simultaneous profiling of compound actions on multiple receptor activities in living cells.

Protective role of Parkin in skeletal muscle contractile and mitochondrial function.

PubMed

Gouspillou, Gilles; Godin, Richard; Piquereau, Jérome; Picard, Martin; Mofarrahi, Mahroo; Mathew, Jasmin; Purves-Smith, Fennigje M; Sgarioto, Nicolas; Hepple, Russell T; Burelle, Yan; Hussain, Sabah N A

2018-04-22

Parkin, an E3 ubiquitin ligase encoded by the Park2 gene, has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are degraded. The exact physiological significance of Parkin in regulating mitochondrial function and contractility in skeletal muscle remains largely unexplored. Using Park2 -/- mice, we show that Parkin ablation causes a decrease in muscle specific force, a severe decrease in mitochondrial respiration, mitochondrial uncoupling and an increased susceptibility to opening of the permeability transition pore. These results demonstrate that Parkin plays a protective role in the maintenance of normal mitochondrial and contractile functions in skeletal muscles. Parkin is an E3 ubiquitin ligase encoded by the Park2 gene. Parkin has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are sequestered in autophagosomes and delivered to lysosomes for degradation. Although Parkin has been mainly studied for its implication in neuronal degeneration in Parkinson disease, its role in other tissues remains largely unknown. In the present study, we investigated the skeletal muscles of Park2 knockout (Park2 -/- ) mice to test the hypothesis that Parkin plays a physiological role in mitochondrial quality control in normal skeletal muscle, a tissue highly reliant on mitochondrial content and function. We first show that the tibialis anterior (TA) of Park2 -/- mice display a slight but significant decrease in its specific force. Park2 -/ - muscles also show a trend for type IIB fibre hypertrophy without alteration in muscle fibre type proportion. Compared to Park2 +/+ muscles, the mitochondrial function of Park2 -/- skeletal muscles was significantly impaired, as indicated by the significant decrease in ADP-stimulated mitochondrial respiratory rates, uncoupling, reduced activities of respiratory chain complexes containing mitochondrial DNA (mtDNA)-encoded subunits and increased susceptibility to opening of the permeability transition pore. Muscles of Park2 -/- mice also displayed a decrease in the content of the mitochondrial pro-fusion protein Mfn2 and an increase in the pro-fission protein Drp1 suggesting an increase in mitochondrial fragmentation. Finally, Park2 ablation resulted in an increase in basal autophagic flux in skeletal muscles. Overall, the results of the present study demonstrate that Parkin plays a protective role in the maintenance of normal mitochondrial and contractile functions in normal skeletal muscles. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Physiological response of juvenile coho salmon (Oncorhynchus kisutch) and rainbow trout (Salmo gairdneri) to handling and crowding stress in intensive fish culture

USGS Publications Warehouse

Wedemeyer, Gary A.

1976-01-01

Moving 4–5-in. coho salmon (Oncorhynchus kisutch) held in soft (20 ppm CaCO3) water from the relatively light loading density of 0.5 lb/ft3 to 1, 2, or 4 lb/ft3 (density index, DI = 0.1, 0.2, 0.4, 0.8) caused significant stress as indicated by loss of feeding behavior, but only minimal physiological disturbances, as indicated by lack of hyperglycemia or hypochloremia. However, moving them to 6 or 12 lb/ft3 (DI = 1.2, 2.4) caused significant physiological stress which required at least a week for recovery. Smolting coho salmon were physiologically stressed by population densities of 1 lb/ft3 or more and a subclinical corynebacterial kidney infection was activated. Rainbow trout (Salmo gairdneri) (4–5 in.) were physiologically stressed when moved and held at 1 lb/ft3 or more but retained normal feeding behavior. This indicates that handling and crowding stress will be minimized in softwater areas if densities in fish distribution trucks or in ponds or raceways during disease treatments are held to 0.1–0.5 lb/gal.

Multiple Oxygen Tension Environments Reveal Diverse Patterns of Transcriptional Regulation in Primary Astrocytes

PubMed Central

Zhou, Yu; Wang, Liyun; Park, Sung-Soo; Martin, Bronwen; Wang, Rui; Becker, Kevin G.; Wood, William H.; Zhang, Yongqing; Peers, Chris; Maudsley, Stuart

2011-01-01

The central nervous system normally functions at O2 levels which would be regarded as hypoxic by most other tissues. However, most in vitro studies of neurons and astrocytes are conducted under hyperoxic conditions without consideration of O2-dependent cellular adaptation. We analyzed the reactivity of astrocytes to 1, 4 and 9% O2 tensions compared to the cell culture standard of 20% O2, to investigate their ability to sense and translate this O2 information to transcriptional activity. Variance of ambient O2 tension for rat astrocytes resulted in profound changes in ribosomal activity, cytoskeletal and energy-regulatory mechanisms and cytokine-related signaling. Clustering of transcriptional regulation patterns revealed four distinct response pattern groups that directionally pivoted around the 4% O2 tension, or demonstrated coherent ascending/decreasing gene expression patterns in response to diverse oxygen tensions. Immune response and cell cycle/cancer-related signaling pathway transcriptomic subsets were significantly activated with increasing hypoxia, whilst hemostatic and cardiovascular signaling mechanisms were attenuated with increasing hypoxia. Our data indicate that variant O2 tensions induce specific and physiologically-focused transcript regulation patterns that may underpin important physiological mechanisms that connect higher neurological activity to astrocytic function and ambient oxygen environments. These strongly defined patterns demonstrate a strong bias for physiological transcript programs to pivot around the 4% O2 tension, while uni-modal programs that do not, appear more related to pathological actions. The functional interaction of these transcriptional ‘programs’ may serve to regulate the dynamic vascular responsivity of the central nervous system during periods of stress or heightened activity. PMID:21738745

A role for the thermal environment in defining co-stimulation requirements for CD4+ T cell activation

PubMed Central

Zynda, Evan R; Grimm, Melissa J; Yuan, Min; Zhong, Lingwen; Mace, Thomas A; Capitano, Maegan; Ostberg, Julie R; Lee, Kelvin P; Pralle, Arnd; Repasky, Elizabeth A

2015-01-01

Maintenance of normal core body temperature is vigorously defended by long conserved, neurovascular homeostatic mechanisms that assist in heat dissipation during prolonged, heat generating exercise or exposure to warm environments. Moreover, during febrile episodes, body temperature can be significantly elevated for at least several hours at a time. Thus, as blood cells circulate throughout the body, physiologically relevant variations in surrounding tissue temperature can occur; moreover, shifts in core temperature occur during daily circadian cycles. This study has addressed the fundamental question of whether the threshold of stimulation needed to activate lymphocytes is influenced by temperature increases associated with physiologically relevant increases in temperature. We report that the need for co-stimulation of CD4+ T cells via CD28 ligation for the production of IL-2 is significantly reduced when cells are exposed to fever-range temperature. Moreover, even in the presence of sufficient CD28 ligation, provision of extra heat further increases IL-2 production. Additional in vivo and in vitro data (using both thermal and chemical modulation of membrane fluidity) support the hypothesis that the mechanism by which temperature modulates co-stimulation is linked to increases in membrane fluidity and membrane macromolecular clustering in the plasma membrane. Thermally-regulated changes in plasma membrane organization in response to physiological increases in temperature may assist in the geographical control of lymphocyte activation, i.e., stimulating activation in lymph nodes rather than in cooler surface regions, and further, may temporarily and reversibly enable CD4+ T cells to become more quickly and easily activated during times of infection during fever. PMID:26131730

Matrix Stiffness Corresponding to Strictured Bowel Induces a Fibrogenic Response in Human Colonic Fibroblasts

PubMed Central

Johnson, Laura A.; Rodansky, Eva S.; Sauder, Kay L.; Horowitz, Jeffrey C.; Mih, Justin D.; Tschumperlin, Daniel J.; Higgins, Peter D.

2013-01-01

Background Crohn’s disease is characterized by repeated cycles of inflammation and mucosal healing which ultimately progress to intestinal fibrosis. This inexorable progression towards fibrosis suggests that fibrosis becomes inflammation-independent and auto-propagative. We hypothesized that matrix stiffness regulates this auto-propagation of intestinal fibrosis. Methods The stiffness of fresh ex vivo samples from normal human small intestine, Crohn’s disease strictures, and the unaffected margin were measured with a microelastometer. Normal human colonic fibroblasts were cultured on physiologically normal or pathologically stiff matrices corresponding to the physiological stiffness of normal or fibrotic bowel. Cellular response was assayed for changes in cell morphology, α-smooth muscle actin (αSMA) staining, and gene expression. Results Microelastometer measurements revealed a significant increase in colonic tissue stiffness between normal human colon and Crohn’s strictures as well as between the stricture and adjacent tissue margin. In Ccd-18co cells grown on stiff matrices corresponding to Crohn’s strictures, cellular proliferation increased. Pathologic stiffness induced a marked change in cell morphology and increased αSMA protein expression. Growth on a stiff matrix induced fibrogenic gene expression, decreased matrix metalloproteinase and pro-inflammatory gene expression, and was associated with nuclear localization of the transcriptional cofactor MRTF-A. Conclusions Matrix stiffness, representative of the pathological stiffness of Crohn’s strictures, activates human colonic fibroblasts to a fibrogenic phenotype. Matrix stiffness affects multiple pathways suggesting the mechanical properties of the cellular environment are critical to fibroblast function and may contribute to autopropagation of intestinal fibrosis in the absence of inflammation, thereby contributing to the intractable intestinal fibrosis characteristic of Crohn’s disease. PMID:23502354

Traffic Lights in Trichodesmium. Regulation of Photosynthesis for Nitrogen Fixation Studied by Chlorophyll Fluorescence Kinetic Microscopy1

PubMed Central

Küpper, Hendrik; Ferimazova, Naila; Šetlík, Ivan; Berman-Frank, Ilana

2004-01-01

We investigated interactions between photosynthesis and nitrogen fixation in the non-heterocystous marine cyanobacterium Trichodesmium IMS101 at the single-cell level by two-dimensional (imaging) microscopic measurements of chlorophyll fluorescence kinetics. Nitrogen fixation was closely associated with the appearance of cells with high basic fluorescence yield (F0), termed bright cells. In cultures aerated with normal air, both nitrogen fixation and bright cells appeared in the middle of the light phase. In cultures aerated with 5% oxygen, both processes occurred at a low level throughout most of the day. Under 50% oxygen, nitrogen fixation commenced at the beginning of the light phase but declined soon afterwards. Rapid reversible switches between fluorescence levels were observed, which indicated that the elevated F0 of the bright cells originates from reversible uncoupling of the photosystem II (PSII) antenna from the PSII reaction center. Two physiologically distinct types of bright cells were observed. Type I had about double F0 compared to the normal F0 in the dark phase and a PSII activity, measured as variable fluorescence (Fv = Fm − F0), similar to normal non-diazotrophic cells. Correlation of type I cells with nitrogen fixation, oxygen concentration, and light suggests that this physiological state is connected to an up-regulation of the Mehler reaction, resulting in oxygen consumption despite functional PSII. Type II cells had more than three times the normal F0 and hardly any PSII activity measurable by variable fluorescence. They did not occur under low-oxygen concentrations, but appeared under high-oxygen levels outside the diazotrophic period, suggesting that this state represents a reaction to oxidative stress not necessarily connected to nitrogen fixation. In addition to the two high-fluorescence states, cells were observed to reversibly enter a low-fluorescence state. This occurred mainly after a cell went through its bright phase and may represent a fluorescence-quenching recovery phase. PMID:15299119

Altered erythrocyte sodium-lithium counter-transport and Na+/K(+)-ATPase activity in cystic fibrosis.

PubMed

Luczay, A; Vásárhelyi, B; Dobos, M; Holics, K; Ujhelyi, R; Tulassay, T

1997-03-01

Patients with cystic fibrosis (CF) exhibit normal concentrations of sodium and chloride in spite of the disturbance of Cl- and Na+ transport in epithelial cells. To characterize compensatory mechanisms in the regulation of sodium homeostasis, erythrocytes of 13 CF patients were analysed for sodium-lithium counter-transport (SLC), Na+/K(+)-ATPase activity and intracellular sodium content. Values were compared to those of healthy controls. Patients with CF had normal serum sodium and chloride concentrations and renal excretions of these ions were within the physiological range. Intracellular sodium concentration was similar in the CF and the control group (6.8 +/- 2.2 vs 5.7 +/- 1.0 mmol/l RBCs). Red blood cells' SLC and Na+/ K(+)-ATPase activity were elevated in CF patients (381 +/- 106 mumol/h/l RBCs vs 281 +/- 64; p < 0.01) and (445 +/- 129 mumol ATP mg prot/h vs 322 +/- 84, p < 0.01). Our study demonstrates that transmembrane cation transport systems are highly activated in CF. The increased sodium transport may be part of a compensatory mechanism of sodium homeostasis in children with CF.

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

Hill, Chris H.; Read, Randy J.; Deane, Janet E., E-mail: jed55@cam.ac.uk

A 1.8 Å resolution structure of the sphingolipid activator protein saposin A has been determined at pH 4.8, the physiologically relevant lysosomal pH for hydrolase enzyme activation and lipid-transfer activity. The saposins are essential cofactors for the normal lysosomal degradation of complex glycosphingolipids by acid hydrolase enzymes; defects in either saposin or hydrolase function lead to severe metabolic diseases. Saposin A (SapA) activates the enzyme β-galactocerebrosidase (GALC), which catalyzes the breakdown of β-d-galactocerebroside, the principal lipid component of myelin. SapA is known to bind lipids and detergents in a pH-dependent manner; this is accompanied by a striking transition from amore » ‘closed’ to an ‘open’ conformation. However, previous structures were determined at non-lysosomal pH. This work describes a 1.8 Å resolution X-ray crystal structure determined at the physiologically relevant lysosomal pH 4.8. In the absence of lipid or detergent at pH 4.8, SapA is observeed to adopt a conformation closely resembling the previously determined ‘closed’ conformation, showing that pH alone is not sufficient for the transition to the ‘open’ conformation. Structural alignments reveal small conformational changes, highlighting regions of flexibility.« less

Metabolic acidosis stimulates the production of the antimicrobial peptide cathelicidin in rabbit urine.

PubMed

Peng, Hu; Purkerson, Jeffrey M; Schwaderer, Andy L; Schwartz, George J

2017-11-01

Intercalated cells of the collecting duct (CD) are critical for acid-base homeostasis and innate immune defense of the kidney. Little is known about the impact of acidosis on innate immune defense in the distal nephron. Urinary tract infections are mainly due to Escherichia coli and are an important risk factor for development of chronic kidney disease. While the effect of urinary pH on growth of E. coli is well established, in this study, we demonstrate that acidosis increases urine antimicrobial activity due, at least in part, to induction of cathelicidin expression within the CD. Acidosis was induced in rabbits by adding NH 4 Cl to the drinking water and reducing food intake over 3 days or by casein supplementation. Microdissected CDs were examined for cathelicidin mRNA expression and antimicrobial activity, and cathelicidin protein levels in rabbit urine were measured. Cathelicidin expression in CD cells was detected in kidney sections. CDs from acidotic rabbits expressed three times more cathelicidin mRNA than those isolated from normal rabbits. Urine from acidotic rabbits had significantly more antimicrobial activity (vs. E. coli ) than normal urine, and most of this increased activity was blocked by cathelicidin antibody. The antibody had little effect on antimicrobial activity of normal urine. Urine from acidotic rabbits had at least twice the amount of cathelicidin protein as did normal urine. We conclude that metabolic acidosis not only stimulates CD acid secretion but also induces expression of cathelicidin and, thereby, enhances innate immune defense against urinary tract infections via induction of antimicrobial peptide expression. Copyright © 2017 the American Physiological Society.

Existence of Inverted Profile in Chemically Responsive Molecular Pathways in the Zebrafish Liver

PubMed Central

Zhang, Xun; Li, Hu; Ma, Jing; Zhang, Louxin; Li, Baowen; Gong, Zhiyuan

2011-01-01

How a living organism maintains its healthy equilibrium in response to endless exposure of potentially harmful chemicals is an important question in current biology. By transcriptomic analysis of zebrafish livers treated by various chemicals, we defined hubs as molecular pathways that are frequently perturbed by chemicals and have high degree of functional connectivity to other pathways. Our network analysis revealed that these hubs were organized into two groups showing inverted functionality with each other. Intriguingly, the inverted activity profiles in these two groups of hubs were observed to associate only with toxicopathological states but not with physiological changes. Furthermore, these inverted profiles were also present in rat, mouse, and human under certain toxicopathological conditions. Thus, toxicopathological-associated anti-correlated profiles in hubs not only indicate their potential use in diagnosis but also development of systems-based therapeutics to modulate gene expression by chemical approach in order to rewire the deregulated activities of hubs back to normal physiology. PMID:22140468

Zolpidem efficacy and safety in disorders of consciousness.

PubMed

Machado, Calixto; Estévez, Mario; Rodriguez-Rojas, Rafael

2018-01-01

Sutton and Clauss presented a detailed review about the effectiveness of zolpidem, discussing recoveries from brain damage due to strokes, trauma and hypoxia. A significant finding has been the unexpected and paradoxical increment of brain activity in vegetative state/unresponsive wakefulness syndrome (VS/UWS). On the contrary, zolpidem is considered one of the best sleep inducers in normal subjects. We have studied series of VS/UWS cases after zolpidem intake. We have demonstrated EEG activation, increment of BOLD signal in different brain regions, and an autonomic influence, mainly characterized by a vagolytic chronotropic effect without a significant increment of the vasomotor sympathetic tone. As this autonomic imbalance might induce cardio- circulatory complications, which we didn't find in any of our patients, we suggest developing future trials under control of physiological indices by bedside monitoring. However, considering that the paradoxical arousing zolpidem effect might be certainly related to brain function improvement, we agree with Sutton and Clauss that future multicentre and multinational clinical trials should be developed, but under control of physiological indices.

Is Physiology the Locus of Health/Health Promotion?

ERIC Educational Resources Information Center

Zbilut, Joseph P.

2008-01-01

A current trend in physiology education involves the use of clinical vignettes to demonstrate the importance of knowing normal physiology to appreciate pathophysiology. Although laudable, in effect, such tactics promote the so-called "disease" model of medicine while at the same time suggesting that the only utility for the knowledge of physiology…

Changes in ganglion cell physiology during retinal degeneration influence excitability by prosthetic electrodes

NASA Astrophysics Data System (ADS)

Cho, Alice; Ratliff, Charles; Sampath, Alapakkam; Weiland, James

2016-04-01

Objective. Here we investigate ganglion cell physiology in healthy and degenerating retina to test its influence on threshold to electrical stimulation. Approach. Age-related Macular Degeneration and Retinitis Pigmentosa cause blindness via outer retinal degeneration. Inner retinal pathways that transmit visual information to the central brain remain intact, so direct electrical stimulation from prosthetic devices offers the possibility for visual restoration. Since inner retinal physiology changes during degeneration, we characterize physiological properties and responses to electrical stimulation in retinal ganglion cells (RGCs) of both wild type mice and the rd10 mouse model of retinal degeneration. Main results. Our aggregate results support previous observations that elevated thresholds characterize diseased retinas. However, a physiology-driven classification scheme reveals distinct sub-populations of ganglion cells with thresholds either normal or strongly elevated compared to wild-type. When these populations are combined, only a weakly elevated threshold with large variance is observed. The cells with normal threshold are more depolarized at rest and exhibit periodic oscillations. Significance. During degeneration, physiological changes in RGCs affect the threshold stimulation currents required to evoke action potentials.

Role of AMP-activated protein kinase in kidney tubular transport, metabolism, and disease.

PubMed

Rajani, Roshan; Pastor-Soler, Nuria M; Hallows, Kenneth R

2017-09-01

AMP-activated protein kinase (AMPK) is a metabolic sensor that regulates cellular energy balance, transport, growth, inflammation, and survival functions. This review explores recent work in defining the effects of AMPK on various renal tubular epithelial ion transport proteins as well as its role in kidney injury and repair in normal and disease states. Recently, several groups have uncovered additional functions of AMPK in the regulation of kidney and transport proteins. These new studies have focused on the role of AMPK in the kidney in the setting of various diseases such as diabetes, which include evaluation of the effects of the hyperglycemic state on podocyte and tubular cell function. Other recent studies have investigated how reduced kidney mass, polycystic kidney disease (PKD), and fibrosis affect AMPK activation status. A general theme of several conditions that lead to chronic kidney disease (CKD) is that AMPK activity is abnormally suppressed relative to that in normal kidneys. Thus, the idea that AMPK activation may be a therapeutic strategy to slow down the progression of CKD has emerged. In addition to drugs such as metformin and 5-aminoimidazole-4-carboxamide ribonucleotide that are classically used as AMPK activators, recent studies have identified the therapeutic potential of other compounds that function at least partly as AMPK activators, such as salicylates, statins, berberine, and resveratrol, in preventing the progression of CKD. AMPK in the kidney plays a unique role at the crossroads of energy metabolism, ion and water transport, inflammation, and stress. Its potential role in modulating recovery from vs. progression of acute and chronic kidney injury has been the topic of recent research findings. The continued study of AMPK in kidney physiology and disease has improved our understanding of these physiological and pathological processes and offers great hope for therapeutic avenues for the increasing population at risk to develop kidney failure.

Auditory processing assessment suggests that Wistar audiogenic rat neural networks are prone to entrainment.

PubMed

Pinto, Hyorrana Priscila Pereira; Carvalho, Vinícius Rezende; Medeiros, Daniel de Castro; Almeida, Ana Flávia Santos; Mendes, Eduardo Mazoni Andrade Marçal; Moraes, Márcio Flávio Dutra

2017-04-07

Epilepsy is a neurological disease related to the occurrence of pathological oscillatory activity, but the basic physiological mechanisms of seizure remain to be understood. Our working hypothesis is that specific sensory processing circuits may present abnormally enhanced predisposition for coordinated firing in the dysfunctional brain. Such facilitated entrainment could share a similar mechanistic process as those expediting the propagation of epileptiform activity throughout the brain. To test this hypothesis, we employed the Wistar audiogenic rat (WAR) reflex animal model, which is characterized by having seizures triggered reliably by sound. Sound stimulation was modulated in amplitude to produce an auditory steady-state-evoked response (ASSR; -53.71Hz) that covers bottom-up and top-down processing in a time scale compatible with the dynamics of the epileptic condition. Data from inferior colliculus (IC) c-Fos immunohistochemistry and electrographic recordings were gathered for both the control Wistar group and WARs. Under 85-dB SLP auditory stimulation, compared to controls, the WARs presented higher number of Fos-positive cells (at IC and auditory temporal lobe) and a significant increase in ASSR-normalized energy. Similarly, the 110-dB SLP sound stimulation also statistically increased ASSR-normalized energy during ictal and post-ictal periods. However, at the transition from the physiological to pathological state (pre-ictal period), the WAR ASSR analysis demonstrated a decline in normalized energy and a significant increase in circular variance values compared to that of controls. These results indicate an enhanced coordinated firing state for WARs, except immediately before seizure onset (suggesting pre-ictal neuronal desynchronization with external sensory drive). These results suggest a competing myriad of interferences among different networks that after seizure onset converge to a massive oscillatory circuit. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha.

PubMed

Desai, Seema S; Tung, Jason C; Zhou, Vivian X; Grenert, James P; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M; Chang, Tammy T

2016-07-01

Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1-6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α), whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho-associated protein kinase pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/Rho-associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (Hepatology 2016;64:261-275). © 2016 by the American Association for the Study of Liver Diseases.

Metabolomic strategies to map functions of metabolic pathways.

PubMed

Mulvihill, Melinda M; Nomura, Daniel K

2014-08-01

Genome sequencing efforts have revealed a strikingly large number of unannotated and uncharacterized genes that fall into metabolic enzymes classes, likely indicating that our current knowledge of biochemical pathways in normal physiology, let alone in disease states, remains largely incomplete. This realization presents a daunting challenge for post-genomic-era scientists in deciphering the biochemical and (patho)physiological roles of these enzymes and their metabolites and metabolic networks. This is further complicated by many recent studies showing a rewiring of normal metabolic networks in disease states to give rise to unique pathophysiological functions of enzymes, metabolites, and metabolic pathways. This review focuses on recent discoveries made using metabolic mapping technologies to uncover novel pathways and metabolite-mediated posttranslational modifications and epigenetic alterations and their impact on physiology and disease. Copyright © 2014 the American Physiological Society.

Abnormal Pulmonary Function in Adults with Sickle Cell Anemia

PubMed Central

Klings, Elizabeth S.; Wyszynski, Diego F.; Nolan, Vikki G.; Steinberg, Martin H.

2006-01-01

Rationale: Pulmonary complications of sickle cell anemia (Hb-SS) commonly cause morbidity, yet few large studies of pulmonary function tests (PFTs) in this population have been reported. Objectives: PFTs (spirometry, lung volumes, and diffusion capacity for carbon monoxide [DLCO]) from 310 adults with Hb-SS were analyzed to determine the pattern of pulmonary dysfunction and their association with other systemic complications of sickle cell disease. Methods: Raw PFT data were compared with predicted values. Each subject was subclassified into one of five groups: obstructive physiology, restrictive physiology, mixed obstructive/restrictive physiology, isolated low DLCO, or normal. The association between laboratory data of patients with decreased DLCO or restrictive physiology and those of normal subjects was assessed by multivariate linear regression. Measurements and Main Results: Normal PFTs were present in only 31 of 310 (10%) patients. Overall, adults with Hb-SS were characterized by decreased total lung capacities (70.2 ± 14.7% predicted) and DlCO (64.5 ± 19.9%). The most common PFT patterns were restrictive physiology (74%) and isolated low DlCO (13%). Decreased DLCO was associated with thrombocytosis (p = 0.05), with hepatic dysfunction (elevated alanine aminotransferase; p = 0.07), and a trend toward renal dysfunction (elevated blood urea nitrogen and creatinine; p = 0.05 and 0.07, respectively). Conclusions: Pulmonary function is abnormal in 90% of adult patients with Hb-SS. Common abnormalities include restrictive physiology and decreased DLCO. Decreased DLCO may indicate more severe sickle vasculopathy characterized by impaired hepatic and renal function. PMID:16556694

Physiology and pathophysiology of potassium homeostasis.

PubMed

Palmer, Biff F; Clegg, Deborah J

2016-12-01

Total body potassium content and proper distribution of potassium across the cell membrane is of critical importance for normal cellular function. Potassium homeostasis is maintained by several different methods. In the kidney, total body potassium content is achieved by alterations in renal excretion of potassium in response to variations in intake. Insulin and beta-adrenergic tone play critical roles in maintaining the internal distribution of potassium under normal conditions. Despite homeostatic pathways designed to maintain potassium levels within the normal range, disorders of altered potassium homeostasis are common. The clinical approach to designing effective treatments relies on understanding the pathophysiology and regulatory influences which govern the internal distribution and external balance of potassium. Here we provide an overview of the key regulatory aspects of normal potassium physiology. This review is designed to provide an overview of potassium homeostasis as well as provide references of seminal papers to guide the reader into a more in depth discussion of the importance of potassium balance. This review is designed to be a resource for educators and well-informed clinicians who are teaching trainees about the importance of potassium balance. Copyright © 2016 the American Physiological Society.

The knockdown of chloroplastic ascorbate peroxidases reveals its regulatory role in the photosynthesis and protection under photo-oxidative stress in rice.

PubMed

Caverzan, Andréia; Bonifacio, Aurenivia; Carvalho, Fabricio E L; Andrade, Claudia M B; Passaia, Gisele; Schünemann, Mariana; Maraschin, Felipe Dos Santos; Martins, Marcio O; Teixeira, Felipe K; Rauber, Rafael; Margis, Rogério; Silveira, Joaquim Albenisio Gomes; Margis-Pinheiro, Márcia

2014-01-01

The inactivation of the chloroplast ascorbate peroxidases (chlAPXs) has been thought to limit the efficiency of the water-water cycle and photo-oxidative protection under stress conditions. In this study, we have generated double knockdown rice (Oryza sativa L.) plants in both OsAPX7 (sAPX) and OsAPX8 (tAPX) genes, which encode chloroplastic APXs (chlAPXs). By employing an integrated approach involving gene expression, proteomics, biochemical and physiological analyses of photosynthesis, we have assessed the role of chlAPXs in the regulation of the protection of the photosystem II (PSII) activity and CO2 assimilation in rice plants exposed to high light (HL) and methyl violagen (MV). The chlAPX knockdown plants were affected more severely than the non-transformed (NT) plants in the activity and structure of PSII and CO2 assimilation in the presence of MV. Although MV induced significant increases in pigment content in the knockdown plants, the increases were apparently not sufficient for protection. Treatment with HL also caused generalized damage in PSII in both types of plants. The knockdown and NT plants exhibited differences in photosynthetic parameters related to efficiency of utilization of light and CO2. The knockdown plants overexpressed other antioxidant enzymes in response to the stresses and increased the GPX activity in the chloroplast-enriched fraction. Our data suggest that a partial deficiency of chlAPX expression modulate the PSII activity and integrity, reflecting the overall photosynthesis when rice plants are subjected to acute oxidative stress. However, under normal growth conditions, the knockdown plants exhibit normal phenotype, biochemical and physiological performance. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Salinity mediates the toxic effect of nano-TiO2 on the juvenile olive flounder Paralichthys olivaceus.

PubMed

Huang, Xizhi; Lan, Yawen; Liu, Zekang; Huang, Wei; Guo, Qindan; Liu, Liping; Hu, Menghong; Sui, Yanming; Wu, Fangli; Lu, Weiqun; Wang, Youji

2018-06-04

Increased production of engineered nanoparticles has raised extensive concern about the potential toxic effects on marine organisms living in estuarine and coastal environments. Meanwhile, salinity is one of the key environmental factors that may influence the physiological activities in flatfish species inhabiting in those waters due to fluctuations caused by freshwater input or rainfall. In this study, we investigated the oxidative stress and histopathological alteration of the juvenile Paralichthys olivaceus exposed to nano-TiO 2 (1 and 10 mg L -1 ) under salinities of 10 and 30 psu for 4 days. In the gills, Na + -K + -ATPase activity significantly deceased after 4 days 10 psu exposure without nano-TiO 2 compared with 1 day of acclimating the salinity from the normal salinity (30 psu) to 10 psu. Under this coastal salinity, low concentration (1 mg L -1 ) of nano-TiO 2 exerted significant impacts. In the liver, the activities of superoxide dismutase, catalase, the levels of lipid peroxide and malondialdehyde increased with nano-TiO 2 exposed under 30 psu. Such increase indicated an oxidative stress response. The result of the integrated biomarker responses showed that P. olivaceus can be adversely affected by high salinity and high concentration of nano-TiO 2 for a short-term (4 days) exposure. The histological analysis revealed the accompanying severe damages for the gill filaments. Principal component analysis further showed that the oxidative stress was associated with the nano-TiO 2 effect at normal salinity. These findings indicated that nano-TiO 2 and normal salinity exert synergistic effects on juvenile P. olivaceus, and low salinity plays a protective role in its physiological state upon short-term exposure to nano-TiO 2 . The mechanism of salinity mediating the toxic effects of NPs on estuarine fish should be further considered. Copyright © 2018 Elsevier B.V. All rights reserved.

Supra-physiological folic acid concentrations induce aberrant DNA methylation in normal human cells in vitro.

PubMed

Charles, Michelle A; Johnson, Ian T; Belshaw, Nigel J

2012-07-01

The micronutrients folate and selenium may modulate DNA methylation patterns by affecting intracellular levels of the methyl donor S-adenosylmethionine (SAM) and/or the product of methylation reactions S-adenosylhomocysteine (SAH). WI-38 fibroblasts and FHC colon epithelial cells were cultured in the presence of two forms of folate or four forms of selenium at physiologically-relevant doses, and their effects on LINE-1 methylation, gene-specific CpG island (CGI) methylation and intracellular SAM:SAH were determined. At physiologically-relevant doses the forms of folate or selenium had no effect on LINE-1 or CGI methylation, nor on intracellular SAM:SAH. However the commercial cell culture media used for the selenium studies, containing supra-physiological concentrations of folic acid, induced LINE-1 hypomethylation, CGI hypermethylation and decreased intracellular SAM:SAH in both cell lines. We conclude that the exposure of normal human cells to supra-physiological folic acid concentrations present in commercial cell culture media perturbs the intracellular SAM:SAH ratio and induces aberrant DNA methylation.

Size-dependent physiological responses of the branching coral Pocillopora verrucosa to elevated temperature and PCO2.

PubMed

Edmunds, Peter J; Burgess, Scott C

2016-12-15

Body size has large effects on organism physiology, but these effects remain poorly understood in modular animals with complex morphologies. Using two trials of a ∼24 day experiment conducted in 2014 and 2015, we tested the hypothesis that colony size of the coral Pocillopora verrucosa affects the response of calcification, aerobic respiration and gross photosynthesis to temperature (∼26.5 and ∼29.7°C) and P CO 2  (∼40 and ∼1000 µatm). Large corals calcified more than small corals, but at a slower size-specific rate; area-normalized calcification declined with size. Whole-colony and area-normalized calcification were unaffected by temperature, P CO 2 , or the interaction between the two. Whole-colony respiration increased with colony size, but the slopes of these relationships differed between treatments. Area-normalized gross photosynthesis declined with colony size, but whole-colony photosynthesis was unaffected by P CO 2 , and showed a weak response to temperature. When scaled up to predict the response of large corals, area-normalized metrics of physiological performance measured using small corals provide inaccurate estimates of the physiological performance of large colonies. Together, these results demonstrate the importance of colony size in modulating the response of branching corals to elevated temperature and high P CO 2 . © 2016. Published by The Company of Biologists Ltd.

The effect of xanthine oxidase and hypoxanthine on the permeability of red cells from patients with sickle cell anemia.

PubMed

Al Balushi, Halima W M; Rees, David C; Brewin, John N; Hannemann, Anke; Gibson, John S

2018-03-01

Red cells from patients with sickle cell anemia (SCA) are under greater oxidative challenge than those from normal individuals. We postulated that oxidants generated by xanthine oxidase (XO) and hypoxanthine (HO) contribute to the pathogenesis of SCA through altering solute permeability. Sickling, activities of the main red cell dehydration pathways (P sickle , Gardos channel, and KCl cotransporter [KCC]), and cell volume were measured at 100, 30, and 0 mmHg O 2 , together with deoxygenation-induced nonelectrolyte hemolysis. Unexpectedly, XO/HO mixtures had mainly inhibitory effects on sickling, P sickle , and Gardos channel activities, while KCC activity and nonelectrolyte hemolysis were increased. Gardos channel activity was significantly elevated in red cells pharmacologically loaded with Ca 2+ using the ionophore A23187, consistent with an effect on the transport system per se as well as via Ca 2+ entry likely via the P sickle pathway. KCC activity is controlled by several pairs of conjugate protein kinases and phosphatases. Its activity, however, was also stimulated by XO/HO mixtures in red cells pretreated with N-ethylmaleimide (NEM), which is thought to prevent regulation via changes in protein phosphorylation, suggesting that the oxidants formed could also have direct effects on this transporter. In the presence of XO/HO, red cell volume was better maintained in deoxygenated red cells. Overall, the most notable effect of XO/HO mixtures was an increase in red cell fragility. These findings increase our understanding of the effects of oxidative challenge in SCA patients and are relevant to the behavior of red cells in vivo. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Pulp-dentin biology in restorative dentistry. Part 1: normal structure and physiology.

PubMed

Mjör, I A; Sveen, O B; Heyeraas, K J

2001-06-01

Considerable knowledge has accumulated over the years on the structure and function of the dental pulp and dentin. Some of this knowledge has important clinical implications. This review, which is the first of seven articles, will be limited to those parts of the normal structure and physiology of the pulp and dentin that have been shown to result in, or are likely lead to, tissue reactions associated with the clinical treatment of these tissues. Although certain normal structures will be highlighted in some detail, a basic knowledge of pulpal and dentinal development and structure is a prerequisite for an understanding of this text.

Evaluation and Management of Refractory Acne Vulgaris in Adolescent and Adult Men.

PubMed

McCarty, Morgan

2016-04-01

Acne vulgaris alters the normal skin physiology, impairing stratum corneum and transepidermal water loss. A male's normal skin physiologic state is different than a female's and may have implications when choosing treatment when the skin is altered in a disease state. Transepidermal water loss, pH, and sebum production are different between the sexes. Several underlying conditions present in male acne patients at several ages that may require a more in-depth evaluation. As knowledge of the pathogenesis of acne expands, the differences in skin physiology between the sexes may alter the manner in which male patients with acne medications are approached. Copyright © 2016 Elsevier Inc. All rights reserved.

Like cures like: a neuroimmunological model based on electromagnetic resonance.

PubMed

Shahabi, Shahram; Kasariyans, Aditya; Noorbakhsh, Farshid

2013-12-01

Recent investigations have pointed to the production of characteristic electromagnetic (EM) waves in highly diluted sterile filtrates of different microorganisms and their associated DNA molecules. Analysis of these diluted solutions that are prepared using methods almost identical to the way that homeopathic medicines are prepared has pointed to the existence of nanostructures capable of emitting EM waves. Combining these results with findings that point to the interaction of EM waves with sensory nerves with subsequent activation of homeostatic efferent pathways, we propose a model to describe mechanisms underlying the effects of homeopathic remedies. THE MODEL: Living cells and tissues are capable of generating EM waves in their physiological conditions. When a cell deviates from its physiological state, in addition to normal EM emissions, it starts to produce EM waves with altered characteristics. According to our model, the main cause of the therapeutic effects of homeopathic remedies is the occurrence of resonance between the non-physiological EM waves of the patient and extremely low-frequency EM waves produced by nanostructures present in the homeopathic remedy. Resonance occurs if the frequency and amplitude characteristics of the patient's non-physiological EM waves and those produced by nanostructures of the applied homeopathic remedy are similar. Once resonance occurs, stimulation of the patient's sensory neurons, which are sensitized due to inflammation of any origin, leads to triggering of different regulatory mechanisms, including the activation of descending antinociceptive and/or cholinergic anti-inflammatory pathways, which leads to the restoration of homeostasis.

Starvation stress affects the interplay among shrimp gut microbiota, digestion and immune activities.

PubMed

Dai, Wen-Fang; Zhang, Jin-Jie; Qiu, Qiong-Fen; Chen, Jiong; Yang, Wen; Ni, Sui; Xiong, Jin-Bo

2018-05-24

Aquatic animals are frequently suffered from starvation due to restricted food availability or deprivation. It is currently known that gut microbiota assists host in nutrient acquisition. Thus, exploring the gut microbiota responses would improve our understanding on physiological adaptation to starvation. To achieve this, we investigated how the gut microbiota and shrimp digestion and immune activities were affected under starvation stress. The results showed that the measured digestion activities in starved shrimp were significantly lower than in normal cohorts; while the measured immune activities exhibited an opposite trend. A structural equation modeling (SEM) revealed that changes in the gut bacterial community were directly related to digestive and immune enzyme activities, which in turn markedly affected shrimp growth traits. Notably, several gut bacterial indicators that characterized the shrimp nutrient status were identified, with more abundant opportunistic pathogens in starved shrimp, although there were no statistical differences in the overall diversity and the structures of gut bacterial communities between starved and normal shrimp. Starved shrimp exhibited less connected and cooperative interspecies interaction as compared with normal cohorts. Additionally, the functional pathways involved in carbohydrate and protein digestion, glycan biosynthesis, lipid and enzyme metabolism remarkably decreased in starved shrimp. These attenuations could increase the susceptibility of starved shrimp to pathogens infection. In summary, this study provides novel insights into the interplay among shrimp digestion, immune activities and gut microbiota in response to starvation stress. Copyright © 2018 Elsevier Ltd. All rights reserved.

[The physiology of the isolated dog pancreas--the influence of the actual blood glucose level on the blood circulation in the pancreas].

PubMed

Hempfling, H; Husemann, B

1975-06-01

1. Glucose loading tests were undertaken on isolated pancreas or pancreas-duodenal preparations. 2. In 75% of cases a vasodilatation can be observed which leads to enhanced blood circulation under constant pressure in the isolated organ. 3. This vasodilatation persists until the level of blood sugar has normalized. 4. The experiment being carried out on an isolated organ, external factors such as the vagus nerve, do not become active.

Reverse genetics: Its origins and prospects

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

Berg, P.

1991-04-01

The nucleotide sequence of a gene and its flanking segments alone will not tell us how its expression is regulated during development and differentiation, or in response to environmental changes. To comprehend the physiological significance of the molecular details requires biological analysis. Recombinant DNA techniques provide a powerful experimental approach. A strategy termed reverse genetics' utilizes the analysis of the activities of mutant and normal genes and experimentally constructed mutants to explore the relationship between gene structure and function thereby helping elucidate the relationship between genotype and phenotype.

Physiological joint line total knee arthroplasty designs are especially sensitive to rotational placement - A finite element analysis.

PubMed

Moewis, Philippe; Checa, Sara; Kutzner, Ines; Hommel, Hagen; Duda, Georg N

2018-01-01

Mechanical and kinematical aligning techniques are the usual positioning methods during total knee arthroplasty. However, alteration of the physiological joint line and unbalanced medio-lateral load distribution are considered disadvantages in the mechanical and kinematical techniques, respectively. The aim of this study was to analyse the influence of the joint line on the strain and stress distributions in an implanted knee and their sensitivity to rotational mal-alignment. Finite element calculations were conducted to analyse the stresses in the PE-Inlay and the mechanical strains at the bone side of the tibia component-tibia bone interface during normal positioning of the components and internal and external mal-rotation of the tibial component. Two designs were included, a horizontal and a physiological implant. The loading conditions are based on internal knee joint loads during walking. A medialization of the stresses on the PE-Inlay was observed in the physiological implant in a normal position, accompanied by higher stresses in the mal-rotated positions. Within the tibia component-tibia bone interface, similar strain distributions were observed in both implant geometries in the normal position. However, a medialization of the strains was observed in the physiological implant in both mal-rotated conditions with greater bone volume affected by higher strains. Although evident changes due to mal-rotation were observed, the stresses do not suggest a local plastic deformation of the PE-Inlay. The strains values within most of the tibia component-tibia bone interface were in the physiological strain zone and no significant bone changes would be expected. The physiological cut on the articular aspect showed no detrimental effect compared to the horizontal implant.

Birth weight and prematurity in infants with single ventricle physiology: pediatric heart network infant single ventricle trial screened population.

PubMed

Williams, Richard V; Ravishankar, Chitra; Zak, Victor; Evans, Frank; Atz, Andrew M; Border, William L; Levine, Jami; Li, Jennifer S; Mahony, Lynn; Mital, Seema; Pearson, Gail D; Prakash, Ashwin; Hsu, Daphne T

2010-01-01

Although congenital heart disease is associated with low birth weight and prematurity, there is little information about these birth outcomes in infants with single ventricle physiology. We describe the birth outcomes (i.e., gestational age and birth weight) in neonates with single ventricle physiology screened for enrollment in the Pediatric Heart Network's Infant Single Ventricle Trial, compare these outcomes with US norms, and examine the association of birth outcomes with anatomic diagnosis and race. All neonates with single ventricle physiology presenting to Infant Single Ventricle Trial centers were screened for enrollment. Demographic data and anatomic diagnoses were obtained from medical records. A total of 1245 neonates with single ventricle physiology were screened at 10 centers (63 to 266 per center). Diagnoses included hypoplastic left heart syndrome in 49%, unbalanced atrioventricular septal defect in 12%, and tricuspid atresia in 9%. Preterm birth occurred in 16% of neonates with single ventricle physiology vs. 12% in normal neonates (P < .001), low birth weight (<2.5 kg) in 18% vs. 8% in normals (P < .001), and small for gestational age (<10th percentile by definition) in 22% vs. 10% in normals (P < .001). A genetic syndrome was reported in 8%. The percentage of preterm birth, low birth weight, and small for gestational age was similar between screened neonates with and without hypoplastic left heart syndrome. In this large, contemporary cohort of neonates with single ventricle physiology, rates of preterm birth, low birth weight, and small for gestational age were higher than in the general population, but similar between screened neonates with and without hypoplastic left heart syndrome.

Physiological and psychological effects of testosterone during severe energy deficit and recovery: A study protocol for a randomized, placebo-controlled trial for Optimizing Performance for Soldiers (OPS).

PubMed

Pasiakos, Stefan M; Berryman, Claire E; Karl, J Philip; Lieberman, Harris R; Orr, Jeb S; Margolis, Lee M; Caldwell, John A; Young, Andrew J; Montano, Monty A; Evans, William J; Vartanian, Oshin; Carmichael, Owen T; Gadde, Kishore M; Harris, Melissa; Rood, Jennifer C

2017-07-01

The physiological consequences of severe energy deficit include hypogonadism and the loss of fat-free mass. Prolonged energy deficit also impacts physical performance, mood, attentiveness, and decision-making capabilities. This study will determine whether maintaining a eugonadal state during severe, sustained energy deficit attenuates physiological decrements and maintains mental performance. This study will also assess the effects of normalizing testosterone levels during severe energy deficit and recovery on gut health and appetite regulation. Fifty physically active men will participate in a 3-phase, randomized, placebo-controlled study. After completing a 14-d, energy-adequate, diet acclimation phase (protein: 1.6g∙kg -1 ∙d -1 ; fat: 30% total energy intake), participants will be randomized to undergo a 28-d, 55% energy deficit phase with (DEF+TEST: 200mg testosterone enanthate per week) or without (DEF) exogenous testosterone. Diet and physical activity will be rigorously controlled. Recovery from the energy deficit (ad libitum diet, no testosterone) will be assessed until body mass has been recovered within ±2.5% of initial body mass. Body composition, stable isotope methodologies, proteomics, muscle biopsies, whole-room calorimetry, molecular biology, activity/sleep monitoring, personality and cognitive function assessments, functional MRI, and comprehensive biochemistries will be used to assess physiological and psychological responses to energy restriction and recovery feeding while volunteers are in an expected hypogonadal versus eugonadal state. The Optimizing Performance for Soldiers (OPS) study aims to determine whether preventing hypogonadism will mitigate declines in physical and mental function that typically occur during prolonged energy deficit, and the efficacy of testosterone replacement on recovery from severe underfeeding. NCT02734238. Copyright © 2017. Published by Elsevier Inc.

Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia.

PubMed

Kudrick, Necla; Chan, Owen; La Gamma, Edmund F; Kim, Juhye Lena; Tank, Arnold William; Sterling, Carol; Nankova, Bistra B

2015-02-01

Acute metabolic stress such as insulin-induced hypoglycemia triggers a counterregulatory response during which the release of catecholamines (epinephrine), the activation of tyrosine hydroxylase (TH) enzyme and subsequent compensatory catecholamine biosynthesis occur in the adrenal medulla. However, recurrent exposure to hypoglycemia (RH), a consequence of tight glycemic control in individuals with type 1 and type 2 diabetes compromises this physiological response. The molecular mechanisms underlying the maladaptive response to repeated glucose deprivation are incompletely understood. We hypothesize that impaired epinephrine release following RH reflects altered regulation of adrenal catecholamine biosynthesis. To test this hypothesis, we compared the effect of single daily (RH) and twice-daily episodes of insulin-induced hypoglycemia (2RH) on adrenal epinephrine release and production in normal rats. Control animals received saline injections under similar conditions (RS and 2RS, respectively). Following 3 days of treatment, we assessed the counterregulatory hormonal responses during a hypoglycemic clamp. Changes in adrenal TH gene expression were also analyzed. The counterregulatory responses, relative TH transcription and TH mRNA levels and Ser40-TH phosphorylation (marker for enzyme activation) were induced to a similar extent in RS, 2RS, and RH groups. In contrast, epinephrine and glucagon responses were attenuated in the 2RH group and this was associated with a limited elevation of adrenal TH mRNA, rapid inactivation of TH enzyme and no significant changes in TH protein. Our results suggest that novel posttranscriptional mechanisms controlling TH mRNA and activated TH enzyme turnover contribute to the impaired epinephrine responses and may provide new therapeutic targets to prevent HAAF. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Modeling temporal sequences of cognitive state changes based on a combination of EEG-engagement, EEG-workload, and heart rate metrics

PubMed Central

Stikic, Maja; Berka, Chris; Levendowski, Daniel J.; Rubio, Roberto F.; Tan, Veasna; Korszen, Stephanie; Barba, Douglas; Wurzer, David

2014-01-01

The objective of this study was to investigate the feasibility of physiological metrics such as ECG-derived heart rate and EEG-derived cognitive workload and engagement as potential predictors of performance on different training tasks. An unsupervised approach based on self-organizing neural network (NN) was utilized to model cognitive state changes over time. The feature vector comprised EEG-engagement, EEG-workload, and heart rate metrics, all self-normalized to account for individual differences. During the competitive training process, a linear topology was developed where the feature vectors similar to each other activated the same NN nodes. The NN model was trained and auto-validated on combat marksmanship training data from 51 participants that were required to make “deadly force decisions” in challenging combat scenarios. The trained NN model was cross validated using 10-fold cross-validation. It was also validated on a golf study in which additional 22 participants were asked to complete 10 sessions of 10 putts each. Temporal sequences of the activated nodes for both studies followed the same pattern of changes, demonstrating the generalization capabilities of the approach. Most node transition changes were local, but important events typically caused significant changes in the physiological metrics, as evidenced by larger state changes. This was investigated by calculating a transition score as the sum of subsequent state transitions between the activated NN nodes. Correlation analysis demonstrated statistically significant correlations between the transition scores and subjects' performances in both studies. This paper explored the hypothesis that temporal sequences of physiological changes comprise the discriminative patterns for performance prediction. These physiological markers could be utilized in future training improvement systems (e.g., through neurofeedback), and applied across a variety of training environments. PMID:25414629

Thromboxane A2-induced bi-directional regulation of cerebral arterial tone.

PubMed

Neppl, Ronald L; Lubomirov, Lubomir T; Momotani, Ko; Pfitzer, Gabriele; Eto, Masumi; Somlyo, Avril V

2009-03-06

Myosin light chain phosphatase plays a critical role in modulating smooth muscle contraction in response to a variety of physiologic stimuli. A downstream target of the RhoA/Rho-kinase and nitric oxide (NO)/cGMP/cyclic GMP-dependent kinase (cGKI) pathways, myosin light chain phosphatase activity reflects the sum of both calcium sensitization and desensitization pathways through phosphorylation and dephosphorylation of the myosin phosphatase targeting subunit (MYPT1). As cerebral blood flow is highly spatio-temporally modulated under normal physiologic conditions, severe perturbations in normal cerebral blood flow, such as in cerebral vasospasm, can induce neurological deficits. In nonpermeabilized cerebral vessels stimulated with U-46619, a stable mimetic of endogenous thromboxane A2 implicated in the etiology of cerebral vasospasm, we observed significant increases in contractile force, RhoA activation, regulatory light chain phosphorylation, as well as phosphorylation of MYPT1 at Thr-696, Thr-853, and surprisingly Ser-695. Inhibition of nitric oxide signaling completely abrogated basal MYPT1 Ser-695 phosphorylation and significantly increased and potentiated U-46619-induced MYPT1 Thr-853 phosphorylation and contractile force, indicating that NO/cGMP/cGKI signaling maintains basal vascular tone through active inhibition of calcium sensitization. Surprisingly, a fall in Ser-695 phosphorylation did not result in an increase in phosphorylation of the Thr-696 site. Although activation of cGKI with exogenous cyclic nucleotides inhibited thromboxane A2-induced MYPT1 membrane association, RhoA activation, contractile force, and regulatory light chain phosphorylation, the anticipated decreases in MYPT1 phosphorylation at Thr-696/Thr-853 were not observed, indicating that the vasorelaxant effects of cGKI are not through dephosphorylation of MYPT1. Thus, thromboxane A2 signaling within the intact cerebral vasculature induces "buffered" vasoconstrictions, in which both the RhoA/Rho-kinase calcium-sensitizing and the NO/cGMP/cGKI calcium-desensitizing pathways are activated.

Relationship Between Psychophysiological Responses to Aversive Odors and Nutritional Status During Normal Aging.

PubMed

Joussain, Pauline; Ferdenzi, Camille; Djordjevic, Jelena; Bensafi, Moustafa

2017-07-01

Psychophysiological responses to disgusting and pleasant smells are one of the most important aspects of olfaction. These emotional signals can constitute an alert against toxic substances, and they may play a major role in food selection and nutritional intake. The aim of this study was to test this hypothesis by examining whether individual physiological responses to odors could predict the subject's nutritional status. Because aging is associated with changes in emotional response to smells, we also examined how aging affects the relationship between olfaction and nutrition. Twenty young and 20 old participants perceived a series of odorants while their psychophysiological responses were simultaneously measured, and completed the Mini-Nutritional Assessment (MNA) questionnaire. Regression between individual correlation coefficients (r-values between odor perceptual ratings and physiological parameters) and individual MNA scores revealed that appropriateness of the physiological responses to aversive odors predicted nutritional status (R2 = 0.22, P < 0.007): participants with higher electromyogram corrugator activity in response to aversive smells had better nutritional status. Furthermore, this relationship was significant in old (R2 = 0.45, P < 0.005) but not young participants (R2 = 0.04, P > 0.44). Taken together, preserved functioning of somatic markers in response to odors during normal aging is associated with better nutritional status, and may facilitate healthier food selection. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Modeling activated states of GPCRs: the rhodopsin template.

PubMed

Niv, Masha Y; Skrabanek, Lucy; Filizola, Marta; Weinstein, Harel

2006-01-01

Activation of G Protein-Coupled Receptors (GPCRs) is an allosteric mechanism triggered by ligand binding and resulting in conformational changes transduced by the transmembrane domain. Models of the activated forms of GPCRs have become increasingly necessary for the development of a clear understanding of signal propagation into the cell. Experimental evidence points to a multiplicity of conformations related to the activation of the receptor, rendered important physiologically by the suggestion that different conformations may be responsible for coupling to different signaling pathways. In contrast to the inactive state of rhodopsin (RHO) for which several high quality X-ray structures are available, the structure-related information for the active states of rhodopsin and all other GPCRs is indirect. We have collected and stored such information in a repository we maintain for activation-specific structural data available for rhodopsin-like GPCRs, http://www.physiology.med.cornell.edu/GPCRactivation/gpcrindex.html . Using these data as structural constraints, we have applied Simulated Annealing Molecular Dynamics to construct a number of different active state models of RHO starting from the known inactive structure. The common features of the models indicate that TM3 and TM5 play an important role in activation, in addition to the well-established rearrangement of TM6. Some of the structural changes observed in these models occur in regions that were not involved in the constraints, and have not been previously tested experimentally; they emerge as interesting candidates for further experimental exploration of the conformational space of activated GPCRs. We show that none of the normal modes calculated from the inactive structure has a dominant contribution along the path of conformational rearrangement from inactive to the active forms of RHO in the models. This result may differentiate rhodopsin from other GPCRs, and the reasons for this difference are discussed in the context of the structural properties and the physiological function of the protein.

Right Ventricular Tissue Doppler in Space Flight

NASA Technical Reports Server (NTRS)

Garcia, Kathleen M.; Hamilton, Douglas R.; Sargsyan, Ashot E.; Ebert, Douglas; Martin, David S.; Barratt, Michael R.; Martin, David S.; Bogomolov, Valery V.; Dulchavsky, Scott A.; Duncan, J. Michael

2010-01-01

The presentation slides review normal physiology of the right ventricle in space, general physiology of the right ventricle; difficulties in imaging the heart in space, imaging methods, tissue Doppler spectrum, right ventricle tissue Doppler, and Rt Tei Index.

Piezo1 regulates mechanotransductive release of ATP from human RBCs.

PubMed

Cinar, Eyup; Zhou, Sitong; DeCourcey, James; Wang, Yixuan; Waugh, Richard E; Wan, Jiandi

2015-09-22

Piezo proteins (Piezo1 and Piezo2) are recently identified mechanically activated cation channels in eukaryotic cells and associated with physiological responses to touch, pressure, and stretch. In particular, human RBCs express Piezo1 on their membranes, and mutations of Piezo1 have been linked to hereditary xerocytosis. To date, however, physiological functions of Piezo1 on normal RBCs remain poorly understood. Here, we show that Piezo1 regulates mechanotransductive release of ATP from human RBCs by controlling the shear-induced calcium (Ca(2+)) influx. We find that, in human RBCs treated with Piezo1 inhibitors or having mutant Piezo1 channels, the amounts of shear-induced ATP release and Ca(2+) influx decrease significantly. Remarkably, a critical extracellular Ca(2+) concentration is required to trigger significant ATP release, but membrane-associated ATP pools in RBCs also contribute to the release of ATP. Our results show how Piezo1 channels are likely to function in normal RBCs and suggest a previously unidentified mechanotransductive pathway in ATP release. Thus, we anticipate that the study will impact broadly on the research of red cells, cellular mechanosensing, and clinical studies related to red cell disorders and vascular disease.

Human organoid cultures: transformative new tools for human virus studies.

PubMed

Ramani, Sasirekha; Crawford, Sue E; Blutt, Sarah E; Estes, Mary K

2018-04-01

Studies of human infectious diseases have been limited by the paucity of functional models that mimic normal human physiology and pathophysiology. Recent advances in the development of multicellular, physiologically active organotypic cultures produced from embryonic and pluripotent stem cells, as well as from stem cells isolated from biopsies and surgical specimens are allowing unprecedented new studies and discoveries about host-microbe interactions. Here, we summarize recent developments in the use of organoids for studying human viral pathogens, including intestinal infections with human rotavirus, norovirus, enteroviruses and adenoviruses (intestinal organoids and enteroids), neuronal infections with Zika virus (cerebral organoids) and respiratory infections with respiratory syncytial virus in (lung bud organoids). Biologic discovery of host-specific genetic and epigenetic factors affecting infection, and responses to infection that lead to disease are possible with the use of organoid cultures. Continued development to increase the complexity of these cultures by including components of the normal host tissue microenvironment such as immune cells, blood vessels and microbiome, will facilitate studies on human viral pathogenesis, and advance the development of platforms for pre-clinical evaluation of vaccines, antivirals and therapeutics. Copyright © 2018 Elsevier B.V. All rights reserved.

Fluoxetine: clinical pharmacology and physiologic disposition

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

Lemberger, L.; Bergstrom, R.F.; Wolen, R.L.

Fluoxetine (30 mg), administered for 7 days to normal volunteers, produced a 66% inhibition of tritiated serotonin uptake into platelets. Plasma concentrations of fluoxetine correlated positively with inhibition of serotonin uptake. Fluoxetine is well absorbed after oral administration in both the fed and fasted states and demonstrates dose proportionality. Fluoxetine disappears from plasma with a half-life of 1-3 days; its metabolite norfluoxetine has a plasma half-life of 7-15 days. After administration of /sup 14/C-fluoxetine, approximately 65% of the administered dose of radioactivity is recovered in urine and about 15% in feces. Fluoxetine, given as a single dose or in multiplemore » doses over 8 days, did not produce significant effects on the plasma disappearance of warfarin, diazepam, tolbutamide, or chlorothiazide. Coadministration of fluoxetine and ethanol did not result in an increase from control values in the blood ethanol levels, nor did it produce significant changes in physiologic, psychometric, or psychomotor activity. Pharmacokinetics of fluoxetine in the elderly and normal volunteers appear to be similar. In addition, pharmacokinetic analyses in patients with varying degrees of renal impairment did not show significant differences from healthy subjects.« less

Cerebral control of the bladder in normal and urge-incontinent women

PubMed Central

Griffiths, Derek; Tadic, Stasa D.; Schaefer, Werner; Resnick, Neil M.

2007-01-01

Aim: To identify age-related changes in the normal brain/bladder control system, and differences between urge incontinence in younger and older women, as shown by brain responses to bladder filling; and to use age, bladder volume, urge incontinence and detrusor overactivity (DO) as probes to reveal control-system function. Functional MRI was used to examine regional brain responses to bladder infusion in 21 females (26 – 85 years): 11 “cases” with urge incontinence and DO (proven previously) and 10 normal “controls”. Responses and their age dependence were determined at small and large bladder volumes, in whole brain and in regions of interest representing right insula and anterior cingulate (ACG). In “controls”, increasing bladder volume/sensation led to increasing insular responses; with increasing age, insular responses became weaker. In younger “cases”, ACG responded abnormally strongly at large bladder volumes/strong sensation. Elderly “cases” showed strong ACG responses even at small bladder volume, but more moderate responses at larger volumes; if DO occurred, pontine micturition center (PMC) activation did not increase. Conclusion: Among normal “controls”, increasing age leads to decreased responses in brain regions involved in bladder control, including right insula, consistent with its role in mapping normal bladder sensations. Strong ACG activation occurs in urge-incontinent “cases” and may be a sign of urgency, indicating recruitment of alternative pathways when loss of bladder control is feared. Easier ACG provocation in older “cases” reflects lack of physiological reserve or different etiology. ACG responses seem associated with PMC inhibition: reduced ACG activity accompanies failure of inhibition (DO). PMID:17574871

Reinnervation following catheter-based radio-frequency renal denervation.

PubMed

Booth, Lindsea C; Nishi, Erika E; Yao, Song T; Ramchandra, Rohit; Lambert, Gavin W; Schlaich, Markus P; May, Clive N

2015-04-20

What is the topic of this review? Does catheter-based renal denervation effectively denervate the afferent and efferent renal nerves and does reinnervation occur? What advances does it highlight? Following catheter-based renal denervation, the afferent and efferent responses to electrical stimulation were abolished, renal sympathetic nerve activity was absent, and levels of renal noradrenaline and immunohistochemistry for tyrosine hydroxylase and calcitonin gene-related peptide were significantly reduced. By 11 months after renal denervation, both the functional responses and anatomical markers of afferent and efferent renal nerves had returned to normal, indicating reinnervation. Renal denervation reduces blood pressure in animals with experimental hypertension and, recently, catheter-based renal denervation was shown to cause a prolonged decrease in blood pressure in patients with resistant hypertension. The randomized, sham-controlled Symplicity HTN-3 trial failed to meet its primary efficacy end-point, but there is evidence that renal denervation was incomplete in many patients. Currently, there is little information regarding the effectiveness of catheter-based renal denervation and the extent of reinnervation. We assessed the effectiveness of renal nerve denervation with the Symplicity Flex catheter and the functional and anatomical reinnervation at 5.5 and 11 months postdenervation. In anaesthetized, non-denervated sheep, there was a high level of renal sympathetic nerve activity, and electrical stimulation of the renal nerve increased blood pressure and reduced heart rate (afferent response) and caused renal vasoconstriction and reduced renal blood flow (efferent response). Immediately after renal denervation, renal sympathetic nerve activity and the responses to electrical stimulation were absent, indicating effective denervation. By 11 months after denervation, renal sympathetic nerve activity was present and the responses to electrical stimulation were normal, indicating reinnervation. Anatomical measures of renal innervation by sympathetic efferent nerves (tissue noradrenaline and tyrosine hydroxylase) and afferent sensory nerves (calcitonin gene-related peptide) demonstrated large decreases at 1 week postdenervation, but normal levels at 11 months postdenervation. In summary, catheter-based renal denervation is effective, but reinnervation occurs. Studies of central and renal changes postdenervation are required to understand the causes of the prolonged hypotensive response to catheter-based renal denervation in human hypertension. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

Tachycardia

MedlinePlus

... normal while at rest. It's normal for your heart rate to rise during exercise or as a physiological ... the heart or both while at rest. Your heart rate is controlled by electrical signals sent across heart ...

Multiorgan insulin sensitivity in lean and obese subjects.

PubMed

Conte, Caterina; Fabbrini, Elisa; Kars, Marleen; Mittendorfer, Bettina; Patterson, Bruce W; Klein, Samuel

2012-06-01

To provide a comprehensive assessment of multiorgan insulin sensitivity in lean and obese subjects with normal glucose tolerance. The hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracer infusions was performed in 40 obese (BMI 36.2 ± 0.6 kg/m(2), mean ± SEM) and 26 lean (22.5 ± 0.3 kg/m(2)) subjects with normal glucose tolerance. Insulin was infused at different rates to achieve low, medium, and high physiological plasma concentrations. In obese subjects, palmitate and glucose R(a) in plasma decreased with increasing plasma insulin concentrations. The decrease in endogenous glucose R(a) was greater during low-, medium-, and high-dose insulin infusions (69 ± 2, 74 ± 2, and 90 ± 2%) than the suppression of palmitate R(a) (52 ± 4, 68 ± 1, and 79 ± 1%). Insulin-mediated increase in glucose disposal ranged from 24 ± 5% at low to 253 ± 19% at high physiological insulin concentrations. The suppression of palmitate R(a) and glucose R(a) were greater in lean than obese subjects during low-dose insulin infusion but were the same in both groups during high-dose insulin infusion, whereas stimulation of glucose R(d) was greater in lean than obese subjects across the entire physiological range of plasma insulin. Endogenous glucose production and adipose tissue lipolytic rate are both very sensitive to small increases in circulating insulin, whereas stimulation of muscle glucose uptake is minimal until high physiological plasma insulin concentrations are reached. Hyperinsulinemia within the normal physiological range can compensate for both liver and adipose tissue insulin resistance, but not skeletal muscle insulin resistance, in obese people who have normal glucose tolerance.

A pseudo-three-dimensional model for quantification of oxygen diffusion from preglomerular arteries to renal tissue and renal venous blood.

PubMed

Lee, Chang-Joon; Ngo, Jennifer P; Kar, Saptarshi; Gardiner, Bruce S; Evans, Roger G; Smith, David W

2017-08-01

To assess the physiological significance of arterial-to-venous (AV) oxygen shunting, we generated a new pseudo-three-dimensional computational model of oxygen diffusion from intrarenal arteries to cortical tissue and veins. The model combines the 11 branching levels (known as "Strahler" orders) of the preglomerular renal vasculature in the rat, with an analysis of an extensive data set obtained using light microscopy to estimate oxygen mass transfer coefficients for each Strahler order. Furthermore, the AV shunting model is now set within a global oxygen transport model that includes transport from arteries, glomeruli, peritubular capillaries, and veins to tissue. While a number of lines of evidence suggest AV shunting is significant, most importantly, our AV oxygen shunting model predicts AV shunting is small under normal physiological conditions (~0.9% of total renal oxygen delivery; range 0.4-1.4%), but increases during renal ischemia, glomerular hyperfiltration (~2.1% of total renal oxygen delivery; range 0.84-3.36%), and some cardiovascular disease states (~3.0% of total renal oxygen delivery; range 1.2-4.8%). Under normal physiological conditions, blood Po 2 is predicted to fall by ~16 mmHg from the root of the renal artery to glomerular entry, with AV oxygen shunting contributing ~40% and oxygen diffusion from arteries to tissue contributing ~60% of this decline. Arterial Po 2 is predicted to fall most rapidly from Strahler order 4 , under normal physiological conditions. We conclude that AV oxygen shunting normally has only a small impact on renal oxygenation, but may exacerbate renal hypoxia during renal ischemia, hyperfiltration, and some cardiovascular disease states. Copyright © 2017 the American Physiological Society.

Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes.

PubMed

Castelli, Fulvia; Frith, Chris; Happé, Francesca; Frith, Uta

2002-08-01

Ten able adults with autism or Asperger syndrome and 10 normal volunteers were PET scanned while watching animated sequences. The animations depicted two triangles moving about on a screen in three different conditions: moving randomly, moving in a goal-directed fashion (chasing, fighting), and moving interactively with implied intentions (coaxing, tricking). The last condition frequently elicited descriptions in terms of mental states that viewers attributed to the triangles (mentalizing). The autism group gave fewer and less accurate descriptions of these latter animations, but equally accurate descriptions of the other animations compared with controls. While viewing animations that elicited mentalizing, in contrast to randomly moving shapes, the normal group showed increased activation in a previously identified mentalizing network (medial prefrontal cortex, superior temporal sulcus at the temporo-parietal junction and temporal poles). The autism group showed less activation than the normal group in all these regions. However, one additional region, extrastriate cortex, which was highly active when watching animations that elicited mentalizing, showed the same amount of increased activation in both groups. In the autism group this extrastriate region showed reduced functional connectivity with the superior temporal sulcus at the temporo-parietal junction, an area associated with the processing of biological motion as well as with mentalizing. This finding suggests a physiological cause for the mentalizing dysfunction in autism: a bottleneck in the interaction between higher order and lower order perceptual processes.

Lag threads organize the brain’s intrinsic activity

PubMed Central

Mitra, Anish; Snyder, Abraham Z.; Blazey, Tyler; Raichle, Marcus E.

2015-01-01

It has been widely reported that intrinsic brain activity, in a variety of animals including humans, is spatiotemporally structured. Specifically, propagated slow activity has been repeatedly demonstrated in animals. In human resting-state fMRI, spontaneous activity has been understood predominantly in terms of zero-lag temporal synchrony within widely distributed functional systems (resting-state networks). Here, we use resting-state fMRI from 1,376 normal, young adults to demonstrate that multiple, highly reproducible, temporal sequences of propagated activity, which we term “lag threads,” are present in the brain. Moreover, this propagated activity is largely unidirectional within conventionally understood resting-state networks. Modeling experiments show that resting-state networks naturally emerge as a consequence of shared patterns of propagation. An implication of these results is that common physiologic mechanisms may underlie spontaneous activity as imaged with fMRI in humans and slowly propagated activity as studied in animals. PMID:25825720

The Phospholipase A2 Activity of Peroxiredoxin 6.

PubMed

Fisher, Aron B

2018-05-01

Peroxiredoxin 6 (Prdx6) is a Ca2+-independent intracellular phospholipase A2 (called aiPLA2) that is localized to cytosol and acidic organelles (lysosomes and lysosomal-related organelles). Activity is minimal at cytosolic pH but is increased significantly at acidic pH, in the presence of oxidized phospholipid substrate, with protein oxidation, and with enzyme phosphorylation; maximal activity with phosphorylated aiPLA2 is ~2 μmol/min/mg protein. Prdx6 is a ″moonlighting″ protein that also expresses peroxidase and lysophosphatidylcholine acyl transferase activities.The active site for aiPLA2 activity is Ser32-H26-D140. Activity is inhibited by a serine ″protease″ inhibitor diethyl p-nitrophenyl phosphate (DENP) ,a transition state analogue 1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol (MJ33),and two naturally occurring proteins, surfactant protein A (SP-A) and p67phox. aiPLA2 activity has important physiological roles in the turnover (degradation and synthesis) of lung surfactant phospholipids, in the repair of peroxidized cell membranes, and in the activation of NADPH oxidase (NOX2). The enzyme has been implicated in acute lung injury, carcinogenesis, neurodegenerative diseases, diabetes, male infertility, and sundry other conditions although its specific roles have not been well defined. Protein mutations and animal models are now available to further investigate the potentially important roles of Prdx6-aiPLA2 activity in normal and pathological physiology. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Evaluation of normal swallowing functions by using dynamic high-density surface electromyography maps.

PubMed

Zhu, Mingxing; Yu, Bin; Yang, Wanzhang; Jiang, Yanbing; Lu, Lin; Huang, Zhen; Chen, Shixiong; Li, Guanglin

2017-11-21

Swallowing is a continuous process with substantive interdependencies among different muscles, and it plays a significant role in our daily life. The aim of this study was to propose a novel technique based on high-density surface electromyography (HD sEMG) for the evaluation of normal swallowing functions. A total of 96 electrodes were placed on the front neck to acquire myoelectric signals from 12 healthy subjects while they were performing different swallowing tasks. HD sEMG energy maps were constructed based on the root mean square values to visualize muscular activities during swallowing. The effects of different volumes, viscosities, and head postures on the normal swallowing process were systemically investigated by using the energy maps. The results showed that the HD sEMG energy maps could provide detailed spatial and temporal properties of the muscle electrical activity, and visualize the muscle contractions that closely related to the swallowing function. The energy maps also showed that the swallowing time and effort was also explicitly affected by the volume and viscosity of the bolus. The concentration of the muscular activities shifted to the opposite side when the subjects turned their head to either side. The proposed method could provide an alternative method to physiologically evaluate the dynamic characteristics of normal swallowing and had the advantage of providing a full picture of how different muscle activities cooperate in time and location. The findings from this study suggested that the HD sEMG technique might be a useful tool for fast screening and objective assessment of swallowing disorders or dysphagia.

Stimulation-induced Ca(2+) influx at nodes of Ranvier in mouse peripheral motor axons.

PubMed

Zhang, Zhongsheng; David, Gavriel

2016-01-01

In peripheral myelinated axons of mammalian spinal motor neurons, Ca(2+) influx was thought to occur only in pathological conditions such as ischaemia. Using Ca(2+) imaging in mouse large motor axons, we find that physiological stimulation with trains of action potentials transiently elevates axoplasmic [C(2+)] around nodes of Ranvier. These stimulation-induced [Ca(2+)] elevations require Ca(2+) influx, and are partially reduced by blocking T-type Ca(2+) channels (e.g. mibefradil) and by blocking the Na(+)/Ca(2+) exchanger (NCX), suggesting an important contribution of Ca(2+) influx via reverse-mode NCX activity. Acute disruption of paranodal myelin dramatically increases stimulation-induced [Ca(2+)] elevations around nodes by allowing activation of sub-myelin L-type (nimodipine-sensitive) Ca(2+) channels. The Ca(2+) that enters myelinated motor axons during normal activity is likely to contribute to several signalling pathways; the larger Ca(2+) influx that occurs following demyelination may contribute to the axonal degeneration that occurs in peripheral demyelinating diseases. Activity-dependent Ca(2+) signalling is well established for somata and terminals of mammalian spinal motor neurons, but not for their axons. Imaging of an intra-axonally injected fluorescent [Ca(2+)] indicator revealed that during repetitive action potential stimulation, [Ca(2+)] elevations localized to nodal regions occurred in mouse motor axons from ventral roots, phrenic nerve and intramuscular branches. These [Ca(2+)] elevations (∼ 0.1 μm with stimulation at 50 Hz, 10 s) were blocked by removal of Ca(2+) from the extracellular solution. Effects of pharmacological blockers indicated contributions from both T-type Ca(2+) channels and reverse mode Na(+)/Ca(2+) exchange (NCX). Acute disruption of paranodal myelin (by stretch or lysophosphatidylcholine) increased the stimulation-induced [Ca(2+)] elevations, which now included a prominent contribution from L-type Ca(2+) channels. These results suggest that the peri-nodal axolemma of motor axons includes multiple pathways for stimulation-induced Ca(2+) influx, some active in normally-myelinated axons (T-type channels, NCX), others active only when exposed by myelin disruption (L-type channels). The modest axoplasmic peri-nodal [Ca(2+)] elevations measured in intact motor axons might mediate local responses to axonal activation. The larger [Ca(2+) ] elevations measured after myelin disruption might, over time, contribute to the axonal degeneration observed in peripheral demyelinating neuropathies. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

The organization of the stress system and its dysregulation in depressive illness.

PubMed

Gold, P W

2015-02-01

Stressors are imminent or perceived challenges to homeostasis. The stress response is an innate, stereotypic, adaptive response to stressors that has evolved in the service of restoring the nonstressed homeostatic set point. It is encoded in specific neuroanatomical sites that activate a specific repertoire of cognitive, behavioral and physiologic phenomena. Adaptive responses, though essential for survival, can become dysregulated and result in disease. A clear example is autoimmune disease. I postulate that depression, like autoimmunity, represents a dysregulated adaptive response: a stress response that has gone awry. The cardinal manifestation of the normal stress response is anxiety. Cognitive programs shift from complex associative operations to rapid retrieval of unconscious emotional memories acquired during prior threatening situations. These emerge automatically to promote survival. To prevent distraction during stressful situations, the capacity to seek and experience pleasure is reduced, food intake is diminished and sexual activity and sleep are held in abeyance. Monoamines, cytokines, glutamate, GABA and other central mediators have key roles in the normal stress response. Many central loci are involved. The subgenual prefrontal cortex restrains the amygdala, the corticotropin-releasing hormone/hypothalamic-pituitary-adrenal (CRH/HPA) axis and the sympathomedullary system. The function of the subgenual prefrontal cortex is moderately diminished during normal stress to disinhibit these loci. This disinhibition promotes anxiety and physiological hyperarousal, while diminishing appetite and sleep. The dorsolateral prefrontal cortex is downregulated, diminishing cognitive regulation of anxiety. The nucleus accumbens is also downregulated, to reduce the propensity for distraction by pleasurable stimuli or the capacity to experience pleasure. Insulin resistance, inflammation and a prothrombotic state acutely emerge. These provide increased glucose for the brain and establish premonitory, proinflammatory and prothrombotic states in anticipation of either injury or hemorrhage during a threatening situation. Essential adaptive intracellular changes include increased neurogenesis, enhancement of neuroplasticity and deployment of a successful endoplasmic reticulum stress response. In melancholic depression, the activities of the central glutamate, norepinephrine and central cytokine systems are significantly and persistently increased. The subgenual prefrontal cortex is functionally impaired, and its size is reduced by as much as 40%. This leads to sustained anxiety and activations of the amygdala, CRH/HPA axis, the sympathomedullary system and their sequella, including early morning awakening and loss of appetite. The sustained activation of the amygdala, in turn, further activates stress system neuroendocrine and autonomic functions. The activity of the nucleus accumbens is further decreased and anhedonia emerges. Concomitantly, neurogenesis and neuroplasticity fall significantly. Antidepressants ameliorate many of these processes. The processes that lead to the behavioral and physiological manifestations of depressive illness produce a significant decrease in lifespan, and a doubling of the incidence of premature coronary artery disease. The incidences of premature diabetes and osteoporosis are also substantially increased. Six physiological processes that occur during stress and that are markedly increased in melancholia set into motion six different mechanisms to produce inflammation, as well as sustained insulin resistance and a prothrombotic state. Clinically, melancholic and atypical depression seem to be antithesis of one another. In melancholia, depressive systems are at their worst in the morning when arousal systems, such as the CRH/HPA axis and the noradrenergic systems, are at their maxima. In atypical depression, depressive symptoms are at their worst in the evening, when these arousal systems are at their minima. Melancholic patients experience anorexia and insomnia, whereas atypical patients experience hyperphagia and hypersomnia. Melancholia seems like an activation and persistence of the normal stress response, whereas atypical depression resembles a stress response that has been excessively inhibited. It is important that we stratify clinical studies of depressed patients to compare melancholic and atypical subtypes and establish their differential pathophysiology. Overall, it is important to note that many of the major mediators of the stress response and melancholic depression, such as the subgenual prefrontal cortex, the amygdala, the noradrenergic system and the CRH/HPA axis participate in multiple reinforcing positive feedback loops. This organization permits the establishment of the markedly exaggerated, persistent elevation of the stress response seen in melancholia. Given their pronounced interrelatedness, it may not matter where in this cascade the first abnormality arises. It will spread to the other loci and initiate each of their activations in a pernicious vicious cycle.

Expression of Translationally Controlled Tumor Protein in Human Kidney and in Renal Cell Carcinoma.

PubMed

Ambrosio, Maria R; Rocca, Bruno J; Barone, Aurora; Onorati, Monica; Mundo, Lucia; Crivelli, Filippo; Di Nuovo, Franca; De Falco, Giulia; del Vecchio, Maria T; Tripodi, Sergio A; Tosi, Piero

2015-01-01

Translationally controlled tumor protein is a multifaceted protein involved in several physiological and biological functions. Its expression in normal kidney and in renal carcinomas, once corroborated by functional data, may add elements to elucidate renal physiology and carcinogenesis. In this study, translationally controlled tumor protein expression was evaluated by quantitative real time polymerase chain reaction and western blotting, and its localization was examined by immunohistochemistry on 84 nephrectomies for cancer. In normal kidney protein expression was found in the cytoplasm of proximal and distal tubular cells, in cells of the thick segment of the loop of Henle, and in urothelial cells of the pelvis. It was also detectable in cells of renal carcinoma with different pattern of localization (membranous and cytoplasmic) depending on tumor histotype. Our data may suggest an involvement of translationally controlled tumor protein in normal physiology and carcinogenesis. However, functional in vitro and in vivo studies are needed to verify this hypothesis.

Expression of Translationally Controlled Tumor Protein in Human Kidney and in Renal Cell Carcinoma

PubMed Central

Ambrosio, Maria R.; Rocca, Bruno J.; Barone, Aurora; Onorati, Monica; Mundo, Lucia; Crivelli, Filippo; Di Nuovo, Franca; De Falco, Giulia; del Vecchio, Maria T.; Tripodi, Sergio A.; Tosi, Piero

2015-01-01

Translationally controlled tumor protein is a multifaceted protein involved in several physiological and biological functions. Its expression in normal kidney and in renal carcinomas, once corroborated by functional data, may add elements to elucidate renal physiology and carcinogenesis. In this study, translationally controlled tumor protein expression was evaluated by quantitative real time polymerase chain reaction and western blotting, and its localization was examined by immunohistochemistry on 84 nephrectomies for cancer. In normal kidney protein expression was found in the cytoplasm of proximal and distal tubular cells, in cells of the thick segment of the loop of Henle, and in urothelial cells of the pelvis. It was also detectable in cells of renal carcinoma with different pattern of localization (membranous and cytoplasmic) depending on tumor histotype. Our data may suggest an involvement of translationally controlled tumor protein in normal physiology and carcinogenesis. However, functional in vitro and in vivo studies are needed to verify this hypothesis. PMID:26425551

Adipose tissue and inflammatory bowel disease pathogenesis.

PubMed

Fink, Christopher; Karagiannides, Iordanes; Bakirtzi, Kyriaki; Pothoulakis, Charalabos

2012-08-01

Creeping fat has long been recognized as an indicator of Crohn's disease (CD) activity. Although most patients with CD have normal or low body mass index (BMI), the ratio of intraabdominal fat to total abdominal fat is far greater than that of controls. The obesity epidemic has instructed us on the inflammatory nature of hypertrophic adipose tissue and similarities between mesenteric depots in obese and CD patients can be drawn. However, several important physiological differences exist between these two depots as well. While the molecular basis of the crosstalk between mesenteric adipose and the inflamed intestine in CD is largely unknown, novel evidence implicates neuropeptides along with adipocyte-derived paracrine mediators (adipokines) as potential targets for future investigations and highlight adipose tissue physiology as a potential important determinant in the course of IBD. Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.

Proceedings of the 1973 Lyndon B. Johnson Space Center Endocrine Program Conference

NASA Technical Reports Server (NTRS)

1975-01-01

Papers given at the conference are presented. Subjects covered include the following: biochemical changes during 28 days of space flight, modulating the pituitary-adrenal response to stress, the significance of biorhythms in space flight, the importance of the rein-angiotensin system in normal cardiovascular homeostasis, a progress report of stress-induced changes in corticosteroid metabolism, recent studies of physiological factors involved in the regulation of serotonin content and turnover in the brain, the role of brain biogenic amines in the control of pituitary-adrenocortical activity, application of the water immersion model to man by studies of acid-base homeostasis during simulated weightlessness, the present status of physiological studies and analysis of calcium homeostasis in the Apollo and Skylab programs, and endocrine considerations in the red-cell-mass and plasma-volume changes of Skylab 2 and 3 crews.

Effects of spinal cord injury-induced changes in muscle activation on foot drag in a computational rat ankle model.

PubMed

Hillen, Brian K; Jindrich, Devin L; Abbas, James J; Yamaguchi, Gary T; Jung, Ranu

2015-04-01

Spinal cord injury (SCI) can lead to changes in muscle activation patterns and atrophy of affected muscles. Moderate levels of SCI are typically associated with foot drag during the swing phase of locomotion. Foot drag is often used to assess locomotor recovery, but the causes remain unclear. We hypothesized that foot drag results from inappropriate muscle coordination preventing flexion at the stance-to-swing transition. To test this hypothesis and to assess the relative contributions of neural and muscular changes on foot drag, we developed a two-dimensional, one degree of freedom ankle musculoskeletal model with gastrocnemius and tibialis anterior muscles. Anatomical data collected from sham-injured and incomplete SCI (iSCI) female Long-Evans rats as well as physiological data from the literature were used to implement an open-loop muscle dynamics model. Muscle insertion point motion was calculated with imposed ankle trajectories from kinematic analysis of treadmill walking in sham-injured and iSCI animals. Relative gastrocnemius deactivation and tibialis anterior activation onset times were varied within physiologically relevant ranges based on simplified locomotor electromyogram profiles. No-atrophy and moderate muscle atrophy as well as normal and injured muscle activation profiles were also simulated. Positive moments coinciding with the transition from stance to swing phase were defined as foot swing and negative moments as foot drag. Whereas decreases in activation delay caused by delayed gastrocnemius deactivation promote foot drag, all other changes associated with iSCI facilitate foot swing. Our results suggest that even small changes in the ability to precisely deactivate the gastrocnemius could result in foot drag after iSCI. Copyright © 2015 the American Physiological Society.

The myths and physiology surrounding intrapartum decelerations: the critical role of the peripheral chemoreflex

PubMed Central

Lear, Christopher A.; Galinsky, Robert; Wassink, Guido; Yamaguchi, Kyohei; Davidson, Joanne O.; Westgate, Jenny A.; Bennet, Laura

2016-01-01

Abstract A distinctive pattern of recurrent rapid falls in fetal heart rate, called decelerations, are commonly associated with uterine contractions during labour. These brief decelerations are mediated by vagal activation. The reflex triggering this vagal response has been variably attributed to a mechanoreceptor response to fetal head compression, to baroreflex activation following increased blood pressure during umbilical cord compression, and/or a Bezold–Jarisch reflex response to reduced venous return from the placenta. Although these complex explanations are still widespread today, there is no consistent evidence that they are common during labour. Instead, the only mechanism that has been systematically investigated, proven to be reliably active during labour and, crucially, capable of producing rapid decelerations is the peripheral chemoreflex. The peripheral chemoreflex is triggered by transient periods of asphyxia that are a normal phenomenon associated with all uterine contractions. This should not cause concern as the healthy fetus has a remarkable ability to adapt to these repeated but short periods of asphyxia. This means that the healthy fetus is typically not at risk of hypotension and injury during uncomplicated labour even during repeated brief decelerations. The physiologically incorrect theories surrounding decelerations that ignore the natural occurrence of repeated asphyxia probably gained widespread support to help explain why many babies are born healthy despite repeated decelerations during labour. We propose that a unified and physiological understanding of intrapartum decelerations that accepts the true nature of labour is critical to improve interpretation of intrapartum fetal heart rate patterns. PMID:27328617

Modulation of Wolframin Expression in Human Placenta during Pregnancy: Comparison among Physiological and Pathological States

PubMed Central

Perna, Angelica; Iannaccone, Alessandro; Cobellis, Luigi; De Luca, Antonio

2014-01-01

The WFS1 gene, encoding a transmembrane glycoprotein of the endoplasmic reticulum called wolframin, is mutated in Wolfram syndrome, an autosomal recessive disorder defined by the association of diabetes mellitus, optic atrophy, and further organ abnormalities. Disruption of the WFS1 gene in mice causes progressive β-cell loss in the pancreas and impaired stimulus-secretion coupling in insulin secretion. However, little is known about the physiological functions of this protein. We investigated the immunohistochemical expression of wolframin in human placenta throughout pregnancy in normal women and diabetic pregnant women. In normal placenta, there was a modulation of wolframin throughout pregnancy with a strong level of expression during the first trimester and a moderate level in the third trimester of gestation. In diabetic women, wolframin expression was strongly reduced in the third trimester of gestation. The pattern of expression of wolframin in normal placenta suggests that this protein may be required to sustain normal rates of cytotrophoblast cell proliferation during the first trimester of gestation. The decrease in wolframin expression in diabetic placenta suggests that this protein may participate in maintaining the physiologic glucose homeostasis in this organ. PMID:24588001

Physiological oxygen prevents frequent silencing of the DLK1-DIO3 cluster during human embryonic stem cells culture.

PubMed

Xie, Pingyuan; Sun, Yi; Ouyang, Qi; Hu, Liang; Tan, Yueqiu; Zhou, Xiaoying; Xiong, Bo; Zhang, Qianjun; Yuan, Ding; Pan, Yi; Liu, Tiancheng; Liang, Ping; Lu, Guangxiu; Lin, Ge

2014-02-01

Genetic and epigenetic alterations are observed in long-term culture (>30 passages) of human embryonic stem cells (hESCs); however, little information is available in early cultures. Through a large-scale gene expression analysis between initial-passage hESCs (ihESCs, <10 passages) and early-passage hESCs (ehESCs, 20-30 passages) of 12 hESC lines, we found that the DLK1-DIO3 gene cluster was normally expressed and showed normal methylation pattern in ihESC, but was frequently silenced after 20 passages. Both the DLK1-DIO3 active status in ihESCs and the inactive status in ehESCs were inheritable during differentiation. Silencing of the DLK1-DIO3 cluster did not seem to compromise the multilineage differentiation ability of hESCs, but was associated with reduced DNA damage-induced apoptosis in ehESCs and their differentiated hepatocyte-like cell derivatives, possibly through attenuation of the expression and phosphorylation of p53. Furthermore, we demonstrated that 5% oxygen, instead of the commonly used 20% oxygen, is required for preserving the expression of the DLK1-DIO3 cluster. Overall, the data suggest that active expression of the DLK1-DIO3 cluster represents a new biomarker for epigenetic stability of hESCs and indicates the importance of using a proper physiological oxygen level during the derivation and culture of hESCs. © AlphaMed Press.

Description of intraoral pressures on sub-palatal space in young adult patients with normal occlusion.

PubMed

Fuentes, Ramón; Engelke, Wilfried; Flores, Tania; Navarro, Pablo; Borie, Eduardo; Curiqueo, Aldo; Salamanca, Carlos

2015-01-01

Under normal conditions, the oral cavity presents a perfect system of equilibrium between teeth, soft tissues and tongue. The equilibrium of soft tissues forms a closed capsular matrix, generating differences with the atmospheric environment. This difference is known as intraoral pressure. Negative intraoral pressure is fundamental to the stabilization of the soft palate and tongue, reducing neuromuscular activity for the permeability of the respiratory tract. Thus, the aim of this study was to describe the variations of intraoral pressure of the sub-palatal space (SPS) under different physiological conditions and biofunctional phases. A case series was conducted with 20 individuals aged between 18 and 25. The intraoral pressures were measured through a system of cannulae connected to a digital pressure meter in the SPS during seven biofunctional phases. Descriptive statistics were used based on the mean and standard deviation. The data recorded pressure variations under physiological conditions, reaching 65 mbar as the intraoral peak in forced inspiration. In the swallowing phase, peaks reached -91.9 mbar. No pressure variations were recorded in terms of atmospheric changes with the mouth open and semi-open. The data obtained during the swallowing and forced inspiration phases indicated forced lingual activity. In the swallowing phase, the adequate position of the tongue creates negative intraoral pressure, which represents a fundamental mechanism for the physical stabilization of the soft palate. This information could contribute to subsequent research into the treatment of primary roncopathies.

Muscle length-dependent contribution of motoneuron Cav1.3 channels to force production in model slow motor unit.

PubMed

Kim, Hojeong

2017-07-01

Persistent inward current (PIC)-generating Ca v 1.3 channels in spinal motoneuron dendrites are thought to be actively recruited during normal behaviors. However, whether and how the activation of PIC channels influences force output of motor unit remains elusive. Here, building a physiologically realistic model of slow motor unit I demonstrated that force production induced by the PIC activation is much smaller for short than lengthened muscles during the regular firing of the motoneuron that transitions from the quiescent state by either a brief current pulse at the soma or a brief synaptic excitation at the dendrites. By contrast, the PIC-induced force potentiation was maximal for short muscles when the motoneuron switched from a stable low-frequency firing state to a stable high-frequency firing state by the current pulse at the soma. Under the synaptic excitation at the dendrites, however, the force could not be potentiated by the transitioning of the motoneuron from a low- to a high-frequency firing state due to the simultaneous onset of PIC at the dendrites and firing at the soma. The strong dependency of the input-output relationship of the motor unit on the neuromodulation and Ia afferent inputs for the PIC channels was further shown under static variations in muscle length. Taken together, these findings suggest that the PIC activation in the motoneuron dendrites may differentially affect the force production of the motor unit, depending not only on the firing state history of the motoneuron and the variation in muscle length but also on the mode of motor activity. NEW & NOTEWORTHY Ca v 1.3 channels in motoneuron dendrites are actively involved during normal motor activities. To investigate the effects of the activation of motoneuron Ca v 1.3 channels on force production, a model motor unit was built based on best-available data. The simulation results suggest that force potentiation induced by Ca v 1.3 channel activation is strongly modulated not only by firing history of the motoneuron but also by length variation of the muscle as well as neuromodulation inputs from the brainstem. Copyright © 2017 the American Physiological Society.

The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells

PubMed Central

Sasaki, Clarence T.; Toman, Julia; Vageli, Dimitra

2016-01-01

Background Extra-esophageal carcinogenesis has been widely discussed in relation to the chronic effects of laryngopharyngeal reflux and most prominently with pepsin historically central to this discussion. With refluxate known to include gastric (pepsin) and duodenal (bile) fluids, we recently demonstrated the mechanistic role of NF-κB in mediating the preneoplastic effects of acidic-bile. However, the role of pepsin in promoting hypopharyngeal premalignant events remains historically unclear. Here, we investigate the in vitro effect of acidic-pepsin on the NF-κB oncogenic pathway to better define its potential role in hypopharyngeal neoplasia. Methods Human hypopharyngeal primary cells (HHPC) and keratinocytes (HHK) were repetitively exposed to physiologic pepsin concentrations (0.1 mg/ml) at pH 4.0, 5.0 and 7.0. Cellular localization of phospho-NF-κB and bcl-2 was determined using immunofluorescence and western blotting. NF-κB transcriptional activity was tested by luc reporter and qPCR. Analysis of DNA content of pepsin treated HHK and HHPC was performed using Fluorescence-activated-cell sorting assay. To explore a possible dose related effect, pepsin concentration was reduced from 0.1 to 0.05 and 0.01 mg/ml. Results At physiologic concentration, acidic-pepsin (0.1 mg/ml at pH 4.0) is lethal to most normal hypopharyngeal cells. However, in surviving cells, no NF-κB transcriptional activity is noted. Acidic-pepsin fails to activate the NF-κB or bcl-2, TNF-α, EGFR, STAT3, and wnt5α but increases the Tp53 mRNAs, in both HHPC and HHK. Weakly acidic-pepsin (pH 5.0) and neutral-pepsin (pH 7.0) induce mild activation of NF-κB with increase in TNF-α mRNAs, without oncogenic transcriptional activity. Lower concentrations of pepsin at varying pH do not produce NF-κB activity or transcriptional activation of the analyzed genes. Conclusion Our findings in vitro do not support the role of acidic-pepsin in NF-κB related hypopharyngeal carcinogenesis. PMID:27973541

Fornix lesions decouple the induction of hippocampal arc transcription from behavior but not plasticity.

PubMed

Fletcher, Bonnie R; Calhoun, Michael E; Rapp, Peter R; Shapiro, Matthew L

2006-02-01

The immediate-early gene (IEG) Arc is transcribed after behavioral and physiological treatments that induce synaptic plasticity and is implicated in memory consolidation. The relative contributions of neuronal activity and learning-related plasticity to the behavioral induction of Arc remain to be defined. To differentiate the contributions of each, we assessed the induction of Arc transcription in rats with fornix lesions that impair hippocampal learning yet leave cortical connectivity and neuronal firing essentially intact. Arc expression was assessed after exploration of novel environments and performance of a novel water maze task during which normal rats learned the spatial location of an escape platform. During the same task, rats with fornix lesions learned to approach a visible platform but did not learn its spatial location. Rats with fornix lesions had normal baseline levels of hippocampal Arc mRNA, but unlike normal rats, expression was not increased in response to water maze training. The integrity of signaling pathways controlling Arc expression was demonstrated by stimulation of the medial perforant path, which induced normal synaptic potentiation and Arc in rats with fornix lesions. Together, the results demonstrate that Arc induction can be decoupled from behavior and is more likely to indicate the engagement of synaptic plasticity mechanisms than synaptic or neuronal activity per se. The results further imply that fornix lesions may impair memory in part by decoupling neuronal activity from signaling pathways required for long-lasting hippocampal synaptic plasticity.

Physiologic Inter-eye Differences in Monkey Optic Nerve Head Architecture and Their Relation to Changes in Early Experimental Glaucoma

PubMed Central

Yang, Hongli; Downs, J. Crawford; Burgoyne, Claude F.

2009-01-01

Purpose To characterize physiologic inter-eye differences in optic nerve head (ONH) architecture within six normal rhesus monkeys and compare them to inter-eye differences within three previously-reported cynomolgus monkeys with early experimental glaucoma (EEG). Methods Trephinated ONH and peripapillary sclera from both eyes of six normal monkeys were serial sectioned, 3D reconstructed, 3D delineated and parameterized. For each normal animal, and each parameter, physiologic inter-eye difference (PID) was calculated (both overall and regionally) by converting all OS data to OD configuration and subtracting the OS from the OD value and Physiologic Inter-eye Percent Difference (PIPD) was calculated as the PID divided by the measurement mean of the two eyes. For each EEG monkey, inter-eye (EEG minus normal) differences and percent differences for each parameter overall and regionally were compared to the PID and PIPD Maximums. Results For all parameters the PID Maximums were relatively small overall. Compared to overall PID maximums, overall inter-eye differences in EEG monkeys were greatest for laminar deformation and thickening, posterior scleral canal enlargement, cupping and prelaminar neural tissue thickening. Compared to the regional PID Maximums, the lamina cribrosa was posteriorly deformed centrally, inferiorly, inferonasally and superiorly and was thickened centrally. The prelaminar neural tissues were thickened inferiorly, inferonasally and superiorly. Conclusion These data provide the first characterization of PID/PIPD maximums for ONH neural and connective tissue parameters in normal monkeys and serve to further clarify the location and character of early ONH change in experimental glaucoma. However, because of the species differences, the findings in EEG need to be confirmed within EEG rhesus monkey eyes. PMID:18775866

Combating adolescent obesity: an integrated physiological and psychological perspective.

PubMed

ten Hoor, Gill A; Plasqui, Guy; Schols, Annemie M W J; Kok, Gerjo

2014-11-01

Optimizing the approach to combat childhood obesity, we emphasize the importance of combining both biological and psychological knowledge. In such an approach, strength exercises might be an important aspect in the treatment and prevention of childhood obesity. Recent evidence indicates plausible effects of the role of resistance exercise in combating the negative health effects of childhood obesity. When looking at body composition, overweight youngsters do not only have a higher fat mass, but also a higher muscle mass compared with their normal-weight counterparts. With that, they are also stronger and better in exercises wherein the focus is on absolute strength, making them - under the right circumstances - more motivated to engage in resistance exercise and ultimately maintain a physically active lifestyle. More and more children are obese, and obese children become obese adults. One reason that overweight youngsters are not physically active is that they are outperformed by normal-weight youngsters, and one reason they are overweight is because they are not physically active. To combat childhood obesity, strength exercise might be a solution to break the vicious cycle.

The effect of acute maximal exercise on postexercise hemodynamics and central arterial stiffness in obese and normal-weight individuals.

PubMed

Bunsawat, Kanokwan; Ranadive, Sushant M; Lane-Cordova, Abbi D; Yan, Huimin; Kappus, Rebecca M; Fernhall, Bo; Baynard, Tracy

2017-04-01

Central arterial stiffness is associated with incident hypertension and negative cardiovascular outcomes. Obese individuals have higher central blood pressure (BP) and central arterial stiffness than their normal-weight counterparts, but it is unclear whether obesity also affects hemodynamics and central arterial stiffness after maximal exercise. We evaluated central hemodynamics and arterial stiffness during recovery from acute maximal aerobic exercise in obese and normal-weight individuals. Forty-six normal-weight and twenty-one obese individuals underwent measurements of central BP and central arterial stiffness at rest and 15 and 30 min following acute maximal exercise. Central BP and normalized augmentation index (AIx@75) were derived from radial artery applanation tonometry, and central arterial stiffness was obtained via carotid-femoral pulse wave velocity (cPWV) and corrected for central mean arterial pressure (cPWV/cMAP). Central arterial stiffness increased in obese individuals but decreased in normal-weight individuals following acute maximal exercise, after adjusting for fitness. Obese individuals also exhibited an overall higher central BP ( P  <   0.05), with no exercise effect. The increase in heart rate was greater in obese versus normal-weight individuals following exercise ( P  <   0.05), but there was no group differences or exercise effect for AIx@75 In conclusion, obese (but not normal-weight) individuals increased central arterial stiffness following acute maximal exercise. An assessment of arterial stiffness response to acute exercise may serve as a useful detection tool for subclinical vascular dysfunction. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Endocannabinoids control vesicle release mode at midbrain periaqueductal grey inhibitory synapses.

PubMed

Aubrey, Karin R; Drew, Geoffrey M; Jeong, Hyo-Jin; Lau, Benjamin K; Vaughan, Christopher W

2017-01-01

The midbrain periaqueductal grey (PAG) forms part of an endogenous analgesic system which is tightly regulated by the neurotransmitter GABA. The role of endocannabinoids in regulating GABAergic control of this system was examined in rat PAG slices. Under basal conditions GABAergic neurotransmission onto PAG output neurons was multivesicular. Activation of the endocannabinoid system reduced GABAergic inhibition by reducing the probability of release and by shifting release to a univesicular mode. Blockade of endocannabinoid system unmasked a tonic control over the probability and mode of GABA release. These findings provides a mechanistic foundation for the control of the PAG analgesic system by disinhibition. The midbrain periaqueductal grey (PAG) has a crucial role in coordinating endogenous analgesic responses to physiological and psychological stressors. Endocannabinoids are thought to mediate a form of stress-induced analgesia within the PAG by relieving GABAergic inhibition of output neurons, a process known as disinhibition. This disinhibition is thought to be achieved by a presynaptic reduction in GABA release probability. We examined whether other mechanisms have a role in endocannabinoid modulation of GABAergic synaptic transmission within the rat PAG. The group I mGluR agonist DHPG ((R,S)-3,5-dihydroxyphenylglycine) inhibited evoked IPSCs and increased their paired pulse ratio in normal external Ca 2+ , and when release probability was reduced by lowering Ca 2+ . However, the effect of DHPG on the coefficient of variation and kinetics of evoked IPSCs differed between normal and low Ca 2+ . Lowering external Ca 2+ had a similar effect on evoked IPSCs to that observed for DHPG in normal external Ca 2+ . The low affinity GABA A receptor antagonist TPMPA ((1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid) inhibited evoked IPSCs to a greater extent in low than in normal Ca 2+ . Together these findings indicate that the normal mode of GABA release is multivesicular within the PAG, and that DHPG and lowering external Ca 2+ switch this to a univesicular mode. The effects of DHPG were mediated by mGlu5 receptor engagement of the retrograde endocannabinoid system. Blockade of endocannabinoid breakdown produced a similar shift in the mode of release. We conclude that endocannabinoids control both the mode and the probability of GABA release within the PAG. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Naturally produced citral can significantly inhibit normal physiology and induce cytotoxicity on Magnaporthe grisea.

PubMed

Li, Rong-Yu; Wu, Xiao-Mao; Yin, Xian-Hui; Long, You-Hua; Li, Ming

2015-02-01

Given the importance of finding alternatives to synthetic fungicides, the antifungal effects of natural product citral on six plant pathogenic fungi (Magnaporthe grisea, Gibberella zeae, Fusarium oxysporum, Valsa mali, Botrytis cinerea, and Rhizoctonia solani) were determined. Mycelial growth rate results showed that citral possessed high antifungal activities on those test fungi with EC50 values ranging from 39.52 to 193.00 µg/mL, which had the highest inhibition rates against M. grisea. Further action mechanism of citral on M. grisea was carried out. Citral treatment was found to alter the morphology of M. grisea hyphae by causing a loss of cytoplasm and distortion of mycelia. Moreover, citral was able to induce an increase in chitinase activity in M. grisea, indicating disruption of the cell wall. These results indicate that citral may act by disrupting cell wall integrity and membrane permeability, thus resulting in physiology changes and causing cytotoxicity. Importantly, the inhibitory effect of citral on M. grisea appears to be associated with its effects on mycelia reducing sugar, soluble protein, chitinase activity, pyruvate content, and malondialdehyde content. Copyright © 2014 Elsevier Inc. All rights reserved.

Swelling and Eicosanoid Metabolites Differentially Gate TRPV4 Channels in Retinal Neurons and Glia

PubMed Central

Ryskamp, Daniel A.; Jo, Andrew O.; Frye, Amber M.; Vazquez-Chona, Felix; MacAulay, Nanna; Thoreson, Wallace B.

2014-01-01

Activity-dependent shifts in ionic concentrations and water that accompany neuronal and glial activity can generate osmotic forces with biological consequences for brain physiology. Active regulation of osmotic gradients and cellular volume requires volume-sensitive ion channels. In the vertebrate retina, critical support to volume regulation is provided by Müller astroglia, but the identity of their osmosensor is unknown. Here, we identify TRPV4 channels as transducers of mouse Müller cell volume increases into physiological responses. Hypotonic stimuli induced sustained [Ca2+]i elevations that were inhibited by TRPV4 antagonists and absent in TRPV4−/− Müller cells. Glial TRPV4 signals were phospholipase A2- and cytochrome P450-dependent, characterized by slow-onset and Ca2+ waves, and, in excess, were sufficient to induce reactive gliosis. In contrast, neurons responded to TRPV4 agonists and swelling with fast, inactivating Ca2+ signals that were independent of phospholipase A2. Our results support a model whereby swelling and proinflammatory signals associated with arachidonic acid metabolites differentially gate TRPV4 in retinal neurons and glia, with potentially significant consequences for normal and pathological retinal function. PMID:25411497

Morphology, physiology, genetics, enigmas, and status of an extremely rare tree: Mutant tanoak

Treesearch

Philip M. McDonald; Jianwei Zhang; Randy S. Senock; Jessica W. Wright

2013-01-01

Important physical characteristics, morphological attributes, physiological functions, and genetic properties of mutant tanoak, Notholithocarpus densiflorus f. attenuato-dentatus (Fagaceae), and normal tanoak, Notholithocarpus densiflorus (Hook. & Arn.) Manos, Cannon & S. H. Oh, were studied on the Challenge...

Anthropometric and physiological profiles of active blind Malaysian males.

PubMed

Singh, R; Singh, H J

1993-12-01

Cardiopulmonary capacities of twelve adults (aged between 14 to 44 years) with varying degrees of blindness engaged in regular recreational activities were compared with twelve age-matched normal sighted healthy males (control group) who were also involved in regular recreational activities. Maximum oxygen consumption (VO2max) was measured directly during exhaustive exercise test on a cycle ergometer. Forced vital capacity, leg strength and power were determined by spirometry, standing long jump and vertical jump respectively. No significant differences in VO2max, forced vital capacity and leg strength and power were observed between the blind and the control groups. No anthropometric differences were evident between the two groups. The results show therefore that the visually handicapped who are active can have a similar level of physical fitness, lung function and explosive leg strength as those of their active sighted counterparts.

Role of STAT3 in Cancer Metastasis and Translational Advances

PubMed Central

Patil, Prachi; Gude, Rajiv P.

2013-01-01

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling. PMID:24199193

Alteration of Electro-Cortical Activity in Microgravity

NASA Astrophysics Data System (ADS)

Schneider, Stefan; Brummer, Vera; Carnahan, Heather; Askew, Christopher D.; Guardiera, Simon; Struder, Heiko K.

2008-06-01

There is growing interest in the effects of weightlessness on central nervous system (CNS) activity. Due to technical and logistical limitations it presently seems impossible to apply imaging techniques as fMRI or PET in weightless environments e.g. on ISS or during parabolic flights. Within this study we evaluated changes in brain cortical activity using low resolution brain electromagnetic tomography (LORETA) during parabolic flights. Results showed a distinct inhibition of right frontal area activity >12Hz during phases of microgravity compared to normal gravity. We conclude that the inhibition of high frequency frontal activity during microgravity may serve as a marker of emotional anxiety and/or indisposition associated with weightlessness. This puts a new light on the debate as to whether cognitive and sensorimotor impairments are attributable to primary physiological effects or secondary psychological effects of a weightless environment.

The anatomy and physiology of the avian endocrine system.

PubMed

Ritchie, Midge; Pilny, Anthony A

2008-01-01

The endocrine system of birds is comparable to that of mammals, although there are many unique aspects to consider when studying the anatomy, physiology, and biochemistry. Avian endocrinology is a field of veterinary medicine that is unfamiliar to many practitioners; however, it is important to have a comprehensive understanding when evaluating companion birds in clinical practice. This article covers the anatomy and physiology of the normal avian, and readers are referred to other articles for a more detailed explanation of altered physiology and pathology.

Extracts from black carrot tissue culture as potent anticancer agents.

PubMed

Sevimli-Gur, Canan; Cetin, Burcu; Akay, Seref; Gulce-Iz, Sultan; Yesil-Celiktas, Ozlem

2013-09-01

Black carrots contain anthocyanins possessing enhanced physiological activities. Explants of young black carrot shoots were cultured in Murashige and Skoog (MS) medium for callus initiation and were transferred to new MS medium supplemented with four different combinations of 2,4-dichlorophenoxyacetic acid and kinetin. Subsequently, the lyophilized calli and black carrot harvested from fields were subjected to ultrasound extraction with ethanol at a ratio of 1:15 (w:v). Obtained extracts were applied to various human cancer cell lines including MCF-7 SK-BR-3 and MDA-MB-231 (human breast adenocarcinomas), HT-29 (human colon adenocarcinoma), PC-3 (human prostate adenocarcinoma), Neuro 2A (Musmusculus neuroblastoma) cancer cell lines and VERO (African green monkey kidney) normal cell line by MTT assay. The highest cytotoxic activity was achieved against Neuro-2A cell lines exhibiting viability of 38-46% at 6.25 μg/ml concentration for all calli and natural extracts. However, a significantly high IC50 value of 170.13 μg/ml was attained in normal cell line VERO indicating that its natural counterpart is an ideal candidate for treatment of brain cancer without causing negative effects to normal healthy cells.

Zinc-Permeable Ion Channels: Effects on Intracellular Zinc Dynamics and Potential Physiological/Pathophysiological Significance

PubMed Central

Inoue, Koichi; O'Bryant, Zaven; Xiong, Zhi-Gang

2015-01-01

Zinc (Zn2+) is one of the most important trace metals in the body. It is necessary for the normal function of a large number of proteins including enzymes and transcription factors. While extracellular fluid may contain up to micromolar Zn2+, intracellular Zn2+ concentration is generally maintained at a subnanomolar level; this steep gradient across the cell membrane is primarily attributable to Zn2+ extrusion by Zn2+ transporting systems. Interestingly, systematic investigation has revealed that activities, previously believed to be dependent on calcium (Ca2+), may be partially mediated by Zn2+. This is also supported by new findings that some Ca2+-permeable channels such as voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate receptors (NMDA), and amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPA-Rs) are also permeable to Zn2+. Thus, the importance of Zn2+ in physiological and pathophysiological processes is now more widely appreciated. In this review, we describe Zn2+-permeable membrane molecules, especially Zn2+-permeable ion channels, in intracellular Zn2+dynamics and Zn2+ mediated physiology/pathophysiology. PMID:25666796

Unperturbed vs. post-transplantation hematopoiesis: both in vivo but different.

PubMed

Busch, Katrin; Rodewald, Hans-Reimer

2016-07-01

Hematopoietic stem cell (HSC) transplantation has yielded tremendous information on experimental properties of HSCs. Yet, it remains unclear whether transplantation reflects the physiology of hematopoiesis. A limitation is the difficulty in accessing HSC functions without isolation, in-vitro manipulation and readout for potential. New genetic fate mapping and clonal marking techniques now shed light on hematopoiesis under physiological conditions. Transposon-based genetic marks were introduced across the entire hematopoietic system to follow the clonal dynamics of these tags over time. A polyclonal source downstream from stem cells was found responsible for the production of at least granulocytes. In independent experiments, HSCs were genetically marked in adult mice, and the kinetics of label emergence throughout the system was followed over time. These experiments uncovered that during physiological steady-state hematopoiesis large numbers of HSCs yield differentiated progeny. Individual HSCs were active only rarely, indicating their very slow periodicity of differentiation rather than quiescence. Noninvasive genetic experiments in mice have identified a major role of stem and progenitor cells downstream from HSCs as drivers of adult hematopoiesis, and revealed that post-transplantation hematopoiesis differs quantitatively from normal steady-state hematopoiesis.

A Dual Role for NOTCH Signaling in Joint Cartilage Maintenance and Osteoarthritis

PubMed Central

Liu, Zhaoyang; Chen, Jianquan; Mirando, Anthony; Wang, Cuicui; Zuscik, Michael J.; O’Keefe, Regis J.; Hilton, Matthew J.

2015-01-01

Loss of NOTCH signaling in postnatal murine joints results in osteoarthritis (OA), indicating a requirement for NOTCH during joint cartilage maintenance. Unexpectedly, NOTCH components are significantly up-regulated in human and murine post-traumatic OA, suggesting either a reparative or pathological role for NOTCH activation in OA. Here we investigated the potential dual role for NOTCH in joint maintenance and OA by generating two mouse models overexpressing the NOTCH1 intracellular domain within postnatal joint cartilage; one with sustained NOTCH activation that likely resembles pathological NOTCH signaling and one with transient NOTCH activation that more closely reflects physiological NOTCH signaling. Sustained NOTCH signaling in joint cartilage leads to an early and progressive OA pathology, while on the contrary, transient NOTCH activation enhances cartilage matrix synthesis and promotes joint maintenance under normal physiological conditions. Using RNA-seq, immunohistochemical, and biochemical approaches we identified several novel targets potentially responsible for NOTCH-mediated cartilage degradation, fibrosis, and OA progression, including components of the IL6/STAT3 and ERK/p38 MAPK pathways; factors that may also contribute to post-traumatic OA development. Collectively, these data demonstrate a dual role for the NOTCH pathway in joint cartilage and identify important downstream NOTCH effectors as potential targets for disease modifying osteoarthritis drugs (DMOADs). PMID:26198357

Cellular and molecular mechanisms in the hypoxic tissue: role of HIF-1 and ROS.

PubMed

Zepeda, Andrea B; Pessoa, Adalberto; Castillo, Rodrigo L; Figueroa, Carolina A; Pulgar, Victor M; Farías, Jorge G

2013-08-01

Reactive oxygen species such as superoxide anion radicals (O2 (-) ) and hydrogen peroxide (H2 O2 ) have for long time been recognized as undesirable by-products of the oxidative mitochondrial generation of adenosine triphosphate (ATP). Recently, these highly reactive species have been associated to important signaling pathways in diverse physiological conditions such as those activated in hypoxic microenvironments. The molecular response to hypoxia requires fast-acting mechanisms acting within a wide range of partial pressures of oxygen (O2 ). Intracellular O2 sensing is an evolutionary preserved feature, and the best characterized molecular responses to hypoxia are mediated through transcriptional activation. The transcription factor, hypoxia-inducible factor 1 (HIF-1), is a critical mediator of these adaptive responses, and its activation by hypoxia involves O2 -dependent posttranslational modifications and nuclear translocation. Through the induction of the expression of its target genes, HIF-1 coordinately regulates tissue O2 supply and energetic metabolism. Other transcription factors such as nuclear factor κB are also redox sensitive and are activated in pro-oxidant and hypoxic conditions. The purpose of this review is to summarize new developments in HIF-mediated O2 sensing mechanisms and their interactions with reactive oxygen species-generating pathways in normal and abnormal physiology. Copyright © 2013 John Wiley & Sons, Ltd.

Piezo2 senses airway stretch and mediates lung inflation-induced apnoea

PubMed Central

Nonomura, Keiko; Woo, Seung-Hyun; Chang, Rui B.; Gillich, Astrid; Qiu, Zhaozhu; Francisco, Allain G.; Ranade, Sanjeev S.; Liberles, Stephen D.; Patapoutian, Ardem

2017-01-01

Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals remain obscured. Here we show that global and sensory neuron-specific ablation of the mechanically activated ion channel Piezo2 causes respiratory distress and death in newborn mice. Optogenetic activation of Piezo2+ vagal sensory neurons causes apnoea in adult mice. Moreover, induced ablation of Piezo2 in sensory neurons of adult mice causes decreased neuronal responses to lung inflation, an impaired Hering–Breuer mechanoreflex, and increased tidal volume under normal conditions. These phenotypes are reproduced in mice lacking Piezo2 in the nodose ganglion. Our data suggest that Piezo2 is an airway stretch sensor and that Piezo2-mediated mechanotransduction within various airway-innervating sensory neurons is critical for establishing efficient respiration at birth and maintaining normal breathing in adults. PMID:28002412

Protein S-nitrosylation as a therapeutic target for neurodegenerative diseases

PubMed Central

Nakamura, Tomohiro; Lipton, Stuart A.

2015-01-01

At physiological levels, nitric oxide (NO) contributes to the maintenance of normal neuronal activity and survival, thus serving as an important regulatory mechanism in the central nervous system. In contrast, accumulating evidence suggests that exposure to environmental toxins or the normal aging process can trigger excessive production of reactive oxygen/nitrogen species (such as NO), contributing to the etiology of several neurodegenerative diseases. Here we highlight protein S-nitrosylation, resulting from covalent attachment of an NO group to a cysteine thiol of the target protein, as a ubiquitous effector of NO signaling in both health and disease. We review our current understanding of this redox-dependent posttranslational modification under neurodegenerative conditions, and evaluate how targeting dysregulated protein S-nitrosylation can lead to novel therapeutics. PMID:26707925

A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity

PubMed Central

Duong, Bao H.; Onizawa, Michio; Oses-Prieto, Juan A.; Advincula, Rommel; Burlingame, Alma; Malynn, Barbara A.; Ma, Averil

2015-01-01

SUMMARY Inappropriate inflammasome activation contributes to multiple human diseases, but the mechanisms by which inflammasomes are suppressed are poorly understood. The NFκB inhibitor A20 is a ubiquitin-modifying enzyme that may prevent human inflammatory diseases and lymphomas. Here, we report that A20-deficient macrophages, unlike normal cells, exhibit spontaneous NLRP3 inflammasome activity to LPS alone. The kinase RIPK3, but not the adaptor MyD88, is required for this response. In normal cells, A20 constitutively associates with caspase-1 and pro-IL-1β, and NLRP3 activation further promotes A20 recruitment to the inflammasome. Pro-IL-1β also co-immunoprecipitates with RIPK1, RIPK3, caspase-1 and caspase-8 in a complex that is modified with K63-linked and unanchored polyubiquitin. In A20-deficient macrophages, this pro-IL-1β-associated ubiquitination is markedly increased in a RIPK3-dependent manner. Mass spectrometric and mutational analyses reveal that K133 of pro-IL-1β is a physiological ubiquitination site that supports processing. Our study reveals a novel mechanism by which A20 prevents inflammatory diseases. PMID:25607459

Effects of soybean meal on digestive enzymes activity, expression of inflammation-related genes, and chromatin modifications in marine fish (Sparus aurata L.) larvae.

PubMed

Perera, Erick; Yúfera, Manuel

2017-04-01

The effects of soybean meal (SBM) in early diet of Sparus aurata larvae at two developmental windows were assessed. Prolonged (beyond 14 days post-hatch, dph) feeding with SBM decreased the activity of pancreatic enzymes of larvae. In the absence of SBM these larvae later resumed enzyme activities, but exhibited a significant delay in development. Larvae response to SBM involved up-regulation of extracellular matrix remodeling enzymes and pro-inflammatory cytokines, coupled with a drop in putative intestinal enzymes. Larvae receiving SBM at first feeding appear later to have lower expression of inflammation-related genes, especially those fed SBM until 14 dph. Multivariate analysis confirmed that the duration of the SBM early feeding period drives the physiology of larvae in different directions. Feeding larvae with SBM increased global histone H3 acetylation, whereas upon removal of SBM the process was reverted. A more in deep analysis revealed a dynamic interplay among several reversible histone modifications such as H3K14ac and H3K27m3. Finally, we showed that SBM feeding of larvae results in global hypomethylation that persist after SBM removal. This study is the first demonstrating an effect of diet on marine fish epigenetics. It is concluded that there are limitations for extending SBM feeding of S. aurata larvae beyond 14 dph even under co-feeding with live feed, affecting key physiological processes and normal growth. However, up to 14 dph, SBM does not affect normal development, and produces apparently lasting effects on some key enzymes, genes, and chromatin modifications.

Change in hepatic function, hemodynamics, and morphology after liver transplant. Physiological effect of therapy.

PubMed

Millikan, W J; Henderson, J M; Stewart, M T; Warren, W D; Marsh, J W; Galloway, J R; Jennings, H; Kawasaki, S; Dodson, T F; Perlino, C A

1989-05-01

Orthotopic liver transplantation (OLT) has become standard therapy for patients with acute hepatic necrosis and end-stage liver disease. This study measured change in hepatic function (galactose elimination capacity [GEC]), liver blood flow (low dose galactose clearance: flow), hepatic volume (CT scan; volume) and morphology after OLT. The aim was to measure the physiologic response after OLT and compare this response with that after selective shunt (SS) and sclerotherapy (ES) to determine which patients should receive specific therapy. Between January 1987 and November 1988, 37 patients underwent OLT. Operative mortality was 18%, which was similar to that of SS in Child's C cirrhotics. GEC and volume were less in transplant patients than in cirrhotics treated with SS or ES. GEC, flow, and volume normalized after OLT; GEC was preserved after ES and SS, but volume decreased. Three preoperative patterns were observed that can aid in selection of OLT candidates. Patients with chronic cirrhosis (chronic active hepatitis; cryptogenic) need OLT when GEC is less than or equal to 225 mg/min and volume is less than or equal to 50% normal. Patients with Budd-Chiari Syndrome require OLT if cirrhosis has evolved. Patients with sclerosing cholangitis and primary biliary cirrhosis qualify for transplants when complications of the portal hypertensive syndrome develop. The studies can also direct therapy for ES failures. Selective shunt is indicated in those patients with stable disease whose GEC is greater than or equal to 300 mg/min and liver volume is greater than 75% normal; OLT is indicated for cirrhotics with GEC that is less than 225 mg/min and liver volume that is less than 50% predicted normal.

Scale-Free Neural and Physiological Dynamics in Naturalistic Stimuli Processing

PubMed Central

Lin, Amy

2016-01-01

Abstract Neural activity recorded at multiple spatiotemporal scales is dominated by arrhythmic fluctuations without a characteristic temporal periodicity. Such activity often exhibits a 1/f-type power spectrum, in which power falls off with increasing frequency following a power-law function: P(f)∝1/fβ, which is indicative of scale-free dynamics. Two extensively studied forms of scale-free neural dynamics in the human brain are slow cortical potentials (SCPs)—the low-frequency (<5 Hz) component of brain field potentials—and the amplitude fluctuations of α oscillations, both of which have been shown to carry important functional roles. In addition, scale-free dynamics characterize normal human physiology such as heartbeat dynamics. However, the exact relationships among these scale-free neural and physiological dynamics remain unclear. We recorded simultaneous magnetoencephalography and electrocardiography in healthy subjects in the resting state and while performing a discrimination task on scale-free dynamical auditory stimuli that followed different scale-free statistics. We observed that long-range temporal correlation (captured by the power-law exponent β) in SCPs positively correlated with that of heartbeat dynamics across time within an individual and negatively correlated with that of α-amplitude fluctuations across individuals. In addition, across individuals, long-range temporal correlation of both SCP and α-oscillation amplitude predicted subjects’ discrimination performance in the auditory task, albeit through antagonistic relationships. These findings reveal interrelations among different scale-free neural and physiological dynamics and initial evidence for the involvement of scale-free neural dynamics in the processing of natural stimuli, which often exhibit scale-free dynamics. PMID:27822495

Resting-state activity in development and maintenance of normal brain function.

PubMed

Pizoli, Carolyn E; Shah, Manish N; Snyder, Abraham Z; Shimony, Joshua S; Limbrick, David D; Raichle, Marcus E; Schlaggar, Bradley L; Smyth, Matthew D

2011-07-12

One of the most intriguing recent discoveries concerning brain function is that intrinsic neuronal activity manifests as spontaneous fluctuations of the blood oxygen level-dependent (BOLD) functional MRI signal. These BOLD fluctuations exhibit temporal synchrony within widely distributed brain regions known as resting-state networks. Resting-state networks are present in the waking state, during sleep, and under general anesthesia, suggesting that spontaneous neuronal activity plays a fundamental role in brain function. Despite its ubiquitous presence, the physiological role of correlated, spontaneous neuronal activity remains poorly understood. One hypothesis is that this activity is critical for the development of synaptic connections and maintenance of synaptic homeostasis. We had a unique opportunity to test this hypothesis in a 5-y-old boy with severe epileptic encephalopathy. The child developed marked neurologic dysfunction in association with a seizure disorder, resulting in a 1-y period of behavioral regression and progressive loss of developmental milestones. His EEG showed a markedly abnormal pattern of high-amplitude, disorganized slow activity with frequent generalized and multifocal epileptiform discharges. Resting-state functional connectivity MRI showed reduced BOLD fluctuations and a pervasive lack of normal connectivity. The child underwent successful corpus callosotomy surgery for treatment of drop seizures. Postoperatively, the patient's behavior returned to baseline, and he resumed development of new skills. The waking EEG revealed a normal background, and functional connectivity MRI demonstrated restoration of functional connectivity architecture. These results provide evidence that intrinsic, coherent neuronal signaling may be essential to the development and maintenance of the brain's functional organization.

From the Cover: Disease-Induced Disparities in Formation of the Nanoparticle-Biocorona and the Toxicological Consequences

PubMed Central

Shannahan, Jonathan H.; Fritz, Kristofer S.; Raghavendra, Achyut J.; Podila, Ramakrishna; Persaud, Indushekar; Brown, Jared M.

2016-01-01

Nanoparticle (NP) association with macromolecules in a physiological environment forms a biocorona (BC), which alters NP distribution, activity, and toxicity. While BC formation is dependent on NP physicochemical properties, little information exists on the influence of the physiological environment. Obese individuals and those with cardiovascular disease exist with altered serum chemistry, which is expected to influence BC formation and NP toxicity. We hypothesize that a BC formed on NPs following incubation in hyperlipidemic serum will result in altered NP–BC protein content, cellular association, and toxicity compared to normal serum conditions. We utilized Fe3O4 NPs, which are being developed as MRI contrast and tumor targeting agents to test our hypothesis. We used rat aortic endothelial cells (RAECs) within a dynamic flow in vitro exposure system to more accurately depict the in vivo environment. A BC was formed on 20nm PVP-suspended Fe3O4 NPs following incubation in water, 10% normal or hyperlipidemic rat serum. Addition of BCs resulted in increased hydrodynamic size and decreased surface charge. More cholesterol associated with Fe3O4 NPs after incubation in hyperlipidemic as compared with normal serum. Using quantitative proteomics, we identified unique differences in BC protein components between the 2 serum types. Under flow conditions, formation of a BC from both serum types reduced RAECs association of Fe3O4 NPs. Addition of BCs was found to exacerbate RAECs inflammatory gene responses to Fe3O4 NPs (Fe3O4-hyperlipidemic > Fe3O4-normal > Fe3O4) including increased expression of IL-6, TNF-α, Cxcl-2, VCAM-1, and ICAM-1. Overall, these findings demonstrate that disease-induced variations in physiological environments have a significant impact NP-BC formation, cellular association, and cell response. PMID:27255384

A functional genomics strategy reveals Rora as a component of the mammalian circadian clock.

PubMed

Sato, Trey K; Panda, Satchidananda; Miraglia, Loren J; Reyes, Teresa M; Rudic, Radu D; McNamara, Peter; Naik, Kinnery A; FitzGerald, Garret A; Kay, Steve A; Hogenesch, John B

2004-08-19

The mammalian circadian clock plays an integral role in timing rhythmic physiology and behavior, such as locomotor activity, with anticipated daily environmental changes. The master oscillator resides within the suprachiasmatic nucleus (SCN), which can maintain circadian rhythms in the absence of synchronizing light input. Here, we describe a genomics-based approach to identify circadian activators of Bmal1, itself a key transcriptional activator that is necessary for core oscillator function. Using cell-based functional assays, as well as behavioral and molecular analyses, we identified Rora as an activator of Bmal1 transcription within the SCN. Rora is required for normal Bmal1 expression and consolidation of daily locomotor activity and is regulated by the core clock in the SCN. These results suggest that opposing activities of the orphan nuclear receptors Rora and Rev-erb alpha, which represses Bmal1 expression, are important in the maintenance of circadian clock function.

Conditional expression of Pomc in the Lepr-positive subpopulation of POMC neurons is sufficient for normal energy homeostasis and metabolism.

PubMed

Lam, Daniel D; Attard, Courtney A; Mercer, Aaron J; Myers, Martin G; Rubinstein, Marcelo; Low, Malcolm J

2015-04-01

Peptides derived from the proopiomelanocortin (POMC) precursor are critical for the normal regulation of many physiological parameters, and POMC deficiency results in severe obesity and metabolic dysfunction. Conversely, augmentation of central nervous system melanocortin function is a promising therapeutic avenue for obesity and diabetes but is confounded by detrimental cardiovascular effects including hypertension. Because the hypothalamic population of POMC-expressing neurons is neurochemically and neuroanatomically heterogeneous, there is interest in the possible dissociation of functionally distinct POMC neuron subpopulations. We used a Cre recombinase-dependent and hypothalamus-specific reactivatable PomcNEO allele to restrict Pomc expression to hypothalamic neurons expressing leptin receptor (Lepr) in mice. In contrast to mice with total hypothalamic Pomc deficiency, which are severely obese, mice with Lepr-restricted Pomc expression displayed fully normal body weight, food consumption, glucose homeostasis, and locomotor activity. Thus, Lepr+ POMC neurons, which constitute approximately two-thirds of the total POMC neuron population, are sufficient for normal regulation of these parameters. This functional dissociation approach represents a promising avenue for isolating therapeutically relevant POMC neuron subpopulations.

Do unliganded thyroid hormone receptors have physiological functions?

PubMed

Chassande, O

2003-08-01

Thyroid hormone (TH) is required for the development of vertebrates and exerts numerous homeostatic functions in adults. TH acts through nuclear receptors which control the transcription of target genes. Unliganded and liganded thyroid hormone receptors (TRs) have been shown to exert opposite effects on the transcription of target genes in vitro. However, the occurance of an aporeceptor activity in vivo and its potential physiological significance has not been clearly addressed. Several data generated using experimental hypothyroidism and thyrotoxicosis in wild type and TR knockout mice support the notion that apoTRs have an intrinsic activity in several tIssues. ApoTRs, and in particular TRalpha1, are predominant during the early stages of vertebrate development and must be turned into holoTRs for post-natal development to proceed normally. However, the absence of striking alterations of embryonic and fetal development in mice devoid of TRs indicates that apoTRs do not play a fundamental role. During development, as well as in adults, apoTRs rather appears as a system which increases the range of transcriptional responses to moderate variations of T3.

Metabolomic strategies to map functions of metabolic pathways

PubMed Central

Mulvihill, Melinda M.

2014-01-01

Genome sequencing efforts have revealed a strikingly large number of unannotated and uncharacterized genes that fall into metabolic enzymes classes, likely indicating that our current knowledge of biochemical pathways in normal physiology, let alone in disease states, remains largely incomplete. This realization presents a daunting challenge for post-genomic-era scientists in deciphering the biochemical and (patho)physiological roles of these enzymes and their metabolites and metabolic networks. This is further complicated by many recent studies showing a rewiring of normal metabolic networks in disease states to give rise to unique pathophysiological functions of enzymes, metabolites, and metabolic pathways. This review focuses on recent discoveries made using metabolic mapping technologies to uncover novel pathways and metabolite-mediated posttranslational modifications and epigenetic alterations and their impact on physiology and disease. PMID:24918200

Zinc and Wound Healing: A Review of Zinc Physiology and Clinical Applications.

PubMed

Kogan, Samuel; Sood, Aditya; Garnick, Mark S

2017-04-01

Our understanding of the role of zinc in normal human physiology is constantly expanding, yet there are major gaps in our knowledge with regard to the function of zinc in wound healing. This review aims to provide the clinician with sufficient understanding of zinc biology and an up-to-date perspective on the role of zinc in wound healing. Zinc is an essential ion that is crucial for maintenance of normal physiology, and zinc deficiency has many manifestations ranging from delayed wound healing to immune dysfunction and impairment of multiple sensory systems. While consensus has been reached regarding the detrimental effects of zinc deficiency on wound healing, there is considerable discord in the literature on the optimal methods and true benefits of zinc supplementation.

Physiological Role of Gap-Junctional Hemichannels

PubMed Central

Quist, Arjan Pieter; Rhee, Seung Keun; Lin, Hai; Lal, Ratneshwar

2000-01-01

Hemichannels in the overlapping regions of apposing cells plasma membranes join to form gap junctions and provide an intercellular communication pathway. Hemichannels are also present in the nonjunctional regions of individual cells and their activity is gated by several agents, including calcium. However, their physiological roles are unknown. Using techniques of atomic force microscopy (AFM), fluorescent dye uptake assay, and laser confocal immunofluorescence imaging, we have examined the extracellular calcium-dependent modulation of cell volume. In response to a change in the extracellular physiological calcium concentration (1.8 to ≤1.6 mM) in an otherwise isosmotic condition, real-time AFM imaging revealed a significant and reversible increase in the volume of cells expressing gap-junctional proteins (connexins). Volume change did not occur in cells that were not expressing connexins. However, after the transient or stable transfection of connexin43, volume change did occur. The volume increase was accompanied by cytochalasin D-sensitive higher cell stiffness, which helped maintain cell integrity. These cellular physical changes were prevented by gap-junctional blockers, oleamide and β-glycyrrhetinic acid, or were reversed by returning extracellular calcium to the normal level. We conclude that nongap-junctional hemichannels regulate cell volume in response to the change in extracellular physiological calcium in an otherwise isosmotic situation. PMID:10704454

The Influence of Hyperthyroidism and Hypothyroidism on the β-Adrenergic Responsiveness of the Turkey Erythrocyte

PubMed Central

Bilezikian, John P.; Loeb, John N.; Gammon, Donald E.

1979-01-01

The mechanisms responsible for altered adrenergic tone in hyperthyroidism and hypothyroidism are not fully understood. To investigate these mechanisms, the β-adrenergic receptor-cyclic AMP complex of the turkey erythrocyte was studied among groups of normal, hyperthyroid, and hypothyroid turkeys. In erythrocytes obtained from hypothyroid turkeys, there were fewer β-adrenergic receptors than in normal cells as determined by the specific binding of [125I]iodohydroxybenzylpindolol, as well as associated decreases both in catecholamine-responsive adenylate cyclase activity and in cellular cyclic AMP content. In contrast, erythrocytes obtained from hyperthyroid turkeys contained the same number of β-receptors and had the same catecholamine-responsive adenylate cyclase activity as cells from normal birds. Other characteristics of the β-receptors in cells from hyperthyroid birds were indistinguishable from those present in normal erythrocytes. However, within the range of circulating catecholamine concentrations, 5-50 nM, the erythrocytes of the hyperthyroid turkeys generated substantially more cyclic AMP after exposure to isoproterenol than did normal cells. These results suggest that thyroid hormone affects β-receptor-cyclic AMP interrelationships in the turkey erythrocyte by two distinct mechanisms: (a) In hypothyroidism, both β-receptors and catecholamine-dependent cyclic AMP formation are coordinately decreased; (b) in hyperthyroidism, β-receptors are unchanged but there is an amplification of the hormonal signal so that occupation of a given number of receptors at physiological concentrations of catecholamines leads to increased levels of cyclic AMP. PMID:219032

Classification of lymphoid neoplasms: the microscope as a tool for disease discovery

PubMed Central

Harris, Nancy Lee; Stein, Harald; Isaacson, Peter G.

2008-01-01

In the past 50 years, we have witnessed explosive growth in the understanding of normal and neoplastic lymphoid cells. B-cell, T-cell, and natural killer (NK)–cell neoplasms in many respects recapitulate normal stages of lymphoid cell differentiation and function, so that they can be to some extent classified according to the corresponding normal stage. Likewise, the molecular mechanisms involved the pathogenesis of lymphomas and lymphoid leukemias are often based on the physiology of the lymphoid cells, capitalizing on deregulated normal physiology by harnessing the promoters of genes essential for lymphocyte function. The clinical manifestations of lymphomas likewise reflect the normal function of lymphoid cells in vivo. The multiparameter approach to classification adopted by the World Health Organization (WHO) classification has been validated in international studies as being highly reproducible, and enhancing the interpretation of clinical and translational studies. In addition, accurate and precise classification of disease entities facilitates the discovery of the molecular basis of lymphoid neoplasms in the basic science laboratory. PMID:19029456

Physiological and pathological relevance of cell competition in fly to mammals.

PubMed

Kon, Shunsuke

2018-01-01

In multicellular organisms, incidentally emerging suboptimal cells are removed to maintain homeostasis of tissues. The unfavorable cells are excluded by a process termed cell competition whereby the resident normal cells actively eliminate the unfit cells of the identical lineage. Although the phenomenon of cell competition was originally discovered in Drosophila, a number of recent studies have provided implications of cell competition in tissue regeneration, development and oncogenesis in mammals. Here the roles of cell competition in fly to mammals are discussed. © 2017 Japanese Society of Developmental Biologists.

The study and application of four kinds of organic ion-selective microsensors

NASA Astrophysics Data System (ADS)

Yu, Bi; Zheng, Xiao; Feng, Chu; Hong, Wen-Bing; Liu, Jun-Tao; Wang, Ru-Jiang

1991-09-01

Four kinds of organic ion-selective microelectrodes (two barrels, tip diameter 0.1-0.5 micron) have been developed for the measurement of acetylcholine, histamine, serotonin, and bile acid. Physiological and pathological models on the cellular or sub-cellular level have been established for the purpose of basic and clinical pharmacological research, treatment or diagnosis of certain diseases. The acetylcholine sensitive microelectrode has been applied to the study of acetylcholine activity in single erythrocytes of normal human subjects and patients suffering from manic depressive disorders. The bile acid selective microelectrode has been used for the direct measurement of intracellular bile acid activities both in colorectal cancer and colorectal mucosa in living condition.

The Drosophila imd signaling pathway.

PubMed

Myllymäki, Henna; Valanne, Susanna; Rämet, Mika

2014-04-15

The fruit fly, Drosophila melanogaster, has helped us to understand how innate immunity is activated. In addition to the Toll receptor and the Toll signaling pathway, the Drosophila immune response is regulated by another evolutionarily conserved signaling cascade, the immune deficiency (Imd) pathway, which activates NF-κB. In fact, the Imd pathway controls the expression of most of the antimicrobial peptides in Drosophila; thus, it is indispensable for normal immunity in flies. In this article, we review the current literature on the Drosophila Imd pathway, with special emphasis on its role in the (patho)physiology of different organs. We discuss the systemic response, as well as local responses, in the epithelial and mucosal surfaces and the nervous system.

Effect of noisy stimulation on neurobiological sensitization systems and its role for normal and pathological physiology

NASA Astrophysics Data System (ADS)

Huber, Martin; Braun, Hans; Krieg, J.\\:Urgen-Christian

2004-03-01

Sensitization is discussed as an important phenomenon playing a role in normal physiology but also with respect to the initiation and progression of a variety of neuropsychiatric disorders such as epilepsia, substance-related disorders or recurrent affective disorders. The relevance to understand the dynamics of sensitization phenomena is emphasized by recent findings that even single stimulations can induce longlasting changes in biological systems. To address specific questions associated with the sensitization dynamics, we use a computational approach and develop simple but physiologically-plausible models. In the present study we examine the effect of noisy stimulation on sensitization development in the model. We consider sub- and suprathresold stimulations with varying noise intensities and determine as response measures the (i) absolute number of stimulus-induced sensitzations and (ii) the temporal relsation of stimulus-sensitization coupling. The findings indicate that stochastic effects including stochastic resonance might well contribute to the physiology of sensitization mechanisms under both nomal and pathological conditions.

Individual Colorimetric Observer Model

PubMed Central

Asano, Yuta; Fairchild, Mark D.; Blondé, Laurent

2016-01-01

This study proposes a vision model for individual colorimetric observers. The proposed model can be beneficial in many color-critical applications such as color grading and soft proofing to assess ranges of color matches instead of a single average match. We extended the CIE 2006 physiological observer by adding eight additional physiological parameters to model individual color-normal observers. These eight parameters control lens pigment density, macular pigment density, optical densities of L-, M-, and S-cone photopigments, and λmax shifts of L-, M-, and S-cone photopigments. By identifying the variability of each physiological parameter, the model can simulate color matching functions among color-normal populations using Monte Carlo simulation. The variabilities of the eight parameters were identified through two steps. In the first step, extensive reviews of past studies were performed for each of the eight physiological parameters. In the second step, the obtained variabilities were scaled to fit a color matching dataset. The model was validated using three different datasets: traditional color matching, applied color matching, and Rayleigh matches. PMID:26862905

The absence of oligonucleosomal DNA fragmentation during apoptosis of IMR-5 neuroblastoma cells: disappearance of the caspase-activated DNase.

PubMed

Yuste, V J; Bayascas, J R; Llecha, N; Sánchez-López, I; Boix, J; Comella, J X

2001-06-22

Caspase-activated DNase is responsible for the oligonucleosomal DNA degradation during apoptosis. DNA degradation is thought to be important for multicellular organisms to prevent oncogenic transformation or as a mechanism of viral defense. It has been reported that certain cells, including some neuroblastoma cell lines such as IMR-5, enter apoptosis without digesting DNA in such a way. We have analyzed the causes for the absence of DNA laddering in staurosporine-treated IMR-5 cells, and we have found that most of the molecular mechanisms controlling apoptosis are well preserved in this cell line. These include degradation of substrates for caspases, blockade of cell death by antiapoptotic genes such as Bcl-2 or Bcl-X(L), or normal levels and adequate activation of caspase-3. Moreover, these cells display normal levels of caspase-activated DNase and its inhibitory protein, inhibitor of caspase-activated DNase, and their cDNA sequences are identical to those reported previously. Nevertheless, IMR-5 cells lose caspase-activated DNase during apoptosis and recover their ability to degrade DNA when human recombinant caspase-activated DNase is overexpressed. Our results lead to the conclusion that caspase-activated DNase is processed during apoptosis of IMR-5 cells, making these cells a good model to study the relevance of this endonuclease in physiological or pathological conditions.

Fibroblast-matrix interplay: Nintedanib and pirfenidone modulate the effect of IPF fibroblast-conditioned matrix on normal fibroblast phenotype.

PubMed

Epstein Shochet, Gali; Wollin, Lutz; Shitrit, David

2018-03-12

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. Activated fibroblasts are the key effector cells in fibrosis, producing excessive amounts of collagen and extracellular matrix (ECM) proteins. Whether the ECM conditioned by IPF fibroblasts determines the phenotype of naïve fibroblasts is difficult to explore. IPF-derived primary fibroblasts were cultured on Matrigel and then cleared using ammonium hydroxide, creating an IPF-conditioned matrix (CM). Normal fibroblast CM served as control. Normal fibroblasts were cultured on both types of CM, and cell count, cell distribution and markers of myofibroblast differentiation; transforming growth factor beta (TGFβ) signalling; and ECM expression were assessed. The effects of the anti-fibrotic drugs nintedanib and pirfenidone at physiologically relevant concentrations were also explored. Normal fibroblasts cultured on IPF-CM arranged in large aggregates as a result of increased proliferation and migration. Moreover, increased levels of pSmad3, pSTAT3 (phospho signal transducer and activator of transcription 3), alpha smooth muscle actin (αSMA) and Collagen1a were found, suggesting a differentiation towards a myofibroblast-like phenotype. SB505124 (10 μmol/L) partially reversed these alterations, suggesting a TGFβ contribution. Furthermore, nintedanib at 100 nmol/L and, to a lesser extent, pirfenidone at 100 μmol/L prevented the IPF-CM-induced fibroblast phenotype alterations, suggesting an attenuation of the ECM-fibroblast interplay. IPF fibroblasts alter the ECM, thus creating a CM that further propagates an IPF-like phenotype in normal fibroblasts. This assay demonstrated differences in drug activities for approved IPF drugs at clinically relevant concentrations. Thus, the matrix-fibroblast phenotype interplay might be a relevant assay to explore drug candidates for IPF treatment. © 2018 Asian Pacific Society of Respirology.

Aging and physiological changes of the kidneys including changes in glomerular filtration rate.

PubMed

Musso, Carlos G; Oreopoulos, Dimitrios G

2011-01-01

In addition to the structural changes in the kidney associated with aging, physiological changes in renal function are also found in older adults, such as decreased glomerular filtration rate, vascular dysautonomia, altered tubular handling of creatinine, reduction in sodium reabsorption and potassium secretion, and diminished renal reserve. These alterations make aged individuals susceptible to the development of clinical conditions in response to usual stimuli that would otherwise be compensated for in younger individuals, including acute kidney injury, volume depletion and overload, disorders of serum sodium and potassium concentration, and toxic reactions to water-soluble drugs excreted by the kidneys. Additionally, the preservation with aging of a normal urinalysis, normal serum urea and creatinine values, erythropoietin synthesis, and normal phosphorus, calcium and magnesium tubular handling distinguishes decreased GFR due to normal aging from that due to chronic kidney disease. Copyright © 2011 S. Karger AG, Basel.

Low-temperature carbon utilization is regulated by novel gene activity in the heart of a hibernating mammal

PubMed Central

Andrews, Matthew T.; Squire, Teresa L.; Bowen, Christopher M.; Rollins, Martha B.

1998-01-01

Hibernation is a physiological adaptation characterized by dramatic decreases in heart rate, body temperature, and metabolism, resulting in long-term dormancy. Hibernating mammals survive for periods up to 6 mo in the absence of food by minimizing carbohydrate catabolism and using triglyceride stores as their primary source of fuel. The cellular and molecular mechanisms underlying the changes from a state of activity to the hibernating state are poorly understood; however, the selective expression of genes offers one level of control. To address this problem, we used a differential gene expression screen to identify genes that are responsible for the physiological characteristics of hibernation in the heart of the thirteen-lined ground squirrel (Spermophilus tridecemlineatus). Here, we report that genes for pancreatic lipase and pyruvate dehydrogenase kinase isozyme 4 are up-regulated in the heart during hibernation. Pancreatic lipase is normally expressed exclusively in the pancreas, but when expressed in the hibernating heart it liberates fatty acids from triglycerides at temperatures as low as 0°C. Pyruvate dehydrogenase kinase isozyme 4 inhibits carbohydrate oxidation and depresses metabolism by preventing the conversion of pyruvate to Ac-CoA. The resulting anaerobic glycolysis and low-temperature lipid catabolism provide evidence that adaptive changes in cardiac physiology are controlled by the differential expression of genes during hibernation. PMID:9653197

Acid-Sensing Ion Channel Pharmacology, Past, Present, and Future ….

PubMed

Rash, Lachlan D

2017-01-01

pH is one of the most strictly controlled parameters in mammalian physiology. An extracellular pH of ~7.4 is crucial for normal physiological processes, and perturbations to this have profound effects on cell function. Acidic microenvironments occur in many physiological and pathological conditions, including inflammation, bone remodeling, ischemia, trauma, and intense synaptic activity. Cells exposed to these conditions respond in different ways, from tumor cells that thrive to neurons that are either suppressed or hyperactivated, often fatally. Acid-sensing ion channels (ASICs) are primary pH sensors in mammals and are expressed widely in neuronal and nonneuronal cells. There are six main subtypes of ASICs in rodents that can form homo- or heteromeric channels resulting in many potential combinations. ASICs are present and activated under all of the conditions mentioned earlier, suggesting that they play an important role in how cells respond to acidosis. Compared to many other ion channel families, ASICs were relatively recently discovered-1997-and there is a substantial lack of potent, subtype-selective ligands that can be used to elucidate their structural and functional properties. In this chapter I cover the history of ASIC channel pharmacology, which began before the proteins were even identified, and describe the current arsenal of tools available, their limitations, and take a glance into the future to predict from where new tools are likely to emerge. © 2017 Elsevier Inc. All rights reserved.

X box binding protein XBP-1s transactivates the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency.

PubMed

Wilson, Sam J; Tsao, Edward H; Webb, Benjamin L J; Ye, Hongtao; Dalton-Griffin, Lucy; Tsantoulas, Christoforos; Gale, Catherine V; Du, Ming-Qing; Whitehouse, Adrian; Kellam, Paul

2007-12-01

Reactivation of lytic replication from viral latency is a defining property of all herpesviruses. Despite this, the authentic physiological cues for the latent-lytic switch are unclear. Such cues should ensure that viral lytic replication occurs under physiological conditions, predominantly in sites which facilitate transmission to permissive uninfected cells and new susceptible hosts. Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with the B-cell neoplasm primary effusion lymphoma (PEL), in which the virus remains latent. We have previously shown that PEL cells have the gene expression profile and immunophenotype of cycling preplasma cells (plasmablasts). Here, we show that the highly active spliced isoform of plasma cell transcription factor X box binding protein 1 (XBP-1s) is a lytic switch for KSHV. XBP-1s is normally absent in PEL, but the induction of endoplasmic reticulum stress leads to XBP-1s generation, plasma cell-like differentiation, and lytic reactivation of KSHV. XBP-1s binds to and activates the KSHV immediate-early gene ORF50 and synergizes with the ORF50 gene product RTA to induce a full lytic cycle. These data suggest that KSHV remains latent until B-cell terminal differentiation into plasma cells, the transcriptional environment of which provides the physiological "lytic switch" through XBP-1s. This links B-cell terminal differentiation to KSHV lytic reactivation.

Creating Simulated Microgravity Patient Models

NASA Technical Reports Server (NTRS)

Hurst, Victor; Doerr, Harold K.; Bacal, Kira

2004-01-01

The Medical Operational Support Team (MOST) has been tasked by the Space and Life Sciences Directorate (SLSD) at the NASA Johnson Space Center (JSC) to integrate medical simulation into 1) medical training for ground and flight crews and into 2) evaluations of medical procedures and equipment for the International Space Station (ISS). To do this, the MOST requires patient models that represent the physiological changes observed during spaceflight. Despite the presence of physiological data collected during spaceflight, there is no defined set of parameters that illustrate or mimic a 'space normal' patient. Methods: The MOST culled space-relevant medical literature and data from clinical studies performed in microgravity environments. The areas of focus for data collection were in the fields of cardiovascular, respiratory and renal physiology. Results: The MOST developed evidence-based patient models that mimic the physiology believed to be induced by human exposure to a microgravity environment. These models have been integrated into space-relevant scenarios using a human patient simulator and ISS medical resources. Discussion: Despite the lack of a set of physiological parameters representing 'space normal,' the MOST developed space-relevant patient models that mimic microgravity-induced changes in terrestrial physiology. These models are used in clinical scenarios that will medically train flight surgeons, biomedical flight controllers (biomedical engineers; BME) and, eventually, astronaut-crew medical officers (CMO).

Anorectal physiology measurements are of no value in clinical practice. True or false?

PubMed Central

Carty, N. J.; Moran, B.; Johnson, C. D.

1994-01-01

This article examines whether there is any clinical value in anorectal physiology measurements. The function of the human rectum is poorly understood and the factors which affect function of the anal sphincters are complex. Several laboratories have reported results of anorectal physiology measurements, but there is extensive variation between normal values in different laboratories. It is argued that anorectal physiology measurements fail to meet the criteria of a useful clinical test: 1. It is not widely available to clinicians; 2. It is not possible to establish a reproducible normal range; 3. Abnormal measurements do not correlate with disease entities or explain symptoms; 4. The results are often unhelpful in diagnosis and management; 5. Clinical outcome after intervention does not correlate with alteration in the measurements obtained. On the other hand it can be argued that anorectal physiology measurements do provide information that assists in the management of conditions such as constipation, anismus, Hirschsprung's disease, faecal incontinence and tenesmus. Management based on biofeedback modification of physiological responses requires these techniques as part of the biofeedback system. There is evidence that this may be appropriate in anismus and solitary rectal ulcer syndrome. However, the assessment of these difficult conditions and the interpretation of the results are probably at present best confined to specialist units. PMID:8074392

Dysphagia in Infants with Single Ventricle Anatomy Following Stage 1 Palliation: Physiologic Correlates and Response to Treatment

PubMed Central

McGrattan, Katlyn Elizabeth; McGhee, Heather; DeToma, Allan; Hill, Elizabeth G.; Zyblewski, Sinai C.; Lefton-Greif, Maureen; Halstead, Lucinda; Bradley, Scott M.; Martin-Harris, Bonnie

2017-01-01

Background Deficits in swallowing physiology are a leading morbidity for infants with functional single ventricles and systemic outflow tract obstruction following stage 1 palliation. Despite the high prevalence of this condition, the underlying deficits that cause this post-operative impairment remain poorly understood. Objective Identify the physiologic correlates of dysphagia in infants with functional single ventricles and systemic outflow tract obstruction following stage 1 palliative surgery. Methods Postoperative fiberoptic laryngoscopies and videofluoroscopic swallow studies (VFSS) were conducted sequentially on infants with functional single ventricles following stage 1 palliative surgery. Infants were dichotomized as having normal or impaired laryngeal function based on laryngoscopy findings. VFSS were evaluated frame-by-frame using a scale that quantifies performance within 11 components of swallowing physiology. Physiologic attributes within each component were categorized as high functioning or low functioning based on their ability to support milk ingestion without bolus airway entry. Results Thirty-six infants (25 male) were included in the investigation. Twenty-four underwent the Norwood procedure and twelve underwent the Hybrid procedure. Low function physiologic patterns were observed within multiple swallowing components during the ingestion of thin barium as characterized by ≥ 4 sucks per swallow (36%), initiation of pharyngeal swallow below the level of the valleculae (83%), and incomplete late laryngeal vestibular closure (56%) at the height of the swallow. Swallowing deficits contributed to aspiration in 50% of infants. Although nectar thick liquids reduced the rate of aspiration (p=0.006), aspiration rates remained high (27%). No differences in rates of penetration or aspiration were observed between infants with normal and impaired laryngeal function. Conclusions Deficits in swallowing physiology contribute to penetration and aspiration following stage 1 palliation among infants with normal and impaired laryngeal function. Although thickened liquids may improve airway protection for select infants, they may inhibit their ability to extract the bolus and meet nutritional needs. PMID:28244680

Dysphagia in infants with single ventricle anatomy following stage 1 palliation: Physiologic correlates and response to treatment.

PubMed

McGrattan, Katlyn Elizabeth; McGhee, Heather; DeToma, Allan; Hill, Elizabeth G; Zyblewski, Sinai C; Lefton-Greif, Maureen; Halstead, Lucinda; Bradley, Scott M; Martin-Harris, Bonnie

2017-05-01

Deficits in swallowing physiology are a leading morbidity for infants with functional single ventricles and systemic outflow tract obstruction following stage 1 palliation. Despite the high prevalence of this condition, the underlying deficits that cause this post-operative impairment remain poorly understood. Identify the physiologic correlates of dysphagia in infants with functional single ventricles and systemic outflow tract obstruction following stage 1 palliative surgery. Postoperative fiberoptic laryngoscopies and videofluoroscopic swallow studies (VFSS) were conducted sequentially on infants with functional single ventricles following stage 1 palliative surgery. Infants were dichotomized as having normal or impaired laryngeal function based on laryngoscopy findings. VFSS were evaluated frame-by-frame using a scale that quantifies performance within 11 components of swallowing physiology. Physiologic attributes within each component were categorized as high functioning or low functioning based on their ability to support milk ingestion without bolus airway entry. Thirty-six infants (25 male) were included in the investigation. Twenty-four underwent the Norwood procedure and twelve underwent the Hybrid procedure. Low function physiologic patterns were observed within multiple swallowing components during the ingestion of thin barium as characterized by ≥4 sucks per swallow (36%), initiation of pharyngeal swallow below the level of the valleculae (83%), and incomplete late laryngeal vestibular closure (56%) at the height of the swallow. Swallowing deficits contributed to aspiration in 50% of infants. Although nectar thick liquids reduced the rate of aspiration (P = .006), aspiration rates remained high (27%). No differences in rates of penetration or aspiration were observed between infants with normal and impaired laryngeal function. Deficits in swallowing physiology contribute to penetration and aspiration following stage 1 palliation among infants with normal and impaired laryngeal function. Although thickened liquids may improve airway protection for select infants, they may inhibit their ability to extract the bolus and meet nutritional needs. © 2017 Wiley Periodicals, Inc.

Imaging seizure activity: a combined EEG/EMG-fMRI study in reading epilepsy.

PubMed

Salek-Haddadi, Afraim; Mayer, Thomas; Hamandi, Khalid; Symms, Mark; Josephs, Oliver; Fluegel, Dominique; Woermann, Friedrich; Richardson, Mark P; Noppeney, Uta; Wolf, Peter; Koepp, Matthias J

2009-02-01

To characterize the spatial relationship between activations related to language-induced seizure activity, language processing, and motor control in patients with reading epilepsy. We recorded and simultaneously monitored several physiological parameters [voice-recording, electromyography (EMG), electrocardiography (ECG), electroencephalography (EEG)] during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in nine patients with reading epilepsy. Individually tailored language paradigms were used to induce and record habitual seizures inside the MRI scanner. Voxel-based morphometry (VBM) was used for structural brain analysis. Reading-induced seizures occurred in six out of nine patients. One patient experienced abundant orofacial reflex myocloni during silent reading in association with bilateral frontal or generalized epileptiform discharges. In a further five patients, symptoms were only elicited while reading aloud with self-indicated events. Consistent activation patterns in response to reading-induced myoclonic seizures were observed within left motor and premotor areas in five of these six patients, in the left striatum (n = 4), in mesiotemporal/limbic areas (n = 4), in Brodmann area 47 (n = 3), and thalamus (n = 2). These BOLD activations were overlapping or adjacent to areas physiologically activated during language and facial motor tasks. No subtle structural abnormalities common to all patients were identified using VBM, but one patient had a left temporal ischemic lesion. Based on the findings, we hypothesize that reflex seizures occur in reading epilepsy when a critical mass of neurons are activated through a provoking stimulus within corticoreticular and corticocortical circuitry subserving normal functions.

Fractal Patterns of Neural Activity Exist within the Suprachiasmatic Nucleus and Require Extrinsic Network Interactions

PubMed Central

Hu, Kun; Meijer, Johanna H.; Shea, Steven A.; vanderLeest, Henk Tjebbe; Pittman-Polletta, Benjamin; Houben, Thijs; van Oosterhout, Floor; Deboer, Tom; Scheer, Frank A. J. L.

2012-01-01

The mammalian central circadian pacemaker (the suprachiasmatic nucleus, SCN) contains thousands of neurons that are coupled through a complex network of interactions. In addition to the established role of the SCN in generating rhythms of ∼24 hours in many physiological functions, the SCN was recently shown to be necessary for normal self-similar/fractal organization of motor activity and heart rate over a wide range of time scales—from minutes to 24 hours. To test whether the neural network within the SCN is sufficient to generate such fractal patterns, we studied multi-unit neural activity of in vivo and in vitro SCNs in rodents. In vivo SCN-neural activity exhibited fractal patterns that are virtually identical in mice and rats and are similar to those in motor activity at time scales from minutes up to 10 hours. In addition, these patterns remained unchanged when the main afferent signal to the SCN, namely light, was removed. However, the fractal patterns of SCN-neural activity are not autonomous within the SCN as these patterns completely broke down in the isolated in vitro SCN despite persistence of circadian rhythmicity. Thus, SCN-neural activity is fractal in the intact organism and these fractal patterns require network interactions between the SCN and extra-SCN nodes. Such a fractal control network could underlie the fractal regulation observed in many physiological functions that involve the SCN, including motor control and heart rate regulation. PMID:23185285

SP and KLF Transcription Factors in Digestive Physiology and Diseases.

PubMed

Kim, Chang-Kyung; He, Ping; Bialkowska, Agnieszka B; Yang, Vincent W

2017-06-01

Specificity proteins (SPs) and Krüppel-like factors (KLFs) belong to the family of transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions. Studies have shown that SPs and KLFs regulate not only physiological processes such as growth, development, differentiation, proliferation, and embryogenesis, but pathogenesis of many diseases, including cancer and inflammatory disorders. Consistently, these proteins have been shown to regulate normal functions and pathobiology in the digestive system. We review recent findings on the tissue- and organ-specific functions of SPs and KLFs in the digestive system including the oral cavity, esophagus, stomach, small and large intestines, pancreas, and liver. We provide a list of agents under development to target these proteins. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Insomnia and Its Impact on Physical and Mental Health

PubMed Central

Fernandez-Mendoza, Julio; Vgontzas, Alexandros N.

2014-01-01

In contrast to the association of insomnia with mental health, its association with physical health has remained largely unexplored until recently. Based on findings that insomnia with objective short sleep duration is associated with activation of both limbs of the stress system and other indices of physiological hyperarousal, which should affect adversely physical and mental health, we have recently demonstrated that this insomnia phenotype is associated with a significant risk of cardiometabolic and neurocognitive morbidity and mortality. In contrast, insomnia with normal sleep duration is associated with sleep misperception and cognitive-emotional arousal but not with signs of physiological hyperarousal or cardiometabolic or neurocognitive morbidity. Interestingly, both insomnia phenotypes are associated with mental health, although most likely through different pathophysiological mechanisms. We propose that objective measures of sleep duration may become part of the routine evaluation and diagnosis of insomnia and that these two insomnia phenotypes may respond differentially to biological vs. psychological treatments. PMID:24189774

Effect of chronic altitude hypoxia on hematologic and glycolytic parameters.

PubMed

Clench, J; Ferrell, R E; Schull, W J

1982-05-01

The physiological effect of chronic exposure to altitude hypoxia on the glycolytic intermediates, adenosine triphosphate and 2,3-diphosphoglyceric acid, and the hematologic parameters, hemoglobin, hematocrit, and mean cell hemoglobin concentration, has been examined in an indigenous population, the Aymara, of the Departamento de Arica, Chile. This population normally resides at three altitudes: the coast (0-500 m), the sierra (2,500-3,500 m), and the altiplano (above 4,200 m). After isolation of altitude from other environmental factors (age, sex, body build, ethnicity, smoking, and residential permanence), an increase in 2,3-diphosphoglycerate and a decrease in adenosine triphosphate was observed. Both hemoglobin and hematocrit increased as expected, but mean cell hemoglobin concentration declined. It is proposed that a decline in the activity of a single enzyme, pyruvate kinase, can account for these observed changes and suggests a pivotal role for pyruvate kinase in the physiological adaptation to altitude hypoxia.

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.

PubMed

Hartwell, Kimberly A; Miller, Peter G; Mukherjee, Siddhartha; Kahn, Alissa R; Stewart, Alison L; Logan, David J; Negri, Joseph M; Duvet, Mildred; Järås, Marcus; Puram, Rishi; Dancik, Vlado; Al-Shahrour, Fatima; Kindler, Thomas; Tothova, Zuzana; Chattopadhyay, Shrikanta; Hasaka, Thomas; Narayan, Rajiv; Dai, Mingji; Huang, Christina; Shterental, Sebastian; Chu, Lisa P; Haydu, J Erika; Shieh, Jae Hung; Steensma, David P; Munoz, Benito; Bittker, Joshua A; Shamji, Alykhan F; Clemons, Paul A; Tolliday, Nicola J; Carpenter, Anne E; Gilliland, D Gary; Stern, Andrew M; Moore, Malcolm A S; Scadden, David T; Schreiber, Stuart L; Ebert, Benjamin L; Golub, Todd R

2013-12-01

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

PubMed Central

Mukherjee, Siddhartha; Kahn, Alissa R; Stewart, Alison L; Logan, David J; Negri, Joseph M; Duvet, Mildred; Järås, Marcus; Puram, Rishi; Dancik, Vlado; Al-Shahrour, Fatima; Kindler, Thomas; Tothova, Zuzana; Chattopadhyay, Shrikanta; Hasaka, Thomas; Narayan, Rajiv; Dai, Mingji; Huang, Christina; Shterental, Sebastian; Chu, Lisa P; Haydu, J Erika; Shieh, Jae Hung; Steensma, David P; Munoz, Benito; Bittker, Joshua A; Shamji, Alykhan F; Clemons, Paul A; Tolliday, Nicola J; Carpenter, Anne E; Gilliland, D Gary; Stern, Andrew M; Moore, Malcolm A S; Scadden, David T; Schreiber, Stuart L; Ebert, Benjamin L; Golub, Todd R

2014-01-01

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone-marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on-target, via inhibition of HMGCoA reductase. These results illustrate the power of merging physiologically-relevant models with high-throughput screening. PMID:24161946

Blood Pressure Regulation: Every Adaptation is an Integration?

PubMed Central

Joyner, Michael J.; Limberg, Jacqueline K.

2013-01-01

This focused review serves to explore relevant issues in regard to blood pressure regulation and by doing so, provides the initial stimulus paper for the Thematic Review series “Blood Pressure Regulation” to be published in the European Journal of Applied Physiology over the coming months. In this introduction, we highlight how variable normal blood pressure can be and challenge the reader to take another look at some key concepts related to blood pressure regulation. We point out that there is frequently an underappreciated balance between peripheral vasodilation and systemic blood pressure regulation and ask the question: Are changes in blood pressure, in effect, reasonable and integrated adaptations to the physiological challenge at hand? We conclude with the idea that blood pressure regulatory systems are both flexible and redundant; ensuring a wide variety of activities associated with life can be accompanied by a perfusion pressure that can serve multiple masters. PMID:23558925

Effects of Hypogravity on Osteoblast Differentiation

NASA Technical Reports Server (NTRS)

Globus, Ruth; Doty, Steven

1997-01-01

Weightbearing is essential for normal skeletal function. Without weightbearing, the rate of bone formation by osteoblasts decreases in the growing rat. Defective formation may account for the decrease in the maturation, strength and mass of bone that is caused by spaceflight. These skeletal defects may be mediated by a combination of physiologic changes triggered by spaceflight, including skeletal unloading, fluid shifts, and stress-induced endocrine factors. The fundamental question of whether the defects in osteoblast function due to weightlessness are mediated by localized skeletal unloading or by systemic physiologic adaptations such as fluid shifts has not been answered. Furthermore, bone-forming activity of osteoblasts during unloading may be affected by paracrine signals from vascular, monocytic, and neural cells that also reside in skeletal tissue. Therefore we proposed to examine whether exposure of cultured rat osteoblasts to spaceflight inhibits cellular differentiation and impairs mineralization when isolated from the influence of both systemic factors and other skeletal cells.

Essentially All Excess Fibroblast Cholesterol Moves from Plasma Membranes to Intracellular Compartments

PubMed Central

Lange, Yvonne; Ye, Jin; Steck, Theodore L.

2014-01-01

It has been shown that modestly increasing plasma membrane cholesterol beyond its physiological set point greatly increases the endoplasmic reticulum and mitochondrial pools, thereby eliciting manifold feedback responses that return cell cholesterol to its resting state. The question arises whether this homeostatic mechanism reflects the targeting of cell surface cholesterol to specific intracellular sites or its general equilibration among the organelles. We now show that human fibroblast cholesterol can be increased as much as two-fold from 2-hydroxypropyl-β-cyclodextrin without changing the size of the cell surface pool. Rather, essentially all of the added cholesterol disperses rapidly among cytoplasmic membranes, increasing their overall cholesterol content by as much as five-fold. We conclude that the level of plasma membrane cholesterol is normally at capacity and that even small increments above this physiological set point redistribute essentially entirely to intracellular membranes, perhaps down their chemical activity gradients. PMID:25014655

Evaluation of type II thyroplasty on phonatory physiology in an excised canine larynx model

PubMed Central

Devine, Erin E.; Hoffman, Matthew R.; McCulloch, Timothy M.; Jiang, Jack J.

2016-01-01

Objective Type II thyroplasty is an alternative treatment for spasmodic dysphonia, addressing hyperadduction by incising and lateralizing the thyroid cartilage. We quantified the effect of lateralization width on phonatory physiology using excised canine larynges. Methods Normal closure, hyperadduction, and type II thyroplasty (lateralized up to 5mm at 1mm increments with hyperadducted arytenoids) were simulated in excised larynges (N=7). Aerodynamic, acoustic, and videokymographic data were recorded at three subglottal pressures relative to phonation threshold pressure (PTP). One-way repeated measures ANOVA assessed effect of condition on aerodynamic parameters. Random intercepts linear mixed effects models assessed effects of condition and subglottal pressure on acoustic and videokymographic parameters. Results PTP differed across conditions (p<0.001). Condition affected percent shimmer (p<0.005) but not percent jitter. Both pressure (p<0.03) and condition (p<0.001) affected fundamental frequency. Pressure affected vibratory amplitude (p<0.05) and intra-fold phase difference (p<0.05). Condition affected phase difference between the vocal folds (p<0.001). Conclusions Hyperadduction increased PTP and worsened perturbation compared to normal, with near normal physiology restored with 1mm lateralization. Further lateralization deteriorated voice quality and increased PTP. Acoustic and videokymographic results indicate that normal physiologic relationships between subglottal pressure and vibration are preserved at optimal lateralization width, but then degrade with further lateralization. The 1mm optimal width observed here is due to the small canine larynx size. Future human trials would likely demonstrate a greater optimal width, with patient-specific value potentially determined based on larynx size and symptom severity. PMID:27223665

NITRIC OXIDE, MITOCHONDRIAL HYPERPOLARIZATION AND T-CELL ACTIVATION

PubMed Central

Nagy, Gyorgy; Koncz, Agnes; Fernandez, David; Perl, Andras

2007-01-01

T lymphocyte activation is associated with nitric oxide (NO) production that plays an essential role in multiple T cell functions. NO acts as a messenger, activating soluble guanyl cyclase and participating in the transduction signaling pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial membrane potential and mitochondrial biogenesis in many cell types, including lymphocytes. Mitochondrial hyperpolarization (MHP), an early and reversible event during both T lymphocyte activation and apoptosis, is regulated by NO. Here, we discuss recent evidence that NO-induced MHP represents a molecular switch in multiple T cell signaling pathways. Overproduction of NO in systemic lupus erythematosus (SLE) induces mitochondrial biogenesis and alters Ca2+ signaling. Thus, while NO plays a physiological role in lymphocyte cell signaling, its overproduction may disturb normal T cell function, contributing to the pathogenesis of autoimmunity. PMID:17462531

Neuronal Function in Male Sprague Dawley Rats During Normal Ageing.

PubMed

Idowu, A J; Olatunji-Bello, I I; Olagunju, J A

2017-03-06

During normal ageing, there are physiological changes especially in high energy demanding tissues including the brain and skeletal muscles. Ageing may disrupt homeostasis and allow tissue vulnerability to disease. To establish an appropriate animal model which is readily available and will be useful to test therapeutic strategies during normal ageing, we applied behavioral approaches to study age-related changes in memory and motor function as a basis for neuronal function in ageing in male Sprague Dawley rats. 3 months, n=5; 6 months, n=5 and 18 months, n=5 male Sprague Dawley Rats were tested using the Novel Object Recognition Task (NORT) and the Elevated plus Maze (EPM) Test. Data was analyzed by ANOVA and the Newman-Keuls post hoc test. The results showed an age-related gradual decline in exploratory behavior and locomotor activity with increasing age in 3 months, 6 months and 18 months old rats, although the values were not statistically significant, but grooming activity significantly increased with increasing age. Importantly, we established a novel finding that the minimum distance from the novel object was statistically significant between 3 months and 18 months old rats and this may be an index for age-related memory impairment in the NORT. Altogether, we conclude that the male Sprague Dawley rat show age-related changes in neuronal function and may be a useful model for carrying out investigations into the mechanisms involved in normal ageing.

Acetylcholine Encodes Long-Lasting Presynaptic Plasticity at Glutamatergic Synapses in the Dorsal Striatum after Repeated Amphetamine Exposure

PubMed Central

Wang, Wengang; Darvas, Martin; Storey, Granville P.; Bamford, Ian J.; Gibbs, Jeffrey T.; Palmiter, Richard D.

2013-01-01

Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson's disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted >50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence. PMID:23785153

Evolution of enzymes in a series is driven by dissimilar functional demands.

PubMed

Salvador, Armindo; Savageau, Michael A

2006-02-14

That distinct enzyme activities in an unbranched metabolic pathway are evolutionarily tuned to a single functional requirement is a pervasive assumption. Here we test this assumption by examining the activities of two consecutively acting enzymes in human erythrocytes with an approach to quantitative evolutionary design that avoids the above-mentioned assumption. We previously found that avoidance of NADPH depletion during the pulses of oxidative load to which erythrocytes are normally exposed is the main functional requirement mediating selection for high glucose-6-phosphate dehydrogenase activity. In the present study, we find that, in contrast, the maintenance of oxidized glutathione at low concentrations is the main functional requirement mediating selection for high glutathione reductase activity. The results in this case show that, contrary to the assumption of a single functional requirement, natural selection for the normal activities of the distinct enzymes in the pathway is mediated by different requirements. On the other hand, the results agree with the more general principles that underlie our approach. Namely, that (i) the values of biochemical parameters evolve so as to fulfill the various performance requirements that are relevant to achieve high fitness, and (ii) these performance requirements can be inferred from quantitative systems theory considerations, informed by knowledge of specific aspects of the biochemistry, physiology, genetics, and ecology of the organism.

Running promotes wakefulness and increases cataplexy in orexin knockout mice.

PubMed

España, Rodrigo A; McCormack, Sarah L; Mochizuki, Takatoshi; Scammell, Thomas E

2007-11-01

People with narcolepsy and mice lacking orexin/hypocretin have disrupted sleep/wake behavior and reduced physical activity. Our objective was to identify physiologic mechanisms through which orexin deficiency reduces locomotor activity. We examined spontaneous wheel running activity and its relationship to sleep/wake behavior in wild type (WT) and orexin knockout (KO) mice. Additionally, given that physical activity promotes alertness, we also studied whether orexin deficiency reduces the wake-promoting effects of exercise. Orexin KO mice ran 42% less than WT mice. Their ability to run appeared normal as they initiated running as often as WT mice and ran at normal speeds. However, their running bouts were considerably shorter, and they often had cataplexy or quick transitions into sleep after running. Wheel running increased the total amount of wakefulness in WT and orexin KO mice similarly, however, KO mice continued to have moderately fragmented sleep/wake behavior. Wheel running also doubled the amount of cataplexy by increasing the probability of transitioning into cataplexy. Orexin KO mice run significantly less than normal, likely due to sleepiness, imminent cataplexy, or a reduced motivation to run. Orexin is not required for the wake-promoting effects of wheel running given that both WT and KO mice had similar increases in wakefulness with running wheels. In addition, the clear increase in cataplexy with wheel running suggests the possibility that positive emotions or reward can trigger murine cataplexy, similar to that seen in people and dogs with narcolepsy.

Over-adaptation and heart rate variability in Japanese high school girls.

PubMed

Sugawara, Yuko; Hiramoto, Izumi; Kodama, Hideya

2013-06-01

In the field of educational psychology in Japan, a model of "over-adaptation" has been applied to conceptualize the personality of students who are vulnerable to external stressors and prone to developing psychiatric problems. However, the influence of over-adaptation on physiological functions in adolescents is still largely unknown. Therefore, the present study aimed to investigate the association between an over-adapted tendency and autonomic nervous system activities in high school girls. Circadian profiles of cardiac autonomic nervous system activities in 47 normal high school girls were evaluated using time-domain measures of heart rate variability (HRV) taken from 24-h ambulatory electrocardiogram recordings, and their relation to an over-adaptation scale composed of 5 subscales was evaluated. A significant increase in RMSSD (root mean square of successive difference of normal-to-normal beat intervals) during daytime (09:00-14:00) was observed in students who scored high on the sum of the over-adaptation subscales (n=6). Two of the over-adaptation subscales, namely, "self-restraint" and "self-insufficiency", were positively correlated with time-domain measures. Parasympathetic activity in over-adapted students was elevated during school, and this autonomic response was suggested to be linked to over-adaptation subscales related to repressed emotions in over-adapted students. Thus, in over-adapted students, repressing emotions appears to be a style of coping, and may lead to a quiet, emotionally stable life in school, which in turn may result in parasympathetic activation. Copyright © 2013 Elsevier B.V. All rights reserved.

Hippo vs. Crab: tissue-specific functions of the mammalian Hippo pathway.

PubMed

Nishio, Miki; Maehama, Tomohiko; Goto, Hiroki; Nakatani, Keisuke; Kato, Wakako; Omori, Hirofumi; Miyachi, Yosuke; Togashi, Hideru; Shimono, Yohei; Suzuki, Akira

2017-01-01

The Hippo signaling pathway is a vital suppressor of tumorigenesis that is often inactivated in human cancers. In normal cells, the Hippo pathway is triggered by external forces such as cell crowding, or changes to the extracellular matrix or cell polarity. Once activated, Hippo signaling down-regulates transcription supported by the paralogous cofactors YAP1 and TAZ. The Hippo pathway's functions in normal and cancer biology have been dissected by studies of mutant mice with null or conditional tissue-specific mutations of Hippo signaling elements. In this review, we attempt to systematically summarize results that have been gleaned from detailed in vivo characterizations of these mutants. Our goal is to describe the physiological roles of Hippo signaling in several normal organ systems, as well as to emphasize how disruption of the Hippo pathway, and particularly hyperactivation of YAP1/TAZ, can be oncogenic. © 2017 The Authors Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Arginaseless Neurospora: Genetics, Physiology, and Polyamine Synthesis

PubMed Central

Davis, Rowland H.; Lawless, Mary B.; Port, Loretta A.

1970-01-01

Four arginaseless mutants of Neurospora crassa have been isolated. All carry mutations which lie at a single locus, aga, on linkage group VIIR. A study of aga strains shows the arginase reaction to be the major, perhaps the only, route of arginine consumption in Neurospora other than protein synthesis. Ornithine-δ-transaminase, the second enzyme of the arginine catabolic pathway, is present and normally inducible by arginine in aga strains, and ornithine transcarbamylase, an enzyme of arginine synthesis, also has normal activity. Arginine inhibits the growth of aga strains. The inhibition can be reversed by spermidine, putrescine (1,4-diaminobutane), or ornithine. The results suggest that ornithine is the major source of the putrescine moiety of polyamines in Neurospora, and that putrescine is an essential growth factor for this organism. The inhibition of aga strains by arginine can be attributed to feedback inhibition of ornithine synthesis by arginine, combined with the complete lack of ornithine normally provided by the arginase reaction. PMID:5419257

Neural control of renal tubular solute and water transport.

PubMed

DiBona, G F

1989-01-01

The neural control of renal tubular solute and water transport is recognized as an important physiological mechanism in the overall regulation of solute and water homeostasis by the mammalian organism. Recent studies have expanded the understanding of this mechanism concerning the transport of diverse solutes with beginning insight into the precise nature of the cellular transport processes involved. The modulatory roles of both circulating and intrarenal hormonal systems on the responses to alterations in the magnitude of efferent renal sympathetic nerve activity are being understood from the nerve terminal release of neurotransmitter to influences on cellular transport processes which determine the overall effect. When dietary sodium intake is normal or only modestly reduced, intact renal innervation is not essential for normal renal sodium conservation. However, when dietary sodium intake is severely restricted, there is maximum engagement of all mechanisms known to participate in renal sodium conservation and, under these conditions, intact renal innervation is essential for normal renal sodium conservation.

Quantitative analysis of iris changes after physiologic and pharmacologic mydriasis in a rural Chinese population.

PubMed

Zhang, Ye; Li, Si Zhen; Li, Lei; He, Ming Guang; Thomas, Ravi; Wang, Ning Li

2014-04-24

To estimate and compare the change in iris cross-sectional area (IA) and iris volume (IV) following physiologic and pharmacologic pupil dilation in primary angle closure suspects (PACS) and normal subjects. Anterior segment-optical coherence tomography (AS-OCT) measurements in light, dark, and following pharmacologic dilation were obtained on 186 PACS and 224 normal subjects examined during the 5-year follow-up of the Handan Eye Study. Iris cross-sectional area, IV, and other biometric parameters calculated using the Zhongshan angle assessment program in the right eyes of all subjects were analyzed. The mean IA and IV decreased in dark compared with light and after pharmacologic dilation in both PACS and normal eyes. This change was statistically significant in normal eyes: light versus pharmacologic dilation for IA (P = 0.038) and for IV, both light versus dark (P = 0.031) and light versus pharmacologic dilation (P = 0.012). A longer axial length (P = 0.028) and a greater change in pupil diameter (PD) (P < 0.001) were associated with a larger decrease of IA for the light to dark comparison. A diagnosis of normal eyes (P = 0.011), larger PD in dark (P = 0.001), and a larger change in PD (P = 0.001) were associated with a larger decrease of IV from light to dark. The differences in iris behavior between PACS and normal rural Chinese subjects following physiologic or pharmacologic pupillary dilation may help provide insights into the pathogenesis of angle closure. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

A comparative study of the characterization of miR-155 in knockout mice

PubMed Central

Zhang, Dong; Cui, Yongchun; Li, Bin; Luo, Xiaokang; Li, Bo; Tang, Yue

2017-01-01

miR-155 is one of the most important miRNAs and plays a very important role in numerous biological processes. However, few studies have characterized this miRNA in mice under normal physiological conditions. We aimed to characterize miR-155 in vivo by using a comparative analysis. In our study, we compared miR-155 knockout (KO) mice with C57BL/6 wild type (WT) mice in order to characterize miR-155 in mice under normal physiological conditions using many evaluation methods, including a reproductive performance analysis, growth curve, ultrasonic estimation, haematological examination, and histopathological analysis. These analyses showed no significant differences between groups in the main evaluation indices. The growth and development were nearly normal for all mice and did not differ between the control and model groups. Using a comparative analysis and a summary of related studies published in recent years, we found that miR-155 was not essential for normal physiological processes in 8-week-old mice. miR-155 deficiency did not affect the development and growth of naturally ageing mice during the 42 days after birth. Thus, studying the complex biological functions of miR-155 requires the further use of KO mouse models. PMID:28278287

Preface: cardiac control pathways: signaling and transport phenomena.

PubMed

Sideman, Samuel

2008-03-01

Signaling is part of a complex system of communication that governs basic cellular functions and coordinates cellular activity. Transfer of ions and signaling molecules and their interactions with appropriate receptors, transmembrane transport, and the consequent intracellular interactions and functional cellular response represent a complex system of interwoven phenomena of transport, signaling, conformational changes, chemical activation, and/or genetic expression. The well-being of the cell thus depends on a harmonic orchestration of all these events and the existence of control mechanisms that assure the normal behavior of the various parameters involved and their orderly expression. The ability of cells to sustain life by perceiving and responding correctly to their microenvironment is the basis for development, tissue repair, and immunity, as well as normal tissue homeostasis. Natural deviations, or human-induced interference in the signaling pathways and/or inter- and intracellular transport and information transfer, are responsible for the generation, modulation, and control of diseases. The present overview aims to highlight some major topics of the highly complex cellular information transfer processes and their control mechanisms. Our goal is to contribute to the understanding of the normal and pathophysiological phenomena associated with cardiac functions so that more efficient therapeutic modalities can be developed. Our objective in this volume is to identify and enhance the study of some basic passive and active physical and chemical transport phenomena, physiological signaling pathways, and their biological consequences.

Induction of chromosome aberrations in cultured human lymphocytes treated with sand dust storm fine particles (PM2.5).

PubMed

Wei, Aili; Meng, Ziqiang

2006-09-30

The clastogenic activity of airborne air fine particulate matter (PM2.5, particulates with an aerodynamic diameter < or =2.5 microm) has already been demonstrated. However little is known about the health risks associated with sand dust storm PM2.5 and its extract. In order to investigate the clastogenic activity of sand dust storm PM2.5 (include its organic and inorganic extract) on human lymphocytes, the normal PM2.5 and sand dust storm PM2.5 samples were collected in Wuwei city (Gansu Province) and Baotou city (Inner Mongolia), China. The chromosomal aberration (CA) test was employed and the cells were treated with 0, 33, 100, 300 microg ml(-1) sand dust storm or normal ambient air PM2.5 suspension (physiological saline as solvent control), or inorganic extract (0, 75, 150, 300 microg ml(-1), physiological saline as solvent control) or organic extract (0, 20, 40, 80 microg ml(-1), DMSO as solvent control) at the beginning of the cell culture. The results indicated that sand dust storm PM2.5 and its extract as well as normal samples can induce increase in CA frequency. With the increase of treatment concentrations the CA frequency increased and the mitotic index (MI) values declined in a dose-response manner. In the same concentrates, the CA frequency of normal ambient air PM2.5 and its extract were significant higher than those of sand dust storm PM2.5 (P<0.05 or 0.01) except the treatment of Wuwei sample at higher doses (100, 300 microg ml(-1)), the treatment of inorganic extract of PM2.5 at the highest dose (300 microg ml(-1)) and the treatment of organic extract of PM2.5 at the higher dose (40 and 80 microg ml(-1)) either in Baotou or in Wuwei (P>0.05). The toxicity of sand dust storm PM2.5 and its extract at high dose is very potent. CA frequency of normal PM2.5 (include its organic extract) from Baotou were higher than those of Wuwei especially in low and middle dose (P<0.05), but the treatment results of sand dust storm PM2.5 (include its all extract) was not significant different between the cities (P>0.05).

Physiological relaxation induced by horticultural activity: transplanting work using flowering plants.

PubMed

Lee, Min-sun; Park, Bum-jin; Lee, Juyoung; Park, Kun-tae; Ku, Ja-hyeong; Lee, Jun-woo; Oh, Kyung-ok; Miyazaki, Yoshifumi

2013-10-10

Despite increasing attention and a growing volume of research data, little physiological evidence is available on the benefits of horticultural activity and the different effects on individuals. Therefore, the aim of the present study was to investigate the physiological effects of horticultural activity and to examine how differences in personality alter these effects. The effects of transplanting real flowers (horticultural activity) and handling artificial flowers (control activity) on human physiological activity were compared. On the first day, eight participants engaged in horticultural activity and another eight in the control activity. On the second day, participants switched roles. Participants' physiological conditions during each activity were assessed by measuring the heart rate and heart rate variability (HRV). Psychological responses, which were measured using a semantic differential rating scale, showed that the horticultural activity promoted comfortable, soothed, and natural feelings, compared to the control activity. Analysis of physiological responses using two-way repeated measures analysis of variance (ANOVA) revealed that sympathetic nervous activity significantly decreased in the late time period (11 to 15 minutes) of horticultural activity only in the type A group. This study supports the fact that the horticultural activity can enhance psychological and physiological relaxation effects, although these physiological effects can differ among individuals with different personalities.

Physiological relaxation induced by horticultural activity: transplanting work using flowering plants

PubMed Central

2013-01-01

Background Despite increasing attention and a growing volume of research data, little physiological evidence is available on the benefits of horticultural activity and the different effects on individuals. Therefore, the aim of the present study was to investigate the physiological effects of horticultural activity and to examine how differences in personality alter these effects. Results The effects of transplanting real flowers (horticultural activity) and handling artificial flowers (control activity) on human physiological activity were compared. On the first day, eight participants engaged in horticultural activity and another eight in the control activity. On the second day, participants switched roles. Participants’ physiological conditions during each activity were assessed by measuring the heart rate and heart rate variability (HRV). Psychological responses, which were measured using a semantic differential rating scale, showed that the horticultural activity promoted comfortable, soothed, and natural feelings, compared to the control activity. Analysis of physiological responses using two-way repeated measures analysis of variance (ANOVA) revealed that sympathetic nervous activity significantly decreased in the late time period (11 to 15 minutes) of horticultural activity only in the type A group. Conclusions This study supports the fact that the horticultural activity can enhance psychological and physiological relaxation effects, although these physiological effects can differ among individuals with different personalities. PMID:24112302

Serum prolactin in coeliac disease: a marker for disease activity

PubMed Central

Reifen, R.; Buskila, D.; Maislos, M.; Press, J.; Lerner, A.

1997-01-01

Accepted 21 April 1997
 Prolactin, a polypeptide hormone of anterior pituitary origin, has pronounced physiological effects on growth, reproduction, and osmoregulation. Increasing evidence indicates that prolactin also has an immunomodulatory influence on the immune system. The status of prolactin in patients with coeliac disease was investigated by obtaining serum samples from 48 patients with active and non-active coeliac disease. These were compared with samples from 20 children with familial Mediterranean fever and 65 normal controls. Serum prolactin in patients with active coeliac disease was significantly higher than in the other groups studied and reference values. Serum prolactin correlated well with the degree of mucosal atrophy and with the serum concentration of antiendomysial antibodies. Prolactin may play a part in immune modulation in the intestinal damage of coeliac disease and serve as a potential marker for disease activity.

 PMID:9301358

Normal uptake of 68Ga-DOTA-TOC by the pancreas uncinate process mimicking malignancy at somatostatin receptor PET.

PubMed

Jacobsson, Hans; Larsson, Patricia; Jonsson, Cathrine; Jussing, Emma; Grybäck, Per

2012-04-01

To characterize a commonly occurring increased uptake by the uncinate process of the pancreas at PET/CT using 68Ga-DOTA-d-Phe1-Tyr3-octreotide (68Ga-DOTA-TOC). This tracer has replaced In pentetreotide (OctreoScan®) for somatostatin receptor scintigraphy at our laboratory. Fifty of our first 74 PET/CT examinations with 68Ga-DOTA-TOC could be evaluated in retrospect. None of these patients had surgery or showed any pathology in the pancreas head at the concomitant CT. Thirty-five of the 50 examinations (70%) showed an uptake by the uncinate process sufficiently intense to be interpreted as pathologic and simulating a tumor. Mean SUVmax was 9.2. Mean SUVmean using an isoactivity cut-off of >75% and >50% was 7.8 and 6.0, respectively. Volume calculations of the uncinate process activity using these definitions gave 0.9 mL and 4.2 mL, respectively. There is a frequent physiological uptake of 68Ga-DOTA-TOC by the pancreas uncinate process. This may be caused by an accumulation of pancreatic polypeptide-containing cells expressing somatostatin receptors. If there is a normal finding at concomitant diagnostic CT, this uptake should be regarded as physiological.

Dietary xenosterols lead to infertility and loss of abdominal adipose tissue in sterolin-deficient mice[S

PubMed Central

Solca, Curzio; Tint, G. Stephen; Patel, Shailendra B.

2013-01-01

The investigation of the human disease sitosterolemia (MIM 210250) has shed light not only on the pathways by which dietary sterols may traffic but also on how the mammalian body rids itself of cholesterol and defends against xenosterols. Two genes, ABCG5 and ABCG8, located at the sitosterolemia locus, each encodes a membrane-bound ABC half-transporter and constitutes a functional unit whose activity has now been shown to account for biliary and intestinal sterol excretion. Knockout mice deficient in Abcg5 or Abcg8 recapitulate many of the phenotypic features of sitosterolemia. During the course of our studies to characterize these knockout mice, we noted that these mice, raised on normal rodent chow, exhibited infertility as well as loss of abdominal fat. We show that, although sitosterolemia does not lead to any structural defects or to any overt endocrine defects, fertility could be restored if xenosterols are specifically blocked from entry and that the loss of fat is also reversed by a variety of maneuvers that limit xenosterol accumulation. These studies show that xenosterols may have a significant biological impact on normal mammalian physiology and that the Abcg5 or Abcg8 knockout mouse model may prove useful in investigating the role of xenosterols on mammalian physiology. PMID:23180829

Normal versus sickle red blood cells: hemodynamic and permeability characteristics in reperfusion lung injury.

PubMed

Haynes, J; Seibert, A; Shah, A; Taylor, A

1990-01-01

Decreased deformability and increased internal viscosity of the sickle red blood cell (SRBC) contribute to abnormal flow in the microcirculation. Since the lungs are commonly affected in sickle cell disease, we compared the hemodynamics of the normal human red blood cell (NRBC) with the SRBC in the pulmonary circulation. The SRBC has decreased antioxidant enzyme activities compared with the NRBC. Thus, using the capillary filtration coefficient (Kfc), we determined the ability of the NRBC and the SRBC to attenuate the increased permeability and resulting edema seen in the oxidant stress of reperfusion lung injury (RLI). We found that lungs perfused with a 5% SRBC perfusate had higher pulmonary arterial pressures (Ppa) and resistances than lungs perfused with a 5% NRBC perfusate. Lungs made ischemic and reperfused with a physiologic cell-free perfusate resulted in a significant increase (P less than .05) in Kfc compared with the preischemic Kfc (.45 +/- .06 to 1.4 +/- 22 mL.min-1.cm H2O.100 g-1). In lungs reperfused with 5% RBC-containing perfusates, the Kfc did not change from preischemic Kfc with NRBCs and decreased from the preischemic Kfc with SRBCs. These findings suggest that the SRBC causes physiologically significant increases in Ppa and resistances and the SRBC, like the NRBC, offers apparent protection in RLI.

Physiological functions of MTA family of proteins.

PubMed

Sen, Nirmalya; Gui, Bin; Kumar, Rakesh

2014-12-01

Although the functional significance of the metastasic tumor antigen (MTA) family of chromatin remodeling proteins in the pathobiology of cancer is fairly well recognized, the physiological role of MTA proteins continues to be an understudied research area and is just beginning to be recognized. Similar to cancer cells, MTA1 also modulates the expression of target genes in normal cells either by acting as a corepressor or coactivator. In addition, physiological functions of MTA proteins are likely to be influenced by its differential expression, subcellular localization, and regulation by upstream modulators and extracellular signals. This review summarizes our current understanding of the physiological functions of the MTA proteins in model systems. In particular, we highlight recent advances of the role MTA proteins play in the brain, eye, circadian rhythm, mammary gland biology, spermatogenesis, liver, immunomodulation and inflammation, cellular radio-sensitivity, and hematopoiesis and differentiation. Based on the growth of knowledge regarding the exciting new facets of the MTA family of proteins in biology and medicine, we speculate that the next burst of findings in this field may reveal further molecular regulatory insights of non-redundant functions of MTA coregulators in the normal physiology as well as in pathological conditions outside cancer.

An overview of the issues: physiological effects of bed rest and restricted physical activity

NASA Technical Reports Server (NTRS)

Convertino, V. A.; Bloomfield, S. A.; Greenleaf, J. E.

1997-01-01

Reduction of exercise capacity with confinement to bed rest is well recognized. Underlying physiological mechanisms include dramatic reductions in maximal stroke volume, cardiac output, and oxygen uptake. However, bed rest by itself does not appear to contribute to cardiac dysfunction. Increased muscle fatigue is associated with reduced muscle blood flow, red cell volume, capillarization and oxidative enzymes. Loss of muscle mass and bone density may be reflected by reduced muscle strength and higher risk for injury to bones and joints. The resultant deconditioning caused by bed rest can be independent of the primary disease and physically debilitating in patients who attempt to reambulate to normal active living and working. A challenge to clinicians and health care specialists has been the identification of appropriate and effective methods to restore physical capacity of patients during or after restricted physical activity associated with prolonged bed rest. The examination of physiological responses to bed rest deconditioning and exercise training in healthy subjects has provided significant information to develop effective rehabilitation treatments. The successful application of acute exercise to enhance orthostatic stability, daily endurance exercise to maintain aerobic capacity, or specific resistance exercises to maintain musculoskeletal integrity rather than the use of surgical, pharmacological, and other medical treatments for clinical conditions has been enhanced by investigation and understanding of underlying mechanisms that distinguish physical deconditioning from the disease. This symposium presents an overview of cardiovascular and musculoskeletal deconditioning associated with reduced physical work capacity following prolonged bed rest and exercise training regimens that have proven successful in ameliorating or reversing these adverse effects.

Physiological roles of pyruvate ferredoxin oxidoreductase and pyruvate formate-lyase in Thermoanaerobacterium saccharolyticum JW/SL-YS485

DOE PAGES

Zhou, Jilai; Olson, Daniel G.; Lanahan, Anthony A.; ...

2015-09-15

We report that Thermoanaerobacter saccharolyticum is a thermophilic microorganism that has been engineered to produce ethanol at high titer (30–70 g/L) and greater than 90 % theoretical yield. However, few genes involved in pyruvate to ethanol production pathway have been unambiguously identified. In T. saccharolyticum, the products of six putative pfor gene clusters and one pfl gene may be responsible for the conversion of pyruvate to acetyl-CoA. To gain insights into the physiological roles of PFOR and PFL, we studied the effect of deletions of several genes thought to encode these activities. We found that that pyruvate ferredoxin oxidoreductase enzymemore » (PFOR) is encoded by the pforA gene and plays a key role in pyruvate dissimilation. We further demonstrated that pyruvate formate-lyase activity (PFL) is encoded by the pfl gene. Although the pfl gene is normally expressed at low levels, it is crucial for biosynthesis in T. saccharolyticum. In pforA deletion strains, pfl expression increased and was able to partially compensate for the loss of PFOR activity. Deletion of both pforA and pfl resulted in a strain that required acetate and formate for growth and produced lactate as the primary fermentation product, achieving 88 % theoretical lactate yield. PFOR encoded by Tsac_0046 and PFL encoded by Tsac_0628 are only two routes for converting pyruvate to acetyl-CoA in T. saccharolyticum. The physiological role of PFOR is pyruvate dissimilation, whereas that of PFL is supplying C1 units for biosynthesis.« less

Normal distribution pattern and physiological variants of 68Ga-PSMA-11 PET/CT imaging.

PubMed

Demirci, Emre; Sahin, Onur Erdem; Ocak, Meltem; Akovali, Burak; Nematyazar, Jamal; Kabasakal, Levent

2016-11-01

Ga-PSMA-11 is a novel PET tracer suggested to be used for imaging of advanced prostate cancer. In this study, we aimed to present a detailed biodistribution of Ga-PSMA-11, including physiological and benign variants of prostate-specific membrane antigen (PSMA) imaging. We carried out a retrospective analysis of 40 patients who underwent PSMA PET/computed tomography (CT) imaging and who had no evidence of residual or metastatic disease on the scans. In addition, 16 patients who underwent PSMA PET/CT imaging with any indication other than prostate cancer were included in the study to evaluate physiological uptake in the normal prostate gland. The median, minimum-maximum, and mean standardized uptake value (SUV) values were calculated for visceral organs, bone marrow and lymph nodes, and mucosal areas. Any physiological variants or benign lesions with Ga-PSMA-11 were also noted. Ga-PSMA-11 uptake was noted in the kidneys, parotid and submandibular glands, duodenum, small intestines, spleen, liver, and lacrimal glands, and mucosal uptake in the nasopharynx, vocal cords, pancreas, stomach, mediastinal blood pool, thyroid gland, adrenal gland, rectum, vertebral bone marrow, and testes. Celiac ganglia showed slight Ga-PSMA-11 uptake in 24 of 40 patients without the presence of any other pathologic lymph nodes in abdominal and pelvic areas. Variable uptake of Ga-PSMA-11 was observed in calcified choroid plexus, a thyroid nodule, an adrenal nodule, axillary lymph nodes and celiac ganglia, occasional osteophytes, and gallbladder. The patient group with PSMA PET/CT for indications other than prostate cancer (n=16) showed a slight radiotracer uptake in normal prostate gland (SUVmax: 5.5±1.6, range: 3.5-8.3). This study shows normal distribution pattern, range of SUVs, and physiological variants of Ga-PSMA-11. In addition, several potential pitfalls were documented to prevent misinterpretations of the scan.

Neuromuscular control of fundamental frequency and glottal posture at phonation onset

PubMed Central

Chhetri, Dinesh K.; Neubauer, Juergen; Berry, David A.

2012-01-01

The laryngeal neuromuscular mechanisms for modulating glottal posture and fundamental frequency are of interest in understanding normal laryngeal physiology and treating vocal pathology. The intrinsic laryngeal muscles in an in vivo canine model were electrically activated in a graded fashion to investigate their effects on onset frequency, phonation onset pressure, vocal fold strain, and glottal distance at the vocal processes. Muscle activation plots for these laryngeal parameters were evaluated for the interaction of following pairs of muscle activation conditions: (1) cricothyroid (CT) versus all laryngeal adductors (TA/LCA/IA), (2) CT versus LCA/IA, (3) CT versus thyroarytenoid (TA) and, (4) TA versus LCA/IA (LCA: lateral cricoarytenoid muscle, IA: interarytenoid). Increases in onset frequency and strain were primarily affected by CT activation. Onset pressure correlated with activation of all adductors in activation condition 1, but primarily with CT activation in conditions 2 and 3. TA and CT were antagonistic for strain. LCA/IA activation primarily closed the cartilaginous glottis while TA activation closed the mid-membranous glottis. PMID:22352513

Physiological impact of patent foramen ovale on pulmonary gas exchange, ventilatory acclimatization, and thermoregulation.

PubMed

Lovering, Andrew T; Elliott, Jonathan E; Davis, James T

2016-08-01

The foramen ovale, which is part of the normal fetal cardiopulmonary circulation, fails to close after birth in ∼35% of the population and represents a potential source of right-to-left shunt. Despite the prevalence of patent foramen ovale (PFO) in the general population, cardiopulmonary, exercise, thermoregulatory, and altitude physiologists may have underestimated the potential effect of this shunted blood flow on normal physiological processes in otherwise healthy humans. Because this shunted blood bypasses the respiratory system, it would not participate in either gas exchange or respiratory system cooling and may have impacts on other physiological processes that remain undetermined. The consequences of this shunted blood flow in PFO-positive (PFO+) subjects can potentially have a significant, and negative, impact on the alveolar-to-arterial oxygen difference (AaDO2), ventilatory acclimatization to high altitude and respiratory system cooling with PFO+ subjects having a wider AaDO2 at rest, during exercise after acclimatization, blunted ventilatory acclimatization, and a higher core body temperature (∼0.4(°)C) at rest and during exercise. There is also an association of PFO with high-altitude pulmonary edema and acute mountain sickness. These effects on physiological processes are likely dependent on both the presence and size of the PFO, with small PFOs not likely to have significant/measureable effects. The PFO can be an important determinant of normal physiological processes and should be considered a potential confounder to the interpretation of former and future data, particularly in small data sets where a significant number of PFO+ subjects could be present and significantly impact the measured outcomes.

Evidence Coupling Increased Hexosamine Biosynthesis Pathway Activity to Membrane Cholesterol Toxicity and Cortical Filamentous Actin Derangement Contributing to Cellular Insulin Resistance†

PubMed Central

Bhonagiri, Padma; Pattar, Guruprasad R.; Habegger, Kirk M.; McCarthy, Alicia M.; Tackett, Lixuan

2011-01-01

Hyperinsulinemia is known to promote the progression/worsening of insulin resistance. Evidence reveals a hidden cost of hyperinsulinemia on plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (F-actin) structure, components critical to the normal operation of the insulin-regulated glucose transport system. Here we delineated whether increased glucose flux through the hexosamine biosynthesis pathway (HBP) causes PIP2/F-actin dysregulation and subsequent insulin resistance. Increased glycosylation events were detected in 3T3-L1 adipocytes cultured under conditions closely resembling physiological hyperinsulinemia (5 nm insulin; 12 h) and in cells in which HBP activity was amplified by 2 mm glucosamine (GlcN). Both the physiological hyperinsulinemia and experimental GlcN challenge induced comparable losses of PIP2 and F-actin. In addition to protecting against the insulin-induced membrane/cytoskeletal abnormality and insulin-resistant state, exogenous PIP2 corrected the GlcN-induced insult on these parameters. Moreover, in accordance with HBP flux directly weakening PIP2/F-actin structure, pharmacological inhibition of the rate-limiting HBP enzyme [glutamine-fructose-6-phosphate amidotransferase (GFAT)] restored PIP2-regulated F-actin structure and insulin responsiveness. Conversely, overexpression of GFAT was associated with a loss of detectable PM PIP2 and insulin sensitivity. Even less invasive challenges with glucose, in the absence of insulin, also led to PIP2/F-actin dysregulation. Mechanistically we found that increased HBP activity increased PM cholesterol, the removal of which normalized PIP2/F-actin levels. Accordingly, these data suggest that glucose transporter-4 functionality, dependent on PIP2 and/or F-actin status, can be critically compromised by inappropriate HBP activity. Furthermore, these data are consistent with the PM cholesterol accrual/toxicity as a mechanistic basis of the HBP-induced defects in PIP2/F-actin structure and impaired glucose transporter-4 regulation. PMID:21712361

A Physiologically Based Kinetic Model of Rat and Mouse Gestation: Disposition of a Weak Acid

EPA Science Inventory

A physiologically based toxicokinetic model of gestation in the rat mouse has been developed. The model is superimposed on the normal growth curve for nonpregnant females. It describes the entire gestation period including organogenesis. The model consists of uterus, mammary tiss...

Predictable root recession coverage.

PubMed

Hoexter, David L

2006-01-01

Gingival recession, exposure of the tooth's root, is undesirable and, in many situations, contrary to normal physiology. Today's root coverage is predictable. With the use of an acellular dermal matrix membrane (Fasciablast), we can achieve a new blood supply and predictable coverage, with no second surgical procedure. Youth, esthetics and physiology are restored.

Practical otic anatomy and physiology of the dog and cat.

PubMed

Njaa, Bradley L; Cole, Lynette K; Tabacca, Natalie

2012-11-01

Knowledge of the normal structure and function of the canine and feline ear is critical to be able to diagnose abnormalities that either involve the ear or originate within one or more of the ear compartments. In addition, a veterinarian must be aware of various structures within or associated with the ear so that they are not damaged or destroyed while treating an animal with otic disease. This article provides a brief discussion of the various anatomic features of the ear and normal physiology of portions of the ear. Copyright © 2012 Elsevier Inc. All rights reserved.

Analysis of space-time projection of differential and Michelson-type speckle-interferometer output signal for cardiovibration measurement

NASA Astrophysics Data System (ADS)

Ulyanov, Sergey S.; Tuchin, Valery V.

1993-06-01

The sex differences in cardiovascular system responses to a mild noise stress are established using the physiological and the dynamic systems theory methods. Lower levels of basal systolic arterial pressure and higher rates of its dropping and normalization under influence and after its cessation are typical for women. There are no hypertensive responses to stresses in women in contrast to men. The normalized entropy of the ECG signal, describing the physiological variability, increases in women and decreases in men. The advantages of female cardiovascular system response to mild stresses are discussed.

The energy expenditure of normal and pathologic gait.

PubMed

Waters, R L; Mulroy, S

1999-07-01

Physiological energy expenditure measurement has proven to be a reliable method of quantitatively assessing the penalties imposed by gait disability. The purpose of this review is to outline the basic principles of exercise physiology relevant to human locomotion; detail the energy expenditure of normal walking; and summarize the results of energy expenditure studies performed in patients with specific neurologic and orthopedic disabilities. The magnitude of the disabilities and the patients' capacity to tolerate the increased energy requirements are compared. This paper also will examine the effectiveness of rehabilitation interventions at mitigating the energetic penalties of disability during ambulation.

Protein tyrosine kinase regulation by ubiquitination: Critical roles of Cbl-family ubiquitin ligases

PubMed Central

Mohapatra, Bhopal; Ahmad, Gulzar; Nadeau, Scott; Zutshi, Neha; An, Wei; Scheffe, Sarah; Dong, Lin; Feng, Dan; Goetz, Benjamin; Arya, Priyanka; Bailey, Tameka A.; Palermo, Nicholas; Borgstahl, Gloria E.O.; Natarajan, Amarnath; Raja, Srikumar M.; Naramura, Mayumi; Band, Vimla; Band, Hamid

2012-01-01

Protein tyrosine kinases (PTKs) coordinate a broad spectrum of cellular responses to extracellular stimuli and cell–cell interactions during development, tissue homeostasis, and responses to environmental challenges. Thus, an understanding of the regulatory mechanisms that ensure physiological PTK function and potential aberrations of these regulatory processes during diseases such as cancer are of broad interest in biology and medicine. Aside from the expected role of phospho-tyrosine phosphatases, recent studies have revealed a critical role of covalent modification of activated PTKs with ubiquitin as a critical mechanism of their negative regulation. Members of the Cbl protein family (Cbl, Cbl-b and Cbl-c in mammals) have emerged as dominant “activated PTK-selective” ubiquitin ligases. Structural, biochemical and cell biological studies have established that Cbl protein-dependent ubiquitination targets activated PTKs for degradation either by facilitating their endocytic sorting into lysosomes or by promoting their proteasomal degradation. This mechanism also targets PTK signaling intermediates that become associated with Cbl proteins in a PTK activation-dependent manner. Cellular and animal studies have established that the relatively broadly expressed mammalian Cbl family members Cbl and Cbl-b play key physiological roles, including their critical functions to prevent the transition of normal immune responses into autoimmune disease and as tumor suppressors; the latter function has received validation from human studies linking mutations in Cbl to human leukemia. These newer insights together with embryonic lethality seen in mice with a combined deletion of Cbl and Cbl-b genes suggest an unappreciated role of the Cbl family proteins, and by implication the ubiquitin-dependent control of activated PTKs, in stem/progenitor cell maintenance. Future studies of existing and emerging animal models and their various cell lineages should help test the broader implications of the evolutionarily-conserved Cbl family protein-mediated, ubiquitin-dependent, negative regulation of activated PTKs in physiology and disease. PMID:23085373

Normal venous anatomy and physiology of the lower extremity.

PubMed

Notowitz, L B

1993-06-01

Venous disease of the lower extremities is common but is often misunderstood. It seems that the focus is on the exciting world of arterial anatomy and pathology, while the topic of venous anatomy and pathology comes in second place. However, venous diseases such as chronic venous insufficiency, leg ulcers, and varicose veins affect much of the population and may lead to disability and death. Nurses are often required to answer complex questions from the patients and his or her family about the patient's disease. Patients depend on nurses to provide accurate information in terms they can understand. Therefore it is important to have an understanding of the normal venous system of the legs before one can understand the complexities of venous diseases and treatments. This presents an overview of normal venous anatomy and physiology.

Effects of elevated CO₂, warming and precipitation change on plant growth, photosynthesis and peroxidation in dominant species from North China grassland.

PubMed

Xu, Zhenzhu; Shimizu, Hideyuki; Ito, Shoko; Yagasaki, Yasumi; Zou, Chunjing; Zhou, Guangsheng; Zheng, Yuanrun

2014-02-01

Warming, watering and elevated atmospheric CO₂-concentration effects have been extensively studied separately; however, their combined impact on plants is not well understood. In the current research, we examined plant growth and physiological responses of three dominant species from the Eurasian Steppe with different functional traits to a combination of elevated CO₂, high temperature, and four simulated precipitation patterns. Elevated CO₂ stimulated plant growth by 10.8-41.7 % for a C₃ leguminous shrub, Caragana microphylla, and by 33.2-52.3 % for a C₃ grass, Stipa grandis, across all temperature and watering treatments. Elevated CO₂, however, did not affect plant biomass of a C₄ grass, Cleistogenes squarrosa, under normal or increased precipitation, whereas a 20.0-69.7 % stimulation of growth occurred with elevated CO₂ under drought conditions. Plant growth was enhanced in the C₃ shrub and the C₄ grass by warming under normal precipitation, but declined drastically with severe drought. The effects of elevated CO₂ on leaf traits, biomass allocation and photosynthetic potential were remarkably species-dependent. Suppression of photosynthetic activity, and enhancement of cell peroxidation by a combination of warming and severe drought, were partly alleviated by elevated CO₂. The relationships between plant functional traits and physiological activities and their responses to climate change were discussed. The present results suggested that the response to CO₂ enrichment may strongly depend on the response of specific species under varying patterns of precipitation, with or without warming, highlighting that individual species and multifactor dependencies must be considered in a projection of terrestrial ecosystem response to climatic change.

Autonomic nervous system activity of preschool-age children who stutter

PubMed Central

Jones, Robin M.; Buhr, Anthony P.; Conture, Edward G.; Tumanova, Victoria; Walden, Tedra A.; Porges, Stephen W.

2014-01-01

Purpose The purpose of this study was to investigate potential differences in autonomic nervous system (ANS) activity to emotional stimuli between preschool-age children who do (CWS) and do not stutter (CWNS). Methods Participants were 20 preschool-age CWS (15 male) and 21 preschool-age CWNS (11 male). Participants were exposed to two emotion-inducing video clips (negative and positive) with neutral clips used to establish pre-and post-arousal baselines, and followed by age-appropriate speaking tasks. Respiratory sinus arrhythmia (RSA) – often used as an index of parasympathetic activity – and skin conductance level (SCL) – often used as an index of sympathetic activity – were measured while participants listened to/watched the audio-video clip presentation and performed a speaking task. Results CWS, compared to CWNS, displayed lower amplitude RSA at baseline and higher SCL during a speaking task following the positive, compared to the negative, condition. During speaking, only CWS had a significant positive relation between RSA and SCL. Conclusion Present findings suggest that preschool-age CWS, when compared to their normally fluent peers, have a physiological state that is characterized by a greater vulnerability to emotional reactivity (i.e., lower RSA indexing less parasympathetic tone) and a greater mobilization of resources in support of emotional reactivity (i.e., higher SCL indexing more sympathetic activity) during positive conditions. Thus, while reducing stuttering to a pure physiological process is unwarranted, the present findings suggest that parasympathetic and sympathetic nervous system activity is involved. PMID:25087166

The significance of oxygen during contact lens wear.

PubMed

Papas, Eric B

2014-12-01

In order to establish the relevance of oxygen to contemporary contact lens practice, a review of the literature was conducted. The results indicate that there are a number of processes occurring in the normal healthy eye where oxygen is required and which are potentially affected by the presence of a contact lens. These activities appear to take place at all corneal levels, as well as at the limbus. Evidence from laboratory, clinical and modelling studies indicates that what constitutes normal oxygenation (normoxia) depends on, among other things, the physiological system under consideration, corneal location and the state of eye closure. This diversity is reflected in the wide range of minimum lens oxygen transmissibility (Dk/t) requirements that are present in a literature. Copyright © 2014 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Novel coumarins and related copper complexes with biological activity: DNA binding, molecular docking and in vitro antiproliferative activity.

PubMed

Pivetta, Tiziana; Valletta, Elisa; Ferino, Giulio; Isaia, Francesco; Pani, Alessandra; Vascellari, Sarah; Castellano, Carlo; Demartin, Francesco; Cabiddu, Maria Grazia; Cadoni, Enzo

2017-12-01

Coumarins show biological activity and are widely exploited for their therapeutic effects. Although a great number of coumarins substituted by heterocyclic moieties have been prepared, few studies have been carried out on coumarins containing pyridine heterocycle, which is known to modulate their physiological activities. We prepared and characterized three novel 3-(pyridin-2-yl)coumarins and their corresponding copper(II) complexes. We extended our investigations also to three known similar coumarins, since no data about their biochemical activity was previously been reported. The antiproliferative activity of the studied compounds was tested against human derived tumor cell lines and one human normal cell line. The DNA binding constants were determined and docking studies with DNA carried out. Selected Quantitative Structure-Activity Relationship (QSAR) descriptors were calculated in order to relate a set of structural and topological descriptors of the studied compounds to their DNA interaction and cytotoxic activity. Copyright © 2017 Elsevier Inc. All rights reserved.

Adenosine signaling in normal and sickle erythrocytes and beyond.

PubMed

Zhang, Yujin; Xia, Yang

2012-08-01

Sickle cell disease (SCD) is a debilitating hemolytic genetic disorder with high morbidity and mortality affecting millions of individuals worldwide. Although SCD was discovered more than a century ago, no effective mechanism-based prevention and treatment are available due to poorly understood molecular basis of sickling, the fundamental pathogenic process of the disease. SCD patients constantly face hypoxia. One of the best-known signaling molecules to be induced under hypoxic conditions is adenosine. Recent studies demonstrate that hypoxia-mediated elevated adenosine signaling plays an important role in normal erythrocyte physiology. In contrast, elevated adenosine signaling contributes to sickling and multiple life threatening complications including tissue damage, pulmonary dysfunction and priapism. Here, we summarize recent research on the role of adenosine signaling in normal and sickle erythrocytes, progression of the disease and therapeutic implications. In normal erythrocytes, both genetic and pharmacological studies demonstrate that adenosine can enhance 2,3-bisphosphoglycerate (2,3-BPG) production via A(2B) receptor (ADORA2B) activation, suggesting that elevated adenosine has an unrecognized role in normal erythrocytes to promote O(2) release and prevent acute ischemic tissue injury. However, in sickle erythrocytes, the beneficial role of excessive adenosine-mediated 2,3-BPG induction becomes detrimental by promoting deoxygenation, polymerization of sickle hemoglobin and subsequent sickling. Additionally, adenosine signaling via the A(2A) receptor (ADORA2A) on invariant natural killer T (iNKT) cells inhibits iNKT cell activation and attenuates pulmonary dysfunction in SCD mice. Finally, elevated adenosine coupled with ADORA2BR activation is responsible for priapism, a dangerous complication seen in SCD. Overall, the research reviewed here reveals a differential role of elevated adenosine in normal erythrocytes, sickle erythrocytes, iNK cells and progression of disease. Thus, adenosine signaling represents a potentially important therapeutic target for the treatment and prevention of disease. Copyright © 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Do changes in neuromuscular activation contribute to the knee extensor angle-torque relationship?

PubMed

Lanza, Marcel B; Balshaw, Thomas G; Folland, Jonathan P

2017-08-01

What is the central question of the study? Do changes in neuromuscular activation contribute to the knee extensor angle-torque relationship? What is the main finding and its importance? Both agonist (quadriceps) and antagonist coactivation (hamstrings) differed with knee joint angle during maximal isometric knee extensions and thus both are likely to contribute to the angle-torque relationship. Specifically, two independent measurement techniques showed quadriceps activation to be lower at more extended positions. These effects might influence the capacity for neural changes in response to training and rehabilitation at different knee joint angles. The influence of joint angle on knee extensor neuromuscular activation is unclear, owing in part to the diversity of surface electromyography (sEMG) and/or interpolated twitch technique (ITT) methods used. The aim of the study was to compare neuromuscular activation, using rigorous contemporary sEMG and ITT procedures, during isometric maximal voluntary contractions (iMVCs) of the quadriceps femoris at different knee joint angles and examine whether activation contributes to the angle-torque relationship. Sixteen healthy active men completed two familiarization sessions and two experimental sessions of isometric knee extension and knee flexion contractions. The experimental sessions included the following at each of four joint angles (25, 50, 80 and 106 deg): iMVCs (with and without superimposed evoked doublets); submaximal contractions with superimposed doublets; and evoked twitch and doublet contractions whilst voluntarily passive, and knee flexion iMVC at the same knee joint positions. The absolute quadriceps femoris EMG was normalized to the peak-to-peak amplitude of an evoked maximal M-wave, and the doublet-voluntary torque relationship was used to calculate activation with the ITT. Agonist activation, assessed with both normalized EMG and the ITT, was reduced at the more extended compared with the more flexed positions (25 and 50 versus 80 and 106 deg; P ≤ 0.016), whereas antagonist coactivation was greatest in the most flexed compared with the extended positions (106 versus 25 and 50 deg; P ≤ 0.02). In conclusion, both agonist and antagonist activation differed with knee joint angle during knee extension iMVCs, and thus both are likely to contribute to the knee extensor angle-torque relationship. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

The study of pain with blood oxygen level dependent functional magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Ibinson, James W.

Using blood oxygen level dependent functional magnetic resonance imaging (BOLD FMRI), the brain areas activated by pain were studied. These initial studies led to interesting new findings about the body's response to pain and to the refinement of one method used in FMRI analysis for correction of physiologic noise (signal fluctuations caused by the cyclic and non-cyclic changes in the cardiovascular and respiratory status of the body). In the first study, evidence was provided suggesting that the multiple painful stimulations used in typical pain FMRI block designs may cause attenuation over time of the BOLD signal within activated areas. The effect this may have on pain investigations using multiple tasks has not been previously investigated. The demonstrated BOLD attenuation seems unique to pain studies. Several possible explanations exist, but two of the most likely are neural activity modulation by descending pain inhibitory mechanisms and changing hemodynamics caused by a physiologic response to pain. The second study began the investigation of hemodynamics by monitoring the physiologic response to pain for eight subjects in two phases. Phase one used a combination of standard operating suite monitors and research equipment to characterizing the physiologic response to pain. Phase two collected magnetic resonance quantitative flow images during painful nerve stimulation to test for changes in global cerebral blood flow. It is well established that changes in respiration and global blood flow can affect the BOLD response, leading to the final investigation of this dissertation. The brain activation induced by pain for the same eight subjects used in the physiologic response experiments described above was then studied by BOLD FMRI. By including the respiration signal and end-tidal carbon dioxide levels in the analysis of the images, the quantification and removal of image intensity variations correlated to breathing and end-tidal carbon dioxide changes could be performed. The technique generally accepted for this analysis, however, uses respiration signals averaged over a 3 second period. Because normal respiratory rate is approximately one breath every 3 to 5 seconds, it was hypothesized that performing the correction using the average breathing data set would miss much of the actual respiration induced variation in each image. Therefore, a new technique for removing signal that covaries with the actual breathing values present during the collection of each image was introduced. (Abstract shortened by UMI.)

Tissue Doppler Imaging can be useful to distinguish pathological from physiological left ventricular hypertrophy: a study in master athletes and mild hypertensive subjects

PubMed Central

Galanti, Giorgio; Toncelli, Loira; Del Furia, Francesca; Stefani, Laura; Cappelli, Brunello; De Luca, Alessio; Vono, Maria Concetta Roberta

2009-01-01

Background Transthoracic echocardiography left ventricular wall thickness is often increased in master athletes and it results by intense physical training. Left Ventricular Hypertrophy can also be due to a constant pressure overload. Conventional Pulsed Wave (PW) Doppler analysis of diastolic function sometimes fails to distinguish physiological from pathological LVH. The aim of this study is to evaluate the role of Pulsed Wave Tissue Doppler Imaging in differentiating pathological from physiological LVH in the middle-aged population. Methods we selected a group of 80 master athletes, a group of 80 sedentary subjects with essential hypertension and an apparent normal diastolic function at standard PW Doppler analysis. The two groups were comparable for increased left ventricular wall thickness and mass index (134.4 ± 19.7 vs 134.5 ± 22.1 gr/m2; p > .05). Diastolic function indexes using the PW technique were in the normal range for both. Results Pulsed Wave TDI study of diastolic function immediately distinguished the two groups. While in master athletes the diastolic TDI-derived parameters remained within normal range (E' 9.4 ± 3.1 cm/sec; E/E' 7.8 ± 2.1), in the hypertensive group these parameters were found to be constantly altered, with mean values and variation ranges always outside normal validated limits (E' 7.2 ± 2.4 cm/sec; E/E' 10.6 ± 3.2), and with E' and E/E' statistically different in the two groups (p < .001). Conclusion Our study showed that the TDI technique can be an easy and validated method to assess diastolic function in differentiating normal from pseudonormal diastolic patterns and it can distinguish physiological from pathological LVH emphasizing the eligibility certification required by legal medical legislation as in Italy. PMID:19845938

Endogenous angiotensin affects responses to stimulation of baroreceptor afferent nerves.

PubMed

DiBona, Gerald F; Jones, Susan Y

2003-08-01

To study effects of endogenous angiotensin II on responses to standardized stimulation of afferent neural input into the central portion of the arterial and cardiac baroreflexes. Different dietary sodium intakes were used to physiologically alter endogenous angiotensin II activity. Candesartan, an angiotensin II type 1 receptor antagonist, was used to assess dependency of observed effects on angiotensin II stimulation of angiotensin II type 1 receptors. Electrical stimulation of arterial and cardiac baroreflex afferent nerves was used to provide a standardized input to the central portion of the arterial and cardiac baroreflexes. In anesthetized rats in balance on low, normal and high dietary sodium intake, arterial pressure, heart rate and renal sympathetic nerve activity responses to electrical stimulation of vagus and aortic depressor nerves were determined. Compared with plasma renin activity values in normal dietary sodium intake rats, those from low dietary sodium intake rats were higher and those from high dietary sodium intake rats were lower. During vagus nerve stimulation, the heart rate, arterial pressure and renal sympathetic nerve activity responses were similar in all three dietary sodium intake groups. During aortic depressor nerve stimulation, the heart rate and arterial pressure responses were similar in all three dietary sodium intake groups. However, the renal sympathetic nerve activity response was significantly greater in the low sodium group than in the normal and high sodium group at 4, 8 and 16 Hz. Candesartan administered to low dietary sodium intake rats had no effect on the heart rate and arterial pressure responses to either vagus or aortic depressor nerve stimulation but increased the magnitude of the renal sympathoinhibitory responses. Increased endogenous angiotensin II in rats on a low dietary sodium intake attenuates the renal sympathoinhibitory response to activation of the cardiac and sinoaortic baroreflexes by standardized vagus and aortic depressor nerve stimulation, respectively.

Madres para la Salud: design of a theory-based intervention for postpartum Latinas.

PubMed

Keller, Colleen; Records, Kathie; Ainsworth, Barbara; Belyea, Michael; Permana, Paska; Coonrod, Dean; Vega-López, Sonia; Nagle-Williams, Allison

2011-05-01

Weight gain in young women suggests that childbearing may be an important contributor to the development of obesity in women. Depressive symptoms can interfere with resumption of normal activity levels following childbirth or with the initiation of or adherence to physical activity programs essential for losing pregnancy weight. Depression symptoms may function directly to promote weight gain through a physiologic mechanism. Obesity and its related insulin resistance may contribute to depressed mood physiologically. Although physical activity has well-established beneficial effects on weight management and depression, women tend to under participate in physical activity during childbearing years. Further, the mechanisms underpinning the interplay of overweight, obesity, physical activity, depression, and inflammatory processes are not clearly explained. This report describes the theoretical rationale, design considerations, and cultural relevance for "Madres para la Salud" [Mothers for Health]. Madres para la Salud is a 12 month prospective, randomized controlled trial exploring the effectiveness of a culturally specific intervention using "bouts" of physical activity to effect changes in body fat, systemic and fat tissue inflammation, and postpartum depression symptoms in sedentary postpartum Latinas. The significance and innovation of Madres para la Salud includes use of a theory-driven approach to intervention, specification and cultural relevance of a social support intervention, use of a Promotora model to incorporate cultural approaches, use of objective measures of physical activity in post partum Latinas women, and the examination of biomarkers indicative of cardiovascular risk related to physical activity behaviors in postpartum Latinas. Copyright © 2011 Elsevier Inc. All rights reserved.

Madres para la Salud: Design of a Theory-based Intervention for Postpartum Latinas

PubMed Central

Keller, Colleen; Records, Kathie; Ainsworth, Barbara; Belyea, Michael; Permana, Paska; Coonrod, Dean; Vega-López, Sonia; Nagle-Williams, Allison

2011-01-01

Background Weight gain in young women suggests that childbearing may be an important contributor to the development of obesity in women. Depressive symptoms can interfere with resumption of normal activity levels following childbirth or with the initiation of or adherence to physical activity programs essential for losing pregnancy weight. Depression symptoms may function directly to promote weight gain through a physiologic mechanism. Obesity and its related insulin resistance may contribute to depressed mood physiologically. Although physical activity has well-established beneficial effects on weight management and depression, women tend to under participate in physical activity during childbearing years. Further, the mechanisms underpinning the interplay of overweight, obesity, physical activity, depression, and inflammatory processes are not clearly explained. Objectives This report describes the theoretical rationale, design considerations, and cultural relevance for “Madres para la Salud” [Mothers for Health]. Design and Methods Madres para la Salud is a 12 month prospective, randomized controlled trial exploring the effectiveness of a culturally specific intervention using “bouts” of physical activity to effect changes in body fat, systemic and fat tissue inflammation, and postpartum depression symptoms in sedentary postpartum Latinas. Summary The significance and innovation of Madres para la Salud includes use of a theory-driven approach to intervention, specification and cultural relevance of a social support intervention, use of a Promotora model to incorporate cultural approaches, use of objective measures of physical activity in post partum Latinas women, and the examination of biomarkers indicative of cardiovascular risk related to physical activity behaviors in postpartum Latinas. PMID:21238614

TAP, a novel T cell-activating protein involved in the stimulation of MHC-restricted T lymphocytes

PubMed Central

1986-01-01

Five mAbs have been generated and used to characterize TAP (T cell activating protein) a novel, functional murine T cell membrane antigen. The TAP molecule is a 12-kD protein that is synthesized by T cells. By antibody crossblocking, it appears to be closely associated with a 16- kD protein on the T cell membrane also identified with a novel mAb. These molecules are clearly distinct from the major well-characterized murine T cell antigens previously described. Antibody binding to TAP can result in the activation of MHC-restricted, antigen-specific inducer T cell hybridomas that is equivalent in magnitude to maximal antigen or lectin stimulation. This is a direct effect of soluble antibody and does not require accessory cells or other factors. The activating anti-TAP mAbs are also mitogenic for normal heterogeneous T lymphocytes in the presence of accessory cells or IL-1. In addition, these antibodies are observed to modulate specific immune stimulation. Thus, the activating anti-TAP mAbs synergise with antigen-specific stimulation of T cells, while a nonactivating anti-TAP mAb inhibits antigen driven activation. These observations suggest that the TAP molecule may participate in physiologic T cell activation. The possible relationship of TAP to known physiologic triggering structures, the T3- T cell receptor complex, is considered. TAP is expressed on 70% of peripheral T cells and therefore defines a major T cell subset, making it perhaps the first example of a murine subset-specific activating protein. PMID:2418146

Pig brain stereotaxic standard space: mapping of cerebral blood flow normative values and effect of MPTP-lesioning.

PubMed

Andersen, Flemming; Watanabe, Hideaki; Bjarkam, Carsten; Danielsen, Erik H; Cumming, Paul

2005-07-15

The analysis of physiological processes in brain by position emission tomography (PET) is facilitated when images are spatially normalized to a standard coordinate system. Thus, PET activation studies of human brain frequently employ the common stereotaxic coordinates of Talairach. We have developed an analogous stereotaxic coordinate system for the brain of the Gottingen miniature pig, based on automatic co-registration of magnetic resonance (MR) images obtained in 22 male pigs. The origin of the pig brain stereotaxic space (0, 0, 0) was arbitrarily placed in the centroid of the pineal gland as identified on the average MRI template. The orthogonal planes were imposed using the line between stereotaxic zero and the optic chiasm. A series of mean MR images in the coronal, sagittal and horizontal planes were generated. To test the utility of the common coordinate system for functional imaging studies of minipig brain, we calculated cerebral blood flow (CBF) maps from normal minipigs and from minipigs with a syndrome of parkisonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-poisoning. These maps were transformed from the native space into the common stereotaxic space. After global normalization of these maps, an undirected search for differences between the groups was then performed using statistical parametric mapping. Using this method, we detected a statistically significant focal increase in CBF in the left cerebellum of the MPTP-lesioned group. We expect the present approach to be of general use in the statistical parametric mapping of CBF and other physiological parameters in living pig brain.

Oxidative phosphorylation in Debaryomyces hansenii: physiological uncoupling at different growth phases.

PubMed

Cabrera-Orefice, Alfredo; Guerrero-Castillo, Sergio; Díaz-Ruíz, Rodrigo; Uribe-Carvajal, Salvador

2014-07-01

Physiological uncoupling of mitochondrial oxidative phosphorylation (OxPhos) was studied in Debaryomyces hansenii. In other species, such as Yarrowia lipolytica and Saccharomyces cerevisiae, OxPhos can be uncoupled through differential expression of branched respiratory chain enzymes or by opening of a mitochondrial unspecific channel (ScMUC), respectively. However D. hansenii mitochondria, which contain both a branched respiratory chain and a mitochondrial unspecific channel (DhMUC), selectively uncouple complex I-dependent rate of oxygen consumption in the stationary growth phase. The uncoupled complex I-dependent respiration was only 20% of the original activity. Inhibition was not due to inactivation of complex I, lack of protein expression or to differential expression of alternative oxidoreductases. Furthermore, all other respiratory chain activities were normal. Decrease of complex I-dependent respiration was due to NAD(+) loss from the matrix, probably through an open of DhMUC. When NAD(+) was added back, coupled complex I-activity was recovered. NAD(+) re-uptake was independent of DhMUC opening and seemed to be catalyzed by a NAD(+)-specific transporter, which was sensitive to bathophenanthroline, bromocresol purple or pyridoxal-5'-phosphate as described for S. cerevisiae mitochondrial NAD(+) transporters. Loss of NAD(+) from the matrix through an open MUC is proposed as an additional mechanism to uncouple OxPhos. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Wolbachia infection in Aedes aegypti mosquitoes alters blood meal excretion and delays oviposition without affecting trypsin activity.

PubMed

Pimenta de Oliveira, Sofia; Dantas de Oliveira, Caroline; Viana Sant'Anna, Mauricio Roberto; Carneiro Dutra, Heverton Leandro; Caragata, Eric Pearce; Moreira, Luciano Andrade

2017-08-01

Blood feeding in Aedes aegypti is essential for reproduction, but also permits the mosquito to act as a vector for key human pathogens such as the Zika and dengue viruses. Wolbachia pipientis is an endosymbiotic bacterium that can manipulate the biology of Aedes aegypti mosquitoes, making them less competent hosts for many pathogens. Yet while Wolbachia affects other aspects of host physiology, it is unclear whether it influences physiological processes associated with blood meal digestion. To that end, we examined the effects of wMel Wolbachia infection in Ae. aegypti, on survival post-blood feeding, blood meal excretion, rate of oviposition, expression levels of key genes involved in oogenesis, and activity levels of trypsin blood digestion enzymes. We observed that wMel infection altered the rate and duration of blood meal excretion, delayed the onset of oviposition and was associated with a greater number of eggs being laid later. wMel-infected Ae. aegypti also had lower levels of key yolk protein precursor genes necessary for oogenesis. However, all of these effects occurred without a change in trypsin activity. These results suggest that Wolbachia infection may disrupt normal metabolic processes associated with blood feeding and reproduction in Ae. aegypti. Copyright © 2017 Elsevier Ltd. All rights reserved.

Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development.

PubMed

Schaer, Dominik J; Vinchi, Francesca; Ingoglia, Giada; Tolosano, Emanuela; Buehler, Paul W

2014-01-01

Hemolysis, which occurs in many disease states, can trigger a diverse pathophysiologic cascade that is related to the specific biochemical activities of free Hb and its porphyrin component heme. Normal erythropoiesis and concomitant removal of senescent red blood cells (RBC) from the circulation occurs at rates of approximately 2 × 10(6) RBCs/second. Within this physiologic range of RBC turnover, a small fraction of hemoglobin (Hb) is released into plasma as free extracellular Hb. In humans, there is an efficient multicomponent system of Hb sequestration, oxidative neutralization and clearance. Haptoglobin (Hp) is the primary Hb-binding protein in human plasma, which attenuates the adverse biochemical and physiologic effects of extracellular Hb. The cellular receptor target of Hp is the monocyte/macrophage scavenger receptor, CD163. Following Hb-Hp binding to CD163, cellular internalization of the complex leads to globin and heme metabolism, which is followed by adaptive changes in antioxidant and iron metabolism pathways and macrophage phenotype polarization. When Hb is released from RBCs within the physiologic range of Hp, the potential deleterious effects of Hb are prevented. However, during hyper-hemolytic conditions or with chronic hemolysis, Hp is depleted and Hb readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric Hb. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. Hemopexin (Hx) is another plasma glycoprotein able to bind heme with high affinity. Hx sequesters heme in an inert, non-toxic form and transports it to the liver for catabolism and excretion. In the present review we discuss the components of physiologic Hb/heme detoxification and their potential therapeutic application in a wide range of hemolytic conditions.

Semiochemicals released by pecan alleviate physiological suppression in overwintering larvae of Acrobasis nuxvorella (Lepidoptera: Pyralidae).

PubMed

Vargas-Arispuro, I; Corella-Madueño, M A G; Harris, M K; Martínez-Téllez, M A; Gardea, A A; Fu-Castillo, A; Orozco-Avitia, A

2013-10-01

Acrobasis nuxvorella Neunzig (pecan nut casebearer) is a monophagous herbivore of Carya illinoinensis (Wang.) K. Koch (pecan); both are indigenous to North America, where Carya has evolved for ≈60 million years. We hypothesized that this close association may have resulted in a parallel evolution allowing casebearer to use pecan volatiles to synchronize seasonality. Casebearer overwinters in diapause as a first-instar larva in a hibernaculum attached to a dormant pecan bud. Larval emergence from this structure after diapause or postdiapause quiescence coincides with the onset of pecan bud growth in the spring, and this interaction was the subject of this study. Dormant pecan twigs with hibernacula-infested buds were exposed to a water control or pecan volatiles from 'Western Schley' cultivar, and monitored to observe larval response by using a microcalorimeter. Initial testing showed that metabolic heat produced by overwintering larvae remained low and unchanged when exposed to water vapor and significantly increased within a few hours after exposure to volatiles from new pecan foliage. This shows that these larvae in hibernacula are in a physiologically suppressed state of diapause or postdiapause quiescence, from which they detect and respond to these pecan volatiles. Further studies to quantify larval responses showed that 90 and 80% of the larvae became active and emerged from their hibernacula ≈6 d after exposure to Western Schley and 'Wichita' volatiles, respectively. Mixtures of 13 sesquiterpenes from those pecan volatiles were identified to induce physiological activity within larvae after hours of exposure, followed some days later by larval emergence from hibernacula. Host volatiles, to our knowledge, have not previously been reported to induce early instar larvae in hibernacula to rouse from a state of physiological arrest to resume normal growth and development. This also has potential for use in pest management.

A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in β-globin expression and erythroid development

PubMed Central

Bultman, Scott J.; Gebuhr, Thomas C.; Magnuson, Terry

2005-01-01

The Brg1 catalytic subunit of SWI/SNF-related complexes has been implicated in many developmental and physiological processes, but null homozygotes die as blastocysts prior to implantation. To circumvent this early embryonic lethality, we performed an ENU mutagenesis screen and generated a Brg1 hypomorph mutation in the ATPase domain. The mutant Brg1 protein is stable, assembles into SWI/SNF-related complexes, and exhibits normal ATPase activity but is unable to establish DNase I hypersensitivity sites characteristic of open chromatin. Mutant embryos develop normally until midgestation but then exhibit a distinct block in the development of the erythroid lineage, leading to anemia and death. The mutant Brg1 protein is recruited to the β-globin locus, but chromatin remodeling and transcription are perturbed. Histone acetylation and DNA methylation are also affected. To our knowledge, Brg1 is the first chromatin-modifying factor shown to be required for β-globin regulation and erythropoiesis in vivo. Not only does this mutation establish a role for Brg1 during organogenesis, it also demonstrates that ATPase activity can be uncoupled from chromatin remodeling. PMID:16287714

Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly.

PubMed

Cunard, Robyn

2015-04-20

Diabetic kidney disease is the leading worldwide cause of end stage kidney disease and a growing public health challenge. The diabetic kidney is exposed to many environmental stressors and each cell type has developed intricate signaling systems designed to restore optimal cellular function. The unfolded protein response (UPR) is a homeostatic pathway that regulates endoplasmic reticulum (ER) membrane structure and secretory function. Studies suggest that the UPR is activated in the diabetic kidney to restore normal ER function and viability. However, when the cell is continuously stressed in an environment that lies outside of its normal physiological range, then the UPR is known as the ER stress response. The UPR reduces protein synthesis, augments the ER folding capacity and downregulates mRNA expression of genes by multiple pathways. Aberrant activation of ER stress can also induce inflammation and cellular apoptosis, and modify signaling of protective processes such as autophagy and mTORC activation. The following review will discuss our current understanding of ER stress in the diabetic kidney and explore novel means of modulating ER stress and its interacting signaling cascades with the overall goal of identifying therapeutic strategies that will improve outcomes in diabetic nephropathy.

The physiological determinants of drug-induced lysosomal stress resistance

PubMed Central

Woldemichael, Tehetina; Rosania, Gus R.

2017-01-01

Many weakly basic, lipophilic drugs accumulate in lysosomes and exert complex, pleiotropic effects on organelle structure and function. Thus, modeling how perturbations of lysosomal physiology affect the maintenance of lysosomal ion homeostasis is necessary to elucidate the key factors which determine the toxicological effects of lysosomotropic agents, in a cell-type dependent manner. Accordingly, a physiologically-based mathematical modeling and simulation approach was used to explore the dynamic, multi-parameter phenomenon of lysosomal stress. With this approach, parameters that are either directly involved in lysosomal ion transportation or lysosomal morphology were transiently altered to investigate their downstream effects on lysosomal physiology reflected by the changes they induce in lysosomal pH, chloride, and membrane potential. In addition, combinations of parameters were simultaneously altered to assess which parameter was most critical for recovery of normal lysosomal physiology. Lastly, to explore the relationship between organelle morphology and induced stress, we investigated the effects of parameters controlling organelle geometry on the restoration of normal lysosomal physiology following a transient perturbation. Collectively, our results indicate a key, interdependent role of V-ATPase number and membrane proton permeability in lysosomal stress tolerance. This suggests that the cell-type dependent regulation of V-ATPase subunit expression and turnover, together with the proton permeability properties of the lysosomal membrane, is critical to understand the differential sensitivity or resistance of different cell types to the toxic effects of lysosomotropic drugs. PMID:29117253

Reward-based hypertension control by a synthetic brain-dopamine interface.

PubMed

Rössger, Katrin; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

2013-11-05

Synthetic biology has significantly advanced the design of synthetic trigger-controlled devices that can reprogram mammalian cells to interface with complex metabolic activities. In the brain, the neurotransmitter dopamine coordinates communication with target neurons via a set of dopamine receptors that control behavior associated with reward-driven learning. This dopamine transmission has recently been suggested to increase central sympathetic outflow, resulting in plasma dopamine levels that correlate with corresponding brain activities. By functionally rewiring the human dopamine receptor D1 (DRD1) via the second messenger cyclic adenosine monophosphate (cAMP) to synthetic promoters containing cAMP response element-binding protein 1(CREB1)-specific cAMP-responsive operator modules, we have designed a synthetic dopamine-sensitive transcription controller that reversibly fine-tunes specific target gene expression at physiologically relevant brain-derived plasma dopamine levels. Following implantation of circuit-transgenic human cell lines insulated by semipermeable immunoprotective microcontainers into mice, the designer device interfaced with dopamine-specific brain activities and produced a systemic expression response when the animal's reward system was stimulated by food, sexual arousal, or addictive drugs. Reward-triggered brain activities were able to remotely program peripheral therapeutic implants to produce sufficient amounts of the atrial natriuretic peptide, which reduced the blood pressure of hypertensive mice to the normal physiologic range. Seamless control of therapeutic transgenes by subconscious behavior may provide opportunities for treatment strategies of the future.

Physiologic and Metabolic Benefits of Formulated Diets and Mangifera indica in Fluoride Toxicity.

PubMed

Karn, Sanjay S; Narasimhacharya, A V R L

2015-06-01

Fluorosis is a major health problem affecting normal physiological and metabolic functions in people living in endemic fluoride areas. The present work was aimed at investigating the role of basal, high carbohydrate low protein (HCLP) and high protein low carbohydrate (HPLC) diets and Mangifera indica fruit powder as a food supplement in fluoride-induced metabolic toxicity. Exposure to fluoride resulted in elevation of plasma glucose levels, ACP, ALP, SGPT, SGOT, and hepatic G-6-Pase activities, plasma and hepatic lipid profiles with decreased plasma protein, HDL-C, hepatic glycogen content and hexokinase activity in basal, HCLP and HPLC diet fed albino rats. However among the three diets tested, HPLC diet was found to be relatively, a better metabolic regulator. All the three formulated diets (basal, HCLP and HPLC) supplemented with mango fruit powder (5 and 10 g), decreased plasma glucose content, ACP, ALP, SGPT, SGOT and hepatic G-6-Pase activities and plasma as well as hepatic lipid profiles. These diets also elevated the hepatic glycogen content and hexokinase activities. These effects however, were prominent with the HPLC diet supplemented with mango fruit powder and, among the two doses of mango fruit powder, the higher dose (10 g) yielded more promising results. It is surmised that the micronutrients and phytochemicals present in the diets and the mango fruit could be responsible for attenuation of fluoride-induced metabolic toxicity.

Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels.

PubMed

Zobeiri, Mehrnoush; Chaudhary, Rahul; Datunashvili, Maia; Heuermann, Robert J; Lüttjohann, Annika; Narayanan, Venu; Balfanz, Sabine; Meuth, Patrick; Chetkovich, Dane M; Pape, Hans-Christian; Baumann, Arnd; van Luijtelaar, Gilles; Budde, Thomas

2018-04-01

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I h , in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I h current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b -/- ). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K + current, I A , in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5-4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings.

PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity

PubMed Central

Madeo, G.; Schirinzi, T.; Martella, G.; Latagliata, E.C.; Puglisi, F.; Shen, J.; Valente, E.M.; Federici, M.; Mercuri, N.B.; Puglisi-Allegra, S.; Bonsi, P.; Pisani, A.

2014-01-01

Background Homozygous or compound heterozygous mutations in the PTEN-induced kinase 1 (PINK1) gene are causative of autosomal recessive, early onset PD. Single heterozygous mutations have been repeatedly detected in a subset of patients as well as in non-affected subjects, and their significance has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have shown the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. Methods In the present study, we performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knock-out (PINK1+/−) mice by a multidisciplinary approach. Results We found that, despite a normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression (LTD) was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, we measured a significantly lower dopamine release in the striatum of PINK1+/−, compared to control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored a normal LTP in heterozygous mice. Moreover, MAO-B inhibitors rescued a physiological LTP and a normal dopamine release. Conclusions Our results provide novel evidence for striatal plasticity abnormalities even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of PD, and a valid tool to characterize early disease stage and design possible disease-modifying therapies. PMID:24167038

Daily Physical Activity and Hot Flashes in the Study of Women's Health Across the Nation FLASHES Study

PubMed Central

Gibson, Carolyn; Matthews, Karen; Thurston, Rebecca

2014-01-01

Objective To examine the role of physical activity in menopausal hot flashes. Competing models conceptualize physical activity as a risk or protective factor for hot flashes. Few studies have examined this relationship prospectively using physiologic measures of hot flashes and physical activity. Design Over two 48 hour-periods, 51 participants wore a physiologic hot flash monitor and activity monitor, and reported their hot flashes in an electronic diary. Physiologic hot flashes, reported hot flashes and reported hot flashes without physiological corroboration were related to activity changes using hierarchical generalized linear modeling, adjusting for potential confounders. Setting Community. Patients Midlife women. Interventions None. Main Outcome Measures Physiologically-detected hot flashes and reported hot flashes with and without physiologic corroboration. Results Hot flash reports without physiologic corroboration were more likely after activity increases (OR 1.04, 95% CI: 1.00-1.10, p=.01), particularly among women with higher levels of depressive symptoms (interaction p=.02). No other types of hot flashes were related to physical activity. Conclusion Acute increases in physical activity were associated with increased reporting of hot flashes lacking physiologic corroboration, particularly among women with depressive symptoms. Clinicians should consider the role of symptom perception and reporting in relations between physical activity and hot flashes. PMID:24491454

Achilles tendon shape and echogenicity on ultrasound among active badminton players.

PubMed

Malliaras, P; Voss, C; Garau, G; Richards, P; Maffulli, N

2012-04-01

The relationship between Achilles tendon ultrasound abnormalities, including a spindle shape and heterogeneous echogenicity, is unclear. This study investigated the relationship between these abnormalities, tendon thickness, Doppler flow and pain. Sixty-one badminton players (122 tendons, 36 men, and 25 women) were recruited. Achilles tendon thickness, shape (spindle, parallel), echogenicity (heterogeneous, homogeneous) and Doppler flow (present or absent) were measured bilaterally with ultrasound. Achilles tendon pain (during or after activity over the last week) and pain and function [Victorian Institute of Sport Achilles Assessment (VISA-A)] were measured. Sixty-eight (56%) tendons were parallel with homogeneous echogenicity (normal), 22 (18%) were spindle shaped with homogeneous echogenicity, 16 (13%) were parallel with heterogeneous echogenicity and 16 (13%) were spindle shaped with heterogeneous echogenicity. Spindle shape was associated with self-reported pain (P<0.05). Heterogeneous echogenicity was associated with lower VISA-A scores than normal tendon (P<0.05). There was an ordinal relationship between normal tendon, parallel and heterogeneous and spindle shaped and heterogeneous tendons with regard to increasing thickness and likelihood of Doppler flow. Heterogeneous echogenicity with a parallel shape may be a physiological phase and may develop into heterogeneous echogenicity with a spindle shape that is more likely to be pathological. © 2010 John Wiley & Sons A/S.

Thyroid peroxidase (TPO) expressed in thyroid and breast tissues shows similar antigenic properties.

PubMed

Godlewska, Marlena; Arczewska, Katarzyna D; Rudzińska, Magdalena; Łyczkowska, Anna; Krasuska, Wanda; Hanusek, Karolina; Ruf, Jean; Kiedrowski, Mirosław; Czarnocka, Barbara

2017-01-01

Thyroid peroxidase (TPO) is essential for physiological function of the thyroid gland. The high prevalence of thyroid peroxidase antibodies (TPOAbs) in patients with breast cancer and their protective role had previously been demonstrated, indicating a link between breast cancer and thyroid autoimmunity. Recently, TPO was shown to be present in breast cancer tissue samples but its antigenicity has not been analyzed. In this study, we investigated TPO expression levels in a series of fifty-six breast cancer samples paired with normal (peri-tumoral) tissue and its antigenic activity using a panel of well-characterized murine anti-human TPOAbs. We have shown that TPO transcripts were present in both normal and cancer tissue samples, although the amounts in the latter were reduced. Additionally, we observed that TPO levels are lower in more advanced cancers. TPO protein expression was confirmed in all tissue samples, both normal and cancerous. We also found that the antigenicity of the immunodominant regions (IDRs) in breast TPO resembles that of thyroid TPO, which is crucial for effective interactions with human TPOAbs. Expression of TPO in breast cancer together with its antigenic activity may have beneficial effects in TPOAb-positive breast cancer patients. However, further studies are needed to confirm the beneficial role of TPOAbs and to better understand the underlying mechanism.

Constitutive Uncoupling of Pathways of Gene Expression That Control Growth and Differentiation in Myeloid Leukemia: A Model for the Origin and Progression of Malignancy

NASA Astrophysics Data System (ADS)

Sachs, Leo

1980-10-01

Chemical carcinogens and tumor promoters have pleiotropic effects. Tumor initiators can produce a variety of mutations and tumor promoters can regulate a variety of physiological molecules that control growth and differentiation. The appropriate mutation and the regulation of the appropriate molecules to induce cell growth can initiate and promote the sequence of changes required for transformation of normal cells into malignant cells. After this sequence of changes, some tumors can still be induced to revert with a high frequency from a malignant phenotype to a nonmalignant phenotype. Results obtained from analysis of regulation of growth and differentiation in normal and leukemic myeloid cells, the phenotypic reversion of malignancy by induction of normal differentiation in myeloid leukemia, and the blocks in differentiation-defective leukemic cell mutants have been used to propose a general model for the origin and progression of malignancy. The model states that malignancy originates by changing specific pathways of gene expression required for growth from inducible to constitutive in cells that can still be induced to differentiate normally by the physiological inducer of differentiation. The malignant cells, unlike the normal cells, then no longer require the physiological inducer for growth. This changes the requirements for growth and uncouples growth from differentiation. Constitutive expression of other specific pathways can uncouple other controls, which then causes blocks in differentiation and the further progression of malignancy. The existence of specific constitutive pathways of gene expression that uncouple controls in malignant cells can also explain the expression of fetal proteins, hormones, and some other specialized products of normal development in various types of tumors.

Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

PubMed Central

2015-01-01

Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24–48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise. PMID:26487009

Metabolism of. cap alpha. -C/sup 14/-histidine in the intact rat. II. Radioactive excretion products in urine

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

Wolf, G.; Wu, P.H.L.; Heck, W.W.

1956-09-01

The normal metabolic pathways in the intact rat was investigated via the radioactive urinary excretion products following administration of a physiological dose of a radioactive compound such as ..cap alpha..-C/sup 14/-DL-histidine. The major metabolites, except one, excreted in the urine 5 hours after administration of ..cap alpha..-C/sup 14/-DL-histidine were isolated and identified. Glutamic acid and urocanic acids had simlar and low activities, whereas carboxyl-labeled imidazoacetic acid was found to be the principal metabolite with a high level of activity. It was concluded that the main end-product of the catabolism of DL-histidine is imidazoleacetic acid probably formed through imidazolepyruvic acid.

Generic Algorithms for Estimating Foliar Pigment Content

NASA Astrophysics Data System (ADS)

Gitelson, Anatoly; Solovchenko, Alexei

2017-09-01

Foliar pigment contents and composition are main factors governing absorbed photosynthetically active radiation, photosynthetic activity, and physiological status of vegetation. In this study the performance of nondestructive techniques based on leaf reflectance were tested for estimating chlorophyll (Chl) and anthocyanin (AnC) contents in species with widely variable leaf structure, pigment content, and composition. Only three spectral bands (green, red edge, and near-infrared) are required for nondestructive Chl and AnC estimation with normalized root-mean-square error (NRMSE) below 4.5% and 6.1%, respectively. The algorithms developed are generic, not requiring reparameterization for each species allowing for accurate nondestructive Chl and AnC estimation using simple handheld field/lab instrumentation. They also have potential in interpretation of airborne and satellite data.

Technical Pitfall in 68Ga-Prostate Specific Membrane Antigen Imaging: Altered Biodistribution Caused by Free 68Ga-Citrate Due to Radiolysis Showing Increased Vascular Activity.

PubMed

Hod, Nir; Anconina, Reut; Levin, Daniel; Ezroh Kazap, Dina; Lantsberg, Sophie

2018-06-01

As with any new molecular imaging modality, accurate characterization of abnormalities on Ga-PSMA PET/CT imaging can be accomplished only if one is aware of the normal distribution pattern, physiological variants, and potential sources of false imaging findings. Altered biodistribution can have a significant impact on scan interpretation. Presented here is a rare case in which radiopharmaceutical radiolysis occurred causing excessive free Ga-citrate showing as an increased vascular activity. As Ga-PSMA PET/CT imaging is a relatively new imaging technique, it is important to be aware of such a potential technical pitfall in clinical practice in order to prevent scan misinterpretation.

Redefining ADHD Using an Adult Population: Should Inattention be Viewed as a Separate Dimension From Cognitive and Physiological Activity Level?

PubMed

Miller, Nathan; Prevatt, Frances

2017-10-01

The purpose of this study was to reexamine the latent structure of ADHD and sluggish cognitive tempo (SCT) due to issues with construct validity. Two proposed changes to the construct include viewing hyperactivity and sluggishness (hypoactivity) as a single continuum of activity level, and viewing inattention as a separate dimension from activity level. Data were collected from 1,398 adults using Amazon's MTurk. A new scale measuring activity level was developed, and scores of Inattention were regressed onto scores of Activity Level using curvilinear regression. The Activity Level scale showed acceptable levels of internal consistency, normality, and unimodality. Curvilinear regression indicates that a quadratic (curvilinear) model accurately explains a small but significant portion of the variance in levels of inattention. Hyperactivity and hypoactivity may be viewed as a continuum, rather than separate disorders. Inattention may have a U-shaped relationship with activity level. Linear analyses may be insufficient and inaccurate for studying ADHD.

Developing Physiologic Stress Profiles for School-Age Children Who Stutter

ERIC Educational Resources Information Center

Ortega, Aishah Y.; Ambrose, Nicoline G.

2011-01-01

Purpose: Physiologic reactivity profiles were generated for 9 school-age children with a history of stuttering. Utilizing salivary sampling, stress biomarkers cortisol and alpha-amylase were measured in response to normal daily stressors. Children with a history of stuttering were characterized as high or low autonomic reactors when compared to…

New Ways of Thinking about (and Teaching about) Intestinal Epithelial Function

ERIC Educational Resources Information Center

Barrett, Kim E.

2008-01-01

This article summarizes a presentation made at the Teaching Refresher Course of the American Physiological Society, which was held at the Experimental Biology meeting in 2007. The intestinal epithelium has important ion transport and barrier functions that contribute pivotally to normal physiological functioning of the intestine and other body…

Measurement of Physiologic Glucose Levels Using Raman Spectroscopy in a Rabbit Aqueous Humor Model

NASA Technical Reports Server (NTRS)

Lambert, J.; Storrie-Lombardi, M.; Borchert, M.

1998-01-01

We have elecited a reliable glucose signature in mammalian physiological ranges using near infrared Raman laser excitation at 785 nm and multivariate analysis. In a recent series of experiments we measured glucose levels in an artificial aqueous humor in the range from 0.5 to 13X normal values.

Functional metabolite assemblies—a review

NASA Astrophysics Data System (ADS)

Aizen, Ruth; Tao, Kai; Rencus-Lazar, Sigal; Gazit, Ehud

2018-05-01

Metabolites are essential for the normal operation of cells and fulfill various physiological functions. It was recently found that in several metabolic disorders, the associated metabolites could self-assemble to generate amyloid-like structures, similar to canonical protein amyloids that have a role in neurodegenerative disorders. Yet, assemblies with typical amyloid characteristics are also known to have physiological function. In addition, many non-natural proteins and peptides presenting amyloidal properties have been used for the fabrication of functional nanomaterials. Similarly, functional metabolite assemblies are also found in nature, demonstrating various physiological roles. A notable example is the structural color formed by guanine crystals or fluorescent crystals in feline eyes responsible for enhanced night vision. Moreover, some metabolites have been used for the in vitro fabrication of functional materials, such as glycine crystals presenting remarkable piezoelectric properties or indigo films used to assemble organic semi-conductive electronic devices. Therefore, we believe that the study of metabolite assemblies is not only important in order to understand their role in normal physiology and in pathology, but also paves a new route in exploring the fabrication of organic, bio-compatible materials.

Loss of hippocampal serine protease BSP1/neuropsin predisposes to global seizure activity.

PubMed

Davies, B; Kearns, I R; Ure, J; Davies, C H; Lathe, R

2001-09-15

Serine proteases in the adult CNS contribute both to activity-dependent structural changes accompanying learning and to the regulation of excitotoxic cell death. Brain serine protease 1 (BSP1)/neuropsin is a trypsin-like serine protease exclusively expressed, within the CNS, in the hippocampus and associated limbic structures. To explore the role of this enzyme, we have used gene targeting to disrupt this gene in mice. Mutant mice were viable and overtly normal; they displayed normal hippocampal long-term synaptic potentiation (LTP) and exhibited no deficits in spatial navigation (water maze). Nevertheless, electrophysiological studies revealed that the hippocampus of mice lacking this specifically expressed protease possessed an increased susceptibility for hyperexcitability (polyspiking) in response to repetitive afferent stimulation. Furthermore, seizure activity on kainic acid administration was markedly increased in mutant mice and was accompanied by heightened immediate early gene (c-fos) expression throughout the brain. In view of the regional selectivity of BSP1/neuropsin brain expression, the observed phenotype may selectively reflect limbic function, further implicating the hippocampus and amygdala in controlling cortical activation. Within the hippocampus, our data suggest that BSP1/neuropsin, unlike other serine proteases, has little effect on physiological synaptic remodeling and instead plays a role in limiting neuronal hyperexcitability induced by epileptogenic insult.

GPER/GPR30 knockout mice: effects of GPER on metabolism

PubMed Central

Sharma, Geetanjali; Prossnitz, Eric R.

2015-01-01

i. Summary Endogenous estrogens, predominantly 17β-estradiol (E2), mediate various very diverse effects throughout the body in both normal physiology and disease. Actions include development (including puberty) and reproduction as well as additional effects throughout life in the metabolic, endocrine, musculoskeletal, nervous, cardiovascular and immune systems. The actions of E2 have traditionally been attributed to the classical nuclear estrogen receptors (ERα and ERβ) that largely mediate transcriptional/genomic activities. However, more recently the G protein-coupled estrogen receptor GPER/GPR30 has become recognized as an essential mediator of certain, and particularly rapid, signaling events in response to E2. Murine genetic knockout (KO) models represent an important approach to understand the mechanisms of E2 action in physiology and disease. Studies of GPER KO mice over the last years have revealed functions for GPER in the regulation of obesity, insulin resistance and glucose intolerance, among other areas of (patho)physiology. This chapter focuses on methods for the evaluation of metabolic parameters in vivo and ex vivo with an emphasis on glucose homeostasis and metabolism through the use of glucose and insulin tolerance tests, pancreatic islet and adipocyte isolation and characterization. PMID:26585159

GPER/GPR30 Knockout Mice: Effects of GPER on Metabolism.

PubMed

Sharma, Geetanjali; Prossnitz, Eric R

2016-01-01

Endogenous estrogens, predominantly 17β-estradiol (E2), mediate various diverse effects throughout the body in both normal physiology and disease. Actions include development (including puberty) and reproduction as well as additional effects throughout life in the metabolic, endocrine, musculoskeletal, nervous, cardiovascular, and immune systems. The actions of E2 have traditionally been attributed to the classical nuclear estrogen receptors (ERα and ERβ) that largely mediate transcriptional/genomic activities. However, more recently the G protein-coupled estrogen receptor GPER/GPR30 has become recognized as an essential mediator of certain, and particularly rapid, signaling events in response to E2. Murine genetic knockout (KO) models represent an important approach to understand the mechanisms of E2 action in physiology and disease. Studies of GPER KO mice over the last years have revealed functions for GPER in the regulation of obesity, insulin resistance and glucose intolerance, among other areas of (patho)physiology. This chapter focuses on methods for the evaluation of metabolic parameters in vivo and ex vivo with an emphasis on glucose homeostasis and metabolism through the use of glucose and insulin tolerance tests, pancreatic islet and adipocyte isolation and characterization.

Unperturbed vs. post-transplantation hematopoiesis: both in vivo but different

PubMed Central

Busch, Katrin; Rodewald, Hans-Reimer

2016-01-01

Purpose of review Hematopoietic stem cell (HSC) transplantation has yielded tremendous information on experimental properties of HSCs. Yet, it remains unclear whether transplantation reflects the physiology of hematopoiesis. A limitation is the difficulty in accessing HSC functions without isolation, in-vitro manipulation and readout for potential. New genetic fate mapping and clonal marking techniques now shed light on hematopoiesis under physiological conditions. Recent findings Transposon-based genetic marks were introduced across the entire hematopoietic system to follow the clonal dynamics of these tags over time. A polyclonal source downstream from stem cells was found responsible for the production of at least granulocytes. In independent experiments, HSCs were genetically marked in adult mice, and the kinetics of label emergence throughout the system was followed over time. These experiments uncovered that during physiological steady-state hematopoiesis large numbers of HSCs yield differentiated progeny. Individual HSCs were active only rarely, indicating their very slow periodicity of differentiation rather than quiescence. Summary Noninvasive genetic experiments in mice have identified a major role of stem and progenitor cells downstream from HSCs as drivers of adult hematopoiesis, and revealed that post-transplantation hematopoiesis differs quantitatively from normal steady-state hematopoiesis. PMID:27213498

Seahorses under a changing ocean: the impact of warming and acidification on the behaviour and physiology of a poor-swimming bony-armoured fish.

PubMed

Faleiro, Filipa; Baptista, Miguel; Santos, Catarina; Aurélio, Maria L; Pimentel, Marta; Pegado, Maria Rita; Paula, José Ricardo; Calado, Ricardo; Repolho, Tiago; Rosa, Rui

2015-01-01

Seahorses are currently facing great challenges in the wild, including habitat degradation and overexploitation, and how they will endure additional stress from rapid climate change has yet to be determined. Unlike most fishes, the poor swimming skills of seahorses, along with the ecological and biological constraints of their unique lifestyle, place great weight on their physiological ability to cope with climate changes. In the present study, we evaluate the effects of ocean warming (+4°C) and acidification (ΔpH = -0.5 units) on the physiological and behavioural ecology of adult temperate seahorses, Hippocampus guttulatus. Adult seahorses were found to be relatively well prepared to face future changes in ocean temperature, but not the combined effect of warming and acidification. Seahorse metabolism increased normally with warming, and behavioural and feeding responses were not significantly affected. However, during hypercapnia the seahorses exhibited signs of lethargy (i.e. reduced activity levels) combined with a reduction of feeding and ventilation rates. Nonetheless, metabolic rates were not significantly affected. Future ocean changes, particularly ocean acidification, may further threaten seahorse conservation, turning these charismatic fishes into important flagship species for global climate change issues.

Visualization and contractile activity of cochlear pericytes in the capillaries of the spiral ligament.

PubMed

Dai, Min; Nuttall, Alfred; Yang, Yue; Shi, Xiaorui

2009-08-01

Pericytes, mural cells located on microvessels, are considered to play an important role in the formation of the vasculature and the regulation of local blood flow in some organs. Little is known about the physiology of cochlear pericytes. In order to investigate the function of cochlear pericytes, we developed a method to visualize cochlear pericytes using diaminofluorescein-2 diacetate (DAF-2DA) and intravital fluorescence microscopy. This method can permit the study of the effect of vasoactive agents on pericytes under the in vivo and normal physiological condition. The specificity of the labeling method was verified by the immunofluorescence labeling of pericyte maker proteins such as desmin, neural proteoglycan (NG2), and thymocyte differentiation antigen 1 (Thy-1). Superfused K(+) and Ca(2+) to the cochlear lateral wall resulted in localized constriction of capillaries at pericyte locations both in vivo and in vitro, while there was no obvious change in cochlear capillary diameters with application of the adrenergic neurotransmitter noradrenaline. The method could be an effective way to visualize cochlear pericytes and microvessels and study lateral wall vascular physiology. Moreover, we demonstrate for the first time that cochlear pericytes have contractility, which may be important for regulation of cochlear blood flow.

Ambulatory diffuse optical tomography and multimodality physiological monitoring system for muscle and exercise applications

NASA Astrophysics Data System (ADS)

Hu, Gang; Zhang, Quan; Ivkovic, Vladimir; Strangman, Gary E.

2016-09-01

Ambulatory diffuse optical tomography (aDOT) is based on near-infrared spectroscopy (NIRS) and enables three-dimensional imaging of regional hemodynamics and oxygen consumption during a person's normal activities. Although NIRS has been previously used for muscle assessment, it has been notably limited in terms of the number of channels measured, the extent to which subjects can be ambulatory, and/or the ability to simultaneously acquire synchronized auxiliary data such as electromyography (EMG) or electrocardiography (ECG). We describe the development of a prototype aDOT system, called NINscan-M, capable of ambulatory tomographic imaging as well as simultaneous auxiliary multimodal physiological monitoring. Powered by four AA size batteries and weighing 577 g, the NINscan-M prototype can synchronously record 64-channel NIRS imaging data, eight channels of EMG, ECG, or other analog signals, plus force, acceleration, rotation, and temperature for 24+ h at up to 250 Hz. We describe the system's design, characterization, and performance characteristics. We also describe examples of isometric, cycle ergometer, and free-running ambulatory exercise to demonstrate tomographic imaging at 25 Hz. NINscan-M represents a multiuse tool for muscle physiology studies as well as clinical muscle assessment.

Magnocellular Neurons and Posterior Pituitary Function.

PubMed

Brown, Colin H

2016-09-15

The posterior pituitary gland secretes oxytocin and vasopressin (the antidiuretic hormone) into the blood system. Oxytocin is required for normal delivery of the young and for delivery of milk to the young during lactation. Vasopressin increases water reabsorption in the kidney to maintain body fluid balance and causes vasoconstriction to increase blood pressure. Oxytocin and vasopressin secretion occurs from the axon terminals of magnocellular neurons whose cell bodies are principally found in the hypothalamic supraoptic nucleus and paraventricular nucleus. The physiological functions of oxytocin and vasopressin depend on their secretion, which is principally determined by the pattern of action potentials initiated at the cell bodies. Appropriate secretion of oxytocin and vasopressin to meet the challenges of changing physiological conditions relies mainly on integration of afferent information on reproductive, osmotic, and cardiovascular status with local regulation of magnocellular neurons by glia as well as intrinsic regulation by the magnocellular neurons themselves. This review focuses on the control of magnocellular neuron activity with a particular emphasis on their regulation by reproductive function, body fluid balance, and cardiovascular status. © 2016 American Physiological Society. Compr Physiol 6:1701-1741, 2016. Copyright © 2016 John Wiley & Sons, Inc.

Measuring mitochondrial uncoupling protein-2 level and activity in insulinoma cells.

PubMed

Barlow, Jonathan; Hirschberg, Verena; Brand, Martin D; Affourtit, Charles

2013-01-01

Mitochondrial uncoupling protein-2 (UCP2) regulates glucose-stimulated insulin secretion (GSIS) by pancreatic beta cells-the physiological role of the beta cell UCP2 remains a subject of debate. Experimental studies informing this debate benefit from reliable measurements of UCP2 protein level and activity. In this chapter, we describe how UCP2 protein can be detected in INS-1 insulinoma cells and how it can be knocked down by RNA interference. We demonstrate briefly that UCP2 knockdown lowers glucose-induced rises in mitochondrial respiratory activity, coupling efficiency of oxidative phosphorylation, levels of mitochondrial reactive oxygen species, and insulin secretion. We provide protocols for the detection of the respective UCP2 phenotypes, which are indirect, but invaluable measures of UCP2 activity. We also introduce a convenient method to normalize cellular respiration to cell density allowing measurement of UCP2 effects on specific mitochondrial oxygen consumption. Copyright © 2013 Elsevier Inc. All rights reserved.

Aluminium and hydrogen ions inhibit a mechanosensory calcium-selective cation channel

NASA Technical Reports Server (NTRS)

Ding, J. P.; Pickard, B. G.

1993-01-01

The tension-dependent activity of mechanosensory calcium-selective cation channels in excised plasmalemmal patches from onion bulb scale epidermis is modulated by pH in the physiologically meaningful range between 4.5 and 7.2. It is rapidly lowered by lowering pH and rapidly raised by raising pH. Channel activity is effectively inhibited by low levels of aluminium ions and activity can be partially restored by washing for a few minutes. We suggest that under normal conditions the sensitivity of the mechanosensory channels to pH of the wall free space plays important roles in regulation of plant activities such as growth. We further suggest that, when levels of acid and aluminium ions in the soil solution are high, they might inhibit similar sensory channels in cells of the root tip, thus contributing critically to the acid soil syndrome.

New modalities of brain stimulation for stroke rehabilitation

PubMed Central

Lucas, T. H.; Carey, J. R.; Fetz, E. E.

2014-01-01

Stroke is a leading cause of disability, and the number of stroke survivors continues to rise. Traditional neurorehabilitation strategies aimed at restoring function to weakened limbs provide only modest benefit. New brain stimulation techniques designed to augment traditional neurorehabilitation hold promise for reducing the burden of stroke-related disability. Investigators discovered that repetitive transcranial magnetic stimulation (rTMS), trans-cranial direct current stimulation (tDCS), and epidural cortical stimulation (ECS) can enhance neural plasticity in the motor cortex post-stroke. Improved outcomes may be obtained with activity-dependent stimulation, in which brain stimulation is contingent on neural or muscular activity during normal behavior. We review the evidence for improved motor function in stroke patients treated with rTMS, tDCS, and ECS and discuss the mediating physiological mechanisms. We compare these techniques to activity-dependent stimulation, discuss the advantages of this newer strategy for stroke rehabilitation, and suggest future applications for activity-dependent brain stimulation. PMID:23192336

The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo

PubMed Central

Riggs, Daniel L.; Roberts, Patricia J.; Chirillo, Samantha C.; Cheung-Flynn, Joyce; Prapapanich, Viravan; Ratajczak, Thomas; Gaber, Richard; Picard, Didier; Smith, David F.

2003-01-01

Hsp90 is required for the normal activity of steroid receptors, and in steroid receptor complexes it is typically bound to one of the immunophilin-related co-chaperones: the peptidylprolyl isomerases FKBP51, FKBP52 or CyP40, or the protein phosphatase PP5. The physiological roles of the immunophilins in regulating steroid receptor function have not been well defined, and so we examined in vivo the influences of immunophilins on hormone-dependent gene activation in the Saccharomyces cerevisiae model for glucocorticoid receptor (GR) function. FKBP52 selectively potentiates hormone-dependent reporter gene activation by as much as 20-fold at limiting hormone concentrations, and this potentiation is readily blocked by co-expression of the closely related FKBP51. The mechanism for potentiation is an increase in GR hormone-binding affinity that requires both the Hsp90-binding ability and the prolyl isomerase activity of FKBP52. PMID:12606580

The Physiology of Adventitious Roots1

PubMed Central

Steffens, Bianka; Rasmussen, Amanda

2016-01-01

Adventitious roots are plant roots that form from any nonroot tissue and are produced both during normal development (crown roots on cereals and nodal roots on strawberry [Fragaria spp.]) and in response to stress conditions, such as flooding, nutrient deprivation, and wounding. They are important economically (for cuttings and food production), ecologically (environmental stress response), and for human existence (food production). To improve sustainable food production under environmentally extreme conditions, it is important to understand the adventitious root development of crops both in normal and stressed conditions. Therefore, understanding the regulation and physiology of adventitious root formation is critical for breeding programs. Recent work shows that different adventitious root types are regulated differently, and here, we propose clear definitions of these classes. We use three case studies to summarize the physiology of adventitious root development in response to flooding (case study 1), nutrient deficiency (case study 2), and wounding (case study 3). PMID:26697895

Physiology of man and animals in the Tenth Five-Year Plan: Proceedings of the Thirteenth Congress of the I. P. Pavlov All-Union Physiological Society

NASA Technical Reports Server (NTRS)

Lange, K. A.

1980-01-01

Research in the field of animal and human physiology is reviewed. The following topics on problems of physiological science and related fields of knowledge are discussed: neurophysiology and higher nervous activity, physiology of sensory systems, physiology of visceral systems, evolutionary and ecological physiology, physiological cybernetics, computer application in physiology, information support of physiological research, history and theory of development of physiology. Also discussed were: artificial intelligence, physiological problems of reflex therapy, correlation of structure and function of the brain, adaptation and activity, microcirculation, and physiological studies in nerve and mental diseases.

[Vitamin D: pathophysiology and clinical applicability in paediatrics].

PubMed

Masvidal Aliberch, R M; Ortigosa Gómez, S; Baraza Mendoza, M C; Garcia-Algar, O

2012-10-01

Vitamin D has always been associated with calcium -phosphate metabolism, but vitamin D receptors or its metabolites have been found in different body cells, indicating a possible involvement in other physiological mechanisms. Vitamin D deficiency has been associated with an increased risk of infections, autoimmune diseases, diabetes, metabolic syndrome, obesity, asthma and certain neurological diseases such as schizophrenia. Currently there are different techniques for measuring 25 (OH) cholecalciferol in blood, but the results are variable and controversial. It is important to achieve standardization of these techniques to be able to compare the results obtained in different studies. Normal physiological vitamin D levels have not yet been established, but they must be higher than 20 ng/ml (50 nmol/l) in order to perform it physiological function. It is still under discussion on how to achieve these minimum levels. Since the main source of vitamin D is sunlight, we should look for strategies that do not contradict the messages of prevention of skin cancer. In recent years, recommendations for vitamin D intake have changed, involving prophylactic activities carried out in Primary Care. This manuscript reviews the physiology, actions, laboratory determination, desirable levels, and vitamin D intake recommendations, and it highlights many questions raised by new research. Copyright © 2012 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Reversal of Physiological Deficits Caused by Diminished Levels of Peptidylglycine α-Amidating Monooxygenase by Dietary Copper

PubMed Central

Bousquet-Moore, D.; Ma, X. M.; Nillni, E. A.; Czyzyk, T. A.; Pintar, J. E.; Eipper, B. A.; Mains, R. E.

2009-01-01

Amidated peptides are critically involved in many physiological functions. Genetic deletion of peptidylglycine α-amidating monooxygenase (PAM), the only enzyme that can synthesize these peptides, is embryonically lethal. The goal of the present study was the identification of physiological functions impaired by haploinsufficiency of PAM. Regulation of the hypothalamic-pituitary-thyroid axis and body temperature, functions requiring contributions from multiple amidated peptides, were selected for evaluation. Based on serum T4 and pituitary TSH-β mRNA levels, mice heterozygous for PAM (PAM+/−) were euthyroid at baseline. Feedback within the hypothalamic-pituitary-thyroid axis was impaired in PAM+/− mice made hypothyroid using a low iodine/propylthiouracil diet. Despite their normal endocrine response to cold, PAM+/− mice were unable to maintain body temperature as well as wild-type littermates when kept in a 4 C environment. When provided with additional dietary copper, PAM+/− mice maintained body temperature as well as wild-type mice. Pharmacological activation of vasoconstriction or shivering also allowed PAM+/− mice to maintain body temperature. Cold-induced vasoconstriction was deficient in PAM+/− mice. This deficit was eliminated in PAM+/− mice receiving a diet with supplemental copper. These results suggest that dietary deficiency of copper, coupled with genetic deficits in PAM, could result in physiological deficits in humans. PMID:19022883

Human albumin: old, new, and emerging applications.

PubMed

Rozga, Jacek; Piątek, Tomasz; Małkowski, Piotr

2013-05-10

Human serum albumin has been widely used in an array of clinical settings for nearly 7 decades. Although there is no evidence to support the use of albumin rather than crystalloid in acute volume resuscitation, many clinicians continue to use albumin because it has other important physiologic effects besides the oncotic function. In keeping with the improved understanding of albumin physiology and pathophysiology of many acute and chronic diseases, use of albumin for medical applications has increased in recent years. This, along with increased costs of manufacturing and lower production volume of medical-grade albumin, has lead to an ongoing shortage and rapid increase in albumin prices. This review is based on the analysis of major publications, related to albumin chemistry, physiology, and medical uses including guidelines developed by professional and governmental organizations. Results reflect current knowledge about the role of albumin in health and disease and relevance of albumin therapy in specific clinical settings. Albumin therapy is currently recommended in spontaneous bacterial peritonitis with ascites, refractory ascites not responsive to diuretics, large-volume paracentesis, post-paracentesis syndrome, and the treatment of hepatorenal syndrome as an adjunct to vasoconstrictors. New indications for albumin therapy are linked to the antioxidant activity of albumin and its effects on capillary integrity. In recent years, large-pore hemofiltration and albumin exchange have emerged as promising liver support therapies for liver failure and other toxic syndromes. They are designed to remove a broad range of blood-borne toxins and to restore normal functions of the circulating albumin by replacing defective forms of albumin and albumin molecules saturated with toxins with normal albumin. In view of the ongoing worldwide shortage and high cost of human albumin (native and recombinant), new usage criteria, protocols, and guidelines for appropriate utilization of albumin are needed.

What have we learned about GPER function in physiology and disease from knockout mice?

PubMed

Prossnitz, Eric R; Hathaway, Helen J

2015-09-01

Estrogens, predominantly 17β-estradiol, exert diverse effects throughout the body in both normal and pathophysiology, during development and in reproductive, metabolic, endocrine, cardiovascular, nervous, musculoskeletal and immune systems. Estrogen and its receptors also play important roles in carcinogenesis and therapy, particularly for breast cancer. In addition to the classical nuclear estrogen receptors (ERα and ERβ) that traditionally mediate predominantly genomic signaling, the G protein-coupled estrogen receptor GPER has become recognized as a critical mediator of rapid signaling in response to estrogen. Mouse models, and in particular knockout (KO) mice, represent an important approach to understand the functions of receptors in normal physiology and disease. Whereas ERα KO mice display multiple significant defects in reproduction and mammary gland development, ERβ KO phenotypes are more limited, and GPER KO exhibit no reproductive deficits. However, the study of GPER KO mice over the last six years has revealed that GPER deficiency results in multiple physiological alterations including obesity, cardiovascular dysfunction, insulin resistance and glucose intolerance. In addition, the lack of estrogen-mediated effects in numerous tissues of GPER KO mice, studied in vivo or ex vivo, including those of the cardiovascular, endocrine, nervous and immune systems, reveals GPER as a genuine mediator of estrogen action. Importantly, GPER KO mice have also demonstrated roles for GPER in breast carcinogenesis and metastasis. In combination with the supporting effects of GPER-selective ligands and GPER knockdown approaches, GPER KO mice demonstrate the therapeutic potential of targeting GPER activity in diseases as diverse as obesity, diabetes, multiple sclerosis, hypertension, atherosclerosis, myocardial infarction, stroke and cancer. Copyright © 2015. Published by Elsevier Ltd.

Typical gray matter axons in mammalian brain fail to conduct action potentials faithfully at fever-like temperatures.

PubMed

Pekala, Dobromila; Szkudlarek, Hanna; Raastad, Morten

2016-10-01

We studied the ability of typical unmyelinated cortical axons to conduct action potentials at fever-like temperatures because fever often gives CNS symptoms. We investigated such axons in cerebellar and hippocampal slices from 10 to 25 days old rats at temperatures between 30 and 43°C. By recording with two electrodes along axonal pathways, we confirmed that the axons were able to initiate action potentials, but at temperatures >39°C, the propagation of the action potentials to a more distal recording site was reduced. This temperature-sensitive conduction may be specific for the very thin unmyelinated axons because similar recordings from myelinated CNS axons did not show conduction failures. We found that the conduction fidelity improved with 1 mmol/L TEA in the bath, probably due to block of voltage-sensitive potassium channels responsible for the fast repolarization of action potentials. Furthermore, by recording electrically activated antidromic action potentials from the soma of cerebellar granule cells, we showed that the axons failed less if they were triggered 10-30 msec after another action potential. This was because individual action potentials were followed by a depolarizing after-potential, of constant amplitude and shape, which facilitated conduction of the following action potentials. The temperature-sensitive conduction failures above, but not below, normal body temperature, and the failure-reducing effect of the spike's depolarizing after-potential, are two intrinsic mechanisms in normal gray matter axons that may help us understand how the hyperthermic brain functions. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Early activation of deleterious molecular pathways in the kidney in experimental heart failure with atrial remodeling.

PubMed

Ichiki, Tomoko; Huntley, Brenda K; Harty, Gail J; Sangaralingham, S Jeson; Burnett, John C

2017-05-01

Heart failure (HF) is a major health problem with worsening outcomes when renal impairment is present. Therapeutics for early phase HF may be effective for cardiorenal protection, however the detailed characteristics of the kidney in early-stage HF (ES-HF), and therefore treatment for potential renal protection, are poorly defined. We sought to determine the gene and protein expression profiles of specific maladaptive pathways of ES-HF in the kidney and heart. Experimental canine ES-HF, characterized by de-novo HF with atrial remodeling but not ventricular fibrosis, was induced by right ventricular pacing for 10 days. Kidney cortex (KC), medulla (KM), left ventricle (LV), and left atrial (LA) tissues from ES-HF versus normal canines ( n  = 4 of each) were analyzed using RT-PCR microarrays and protein assays to assess genes and proteins related to inflammation, renal injury, apoptosis, and fibrosis. ES-HF was characterized by increased circulating natriuretic peptides and components of the renin-angiotensin-aldosterone system and decreased sodium and water excretion with mild renal injury and up-regulation of CNP and renin genes in the kidney. Compared to normals, widespread genes, especially genes of the inflammatory pathways, were up-regulated in KC similar to increases seen in LA Protein expressions related to inflammatory cytokines were also augmented in the KC Gene and protein changes were less prominent in the LV and KM The ES-HF displayed mild renal injury with widespread gene changes and increased inflammatory cytokines. These changes may provide important clues into the pathophysiology of ES-HF and for therapeutic molecular targets in the kidney of ES-HF. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Research to determine the role of gravity in neurosecretory physiology

NASA Technical Reports Server (NTRS)

Clemens, L. E.; Life, J. S.

1972-01-01

In an effort to determine the effects of gravity in regulating the synthesis, transport, storage, and release of octopeptides from the hypothalamo-neurophypophyseal system, the teleost fresh water fish was studied. A labyrinthectomized fish was subjected to a gravitational orientation of -G sub z for three days. Results show the fish had reduced levels of adenyl cyclose activity in its kidneys when compared to labyrinthectomized and unoperated fish exposed to normal gravitational orientation (+G sub 2) for the same period of time. Efforts were also made to determine the presence of vasopressin in the neurophypophysis and peripheral target organs.

Modeling and control of a brushless DC axial flow ventricular assist device.

PubMed

Giridharan, Guruprasad A; Skliar, Mikhail; Olsen, Donald B; Pantalos, George M

2002-01-01

This article presents an integrated model of the human circulatory system that incorporates circulatory support by a brushless DC axial flow ventricular assist device (VAD), and a feedback VAD controller designed to maintain physiologically sufficient perfusion. The developed integrated model combines a network type model of the circulatory system with a nonlinear dynamic model of the brushless DC pump We show that maintaining a reference differential pressure between the left ventricle and aorta leads to adequate perfusion for different pathologic cases, ranging from normal heart to left heart asystole, and widely varying physical activity scenarios from rest to exercise.

The Medawar Lecture 2001 Knowledge for vision: vision for knowledge

PubMed Central

Gregory, Richard L

2005-01-01

An evolutionary development of perception is suggested—from passive reception to active perception to explicit conception—earlier stages being largely retained and incorporated in later species. A key is innate and then individually learned knowledge, giving meaning to sensory signals. Inappropriate or misapplied knowledge produces rich cognitive phenomena of illusions, revealing normally hidden processes of vision, tentatively classified here in a ‘peeriodic table’. Phenomena of physiology are distinguished from phenomena of general rules and specific object knowledge. It is concluded that vision uses implicit knowledge, and provides knowledge for intelligent behaviour and for explicit conceptual understanding including science. PMID:16147519

Extracorporeal Membrane Oxygenation for End-Stage Interstitial Lung Disease With Secondary Pulmonary Hypertension at Rest and Exercise: Insights From Simulation Modeling.

PubMed

Chicotka, Scott; Burkhoff, Daniel; Dickstein, Marc L; Bacchetta, Matthew

Interstitial lung disease (ILD) represents a collection of lung disorders with a lethal trajectory with few therapeutic options with the exception of lung transplantation. Various extracorporeal membrane oxygenation (ECMO) configurations have been used for bridge to transplant (BTT), yet no optimal configuration has been clearly demonstrated. Using a cardiopulmonary simulation, we assessed different ECMO configurations for patients with end-stage ILD to assess the physiologic deficits and help guide the development of new long-term pulmonary support devices. A cardiopulmonary ECMO simulation was created, and changes in hemodynamics and blood gases were compared for different inflow and outflow anatomic locations and for different sweep gas and blood pump flow rates. The system simulated the physiologic response of patients with severe ILD at rest and during exercise with central ECMO, peripheral ECMO, and with no ECMO. The output parameters were total cardiac output (CO), mixed venous oxygen (O2) saturation, arterial pH, and O2 delivery (DO2)/O2 utilization (VO2) at different levels of exercise. The model described the physiologic state of progressive ILD and showed the relative effects of using various ECMO configurations to support them. It elucidated the optimal device configurations and required physiologic pump performance and provided insight into the physiologic demands of exercise in ILD patients. The simulation program was able to model the pathophysiologic state of progressive ILD with PH and demonstrate how mechanical support devices can be implemented to improve cardiopulmonary function at rest and during exercise. The information generated from simulation can be used to optimize ECMO configuration selection for BTT patients and provide design guidance for new devices to better meet the physiologic demands of exercise associated with normal activities of daily living.

Improved intra-array and interarray normalization of peptide microarray phosphorylation for phosphorylome and kinome profiling by rational selection of relevant spots

PubMed Central

Scholma, Jetse; Fuhler, Gwenny M.; Joore, Jos; Hulsman, Marc; Schivo, Stefano; List, Alan F.; Reinders, Marcel J. T.; Peppelenbosch, Maikel P.; Post, Janine N.

2016-01-01

Massive parallel analysis using array technology has become the mainstay for analysis of genomes and transcriptomes. Analogously, the predominance of phosphorylation as a regulator of cellular metabolism has fostered the development of peptide arrays of kinase consensus substrates that allow the charting of cellular phosphorylation events (often called kinome profiling). However, whereas the bioinformatical framework for expression array analysis is well-developed, no advanced analysis tools are yet available for kinome profiling. Especially intra-array and interarray normalization of peptide array phosphorylation remain problematic, due to the absence of “housekeeping” kinases and the obvious fallacy of the assumption that different experimental conditions should exhibit equal amounts of kinase activity. Here we describe the development of analysis tools that reliably quantify phosphorylation of peptide arrays and that allow normalization of the signals obtained. We provide a method for intraslide gradient correction and spot quality control. We describe a novel interarray normalization procedure, named repetitive signal enhancement, RSE, which provides a mathematical approach to limit the false negative results occuring with the use of other normalization procedures. Using in silico and biological experiments we show that employing such protocols yields superior insight into cellular physiology as compared to classical analysis tools for kinome profiling. PMID:27225531

Performance in physiology evaluation: possible improvement by active learning strategies.

PubMed

Montrezor, Luís H

2016-12-01

The evaluation process is complex and extremely important in the teaching/learning process. Evaluations are constantly employed in the classroom to assist students in the learning process and to help teachers improve the teaching process. The use of active methodologies encourages students to participate in the learning process, encourages interaction with their peers, and stimulates thinking about physiological mechanisms. This study examined the performance of medical students on physiology over four semesters with and without active engagement methodologies. Four activities were used: a puzzle, a board game, a debate, and a video. The results show that engaging in activities with active methodologies before a physiology cognitive monitoring test significantly improved student performance compared with not performing the activities. We integrate the use of these methodologies with classic lectures, and this integration appears to improve the teaching/learning process in the discipline of physiology and improves the integration of physiology with cardiology and neurology. In addition, students enjoy the activities and perform better on their evaluations when they use them. Copyright © 2016 The American Physiological Society.

Low-affinity binding in cis to P2Y2R mediates force-dependent integrin activation during hantavirus infection

PubMed Central

Bondu, Virginie; Wu, Chenyu; Cao, Wenpeng; Simons, Peter C.; Gillette, Jennifer; Zhu, Jieqing; Erb, Laurie; Zhang, X. Frank; Buranda, Tione

2017-01-01

Pathogenic hantaviruses bind to the plexin-semaphorin-integrin (PSI) domain of inactive, β3 integrins. Previous studies have implicated a cognate cis interaction between the bent conformation β5/β3 integrins and an arginine-glycine-aspartic acid (RGD) sequence in the first extracellular loop of P2Y2R. With single-molecule atomic force microscopy, we show a specific interaction between an atomic force microscopy tip decorated with recombinant αIIbβ3 integrins and (RGD)P2Y2R expressed on cell membranes. Mutation of the RGD sequence to RGE in the P2Y2R removes this interaction. Binding of inactivated and fluorescently labeled Sin Nombre virus (SNV) to the integrin PSI domain stimulates higher affinity for (RGD)P2Y2R on cells, as measured by an increase in the unbinding force. In CHO cells, stably expressing αIIbβ3 integrins, virus engagement at the integrin PSI domain, recapitulates physiologic activation of the integrin as indicated by staining with the activation-specific mAB PAC1. The data also show that blocking of the Gα13 protein from binding to the cytoplasmic domain of the β3 integrin prevents outside-in signaling and infection. We propose that the cis interaction with P2Y2R provides allosteric resistance to the membrane-normal motion associated with the switchblade model of integrin activation, where the development of tensile force yields physiological integrin activation. PMID:28835374

Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise.

PubMed

O'Neill, Hayley M; Lally, James S; Galic, Sandra; Pulinilkunnil, Thomas; Ford, Rebecca J; Dyck, Jason R B; van Denderen, Bryce J; Kemp, Bruce E; Steinberg, Gregory R

2015-07-01

During submaximal exercise fatty acids are a predominant energy source for muscle contractions. An important regulator of fatty acid oxidation is acetyl-CoA carboxylase (ACC), which exists as two isoforms (ACC1 and ACC2) with ACC2 predominating in skeletal muscle. Both ACC isoforms regulate malonyl-CoA production, an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT-1); the primary enzyme controlling fatty acyl-CoA flux into mitochondria for oxidation. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is activated during exercise or by pharmacological agents such as metformin and AICAR. In resting muscle the activation of AMPK with AICAR leads to increased phosphorylation of ACC (S79 on ACC1 and S221 on ACC2), which reduces ACC activity and malonyl-CoA; effects associated with increased fatty acid oxidation. However, whether this pathway is vital for regulating skeletal muscle fatty acid oxidation during conditions of increased metabolic flux such as exercise/muscle contractions remains unknown. To examine this we characterized mice lacking AMPK phosphorylation sites on ACC2 (S212 in mice/S221 in humans-ACC2-knock-in [ACC2-KI]) or both ACC1 (S79) and ACC2 (S212) (ACC double knock-in [ACCD-KI]) during submaximal treadmill exercise and/or ex vivo muscle contractions. We find that surprisingly, ACC2-KI mice had normal exercise capacity and whole-body fatty acid oxidation during treadmill running despite elevated muscle ACC2 activity and malonyl-CoA. Similar results were observed in ACCD-KI mice. Fatty acid oxidation was also maintained in muscles from ACC2-KI mice contracted ex vivo. These findings indicate that pathways independent of ACC phosphorylation are important for regulating skeletal muscle fatty acid oxidation during exercise/muscle contractions. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Sleep, consciousness and the spontaneous and evoked electrical activity of the brain. Is there a cortical integrating mechanism?

PubMed

Evans, B M

2003-02-01

The physiological mechanisms that underlie consciousness and unconsciousness are the sleep/wake mechanisms. Deep sleep is a state of physiological reversible unconsciousness. The change from that state to wakefulness is mediated by the reticular activating mechanism. The reverse change from wakefulness to sleep is also an active process effected by an arousal inhibitory mechanism based on a partial blockade of the thalamus and upper brain stem, associated with thalamic sleep spindles and also with cortical sub-delta activity (<1 Hz). The deactivation of the thalamus has been demonstrated both electrically and by positron emission tomography during deep sleep. Normally, wakefulness is associated with instant awareness (defined as the ability to integrate all sensory information from the external environment and the internal environment of the body). Awareness may be a function of the thalamo-cortical network in the cerebral hemispheres, which forms the final path of the sleep/wake mechanism. Anatomical and physiological studies suggest that there may be a double thalamo-cortical network; one relating to cortical and thalamic areas with specific functions and the other global, involving all cortical areas and so-called 'non-specific' thalamic nuclei. The global system might function as a cortical integrating mechanism permitting the spread of information between the specific cortical areas and thus underlying awareness. The global system may also be responsible for much of the spontaneous and evoked electrical activity of the brain. The cognitive change between sleep and wakefulness is accompanied by changes in the autonomic system, the cerebral blood flow and cerebral metabolism. Awareness is an essential component of total consciousness (defined as continuous awareness of the external and internal environment, both past and present, together with the emotions arising from it). In addition to awareness, full consciousness requires short-term and explicit memory and intact emotional responses.

The Structural Basis of IKs Ion-Channel Activation: Mechanistic Insights from Molecular Simulations.

PubMed

Ramasubramanian, Smiruthi; Rudy, Yoram

2018-06-05

Relating ion channel (iCh) structural dynamics to physiological function remains a challenge. Current experimental and computational techniques have limited ability to explore this relationship in atomistic detail over physiological timescales. A framework associating iCh structure to function is necessary for elucidating normal and disease mechanisms. We formulated a modeling schema that overcomes the limitations of current methods through applications of artificial intelligence machine learning. Using this approach, we studied molecular processes that underlie human IKs voltage-mediated gating. IKs malfunction underlies many debilitating and life-threatening diseases. Molecular components of IKs that underlie its electrophysiological function include KCNQ1 (a pore-forming tetramer) and KCNE1 (an auxiliary subunit). Simulations, using the IKs structure-function model, reproduced experimentally recorded saturation of gating-charge displacement at positive membrane voltages, two-step voltage sensor (VS) movement shown by fluorescence, iCh gating statistics, and current-voltage relationship. Mechanistic insights include the following: 1) pore energy profile determines iCh subconductance; 2) the entire protein structure, not limited to the pore, contributes to pore energy and channel subconductance; 3) interactions with KCNE1 result in two distinct VS movements, causing gating-charge saturation at positive membrane voltages and current activation delay; and 4) flexible coupling between VS and pore permits pore opening at lower VS positions, resulting in sequential gating. The new modeling approach is applicable to atomistic scale studies of other proteins on timescales of physiological function. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

TRPM4 channels in the cardiovascular system: physiology, pathophysiology, and pharmacology.

PubMed

Abriel, Hugues; Syam, Ninda; Sottas, Valentin; Amarouch, Mohamed Yassine; Rougier, Jean-Sébastien

2012-10-01

The transient receptor potential channel (TRP) family comprises at least 28 genes in the human genome. These channels are widely expressed in many different tissues, including those of the cardiovascular system. The transient receptor potential channel melastatin 4 (TRPM4) is a Ca(2+)-activated non-specific cationic channel, which is impermeable to Ca(2+). TRPM4 is expressed in many cells of the cardiovascular system, such as cardiac cells of the conduction pathway and arterial and venous smooth muscle cells. This review article summarizes the recently described roles of TRPM4 in normal physiology and in various disease states. Genetic variants in the human gene TRPM4 have been linked to several cardiac conduction disorders. TRPM4 has also been proposed to play a crucial role in secondary hemorrhage following spinal cord injuries. Spontaneously hypertensive rats with cardiac hypertrophy were shown to over-express the cardiac TRPM4 channel. Recent studies suggest that TRPM4 plays an important role in cardiovascular physiology and disease, even if most of the molecular and cellular mechanisms have yet to be elucidated. We conclude this review article with a brief overview of the compounds that have been shown to either inhibit or activate TRPM4 under experimental conditions. Based on recent findings, the TRPM4 channel can be proposed as a future target for the pharmacological treatment of cardiovascular disorders, such as hypertension and cardiac arrhythmias. Copyright © 2012 Elsevier Inc. All rights reserved.

BRN 3.1 Knockouts Affect the Vestibular, Autonomic, and Circadian Rhythm Responses to 2G Exposure

NASA Technical Reports Server (NTRS)

Murakami, D. M.; Erkman, L.; Rosenfeld, M. G.; Fuller, C. A.

1999-01-01

Our previous studies have demonstrated that 2G exposure via centrifugation significantly attenuated the daily mean and circadian rhythm amplitude of rat body temperature (Tb), heart rate, and activity (Act). In addition, 2G exposure activates neural responses in several vestibular, autonomic, and circadian nuclei. Although we have characterized the effect of 2G on an animal's physiological, neuronal, and behavioral responses, it will be important to understand the underlying neural and physiological mechanisms that mediate those responses. For example, the vestibular responses, proprioceptive feedback, or fluid shifts may be the critical factors that mediate the responses to 2G. As a first step to understand the relative importance of these different response pathways to altered gravitational fields, this study examined the contribution of the vestibular system by utilizing an animal model from molecular biology. Brain 3.1 (Bm 3.1) is a POU domain homeobox gene involved in the normal development of the vestibular and auditory system. Brn 3.1 deletion results in a loss of hair cells in the otoliths, semicircular canals, and cochlea. As a result mice with a Brn 3.1 deletion do not have a functioning vestibular or auditory system. The BRN 3.1 knockout mouse could be a very useful animal model for isolating the role of the vestibular system in mediating the physiological responses to 2G exposure. Therefore, this study compared the effect of 2G exposure via centrifugation between Brn 3.1 knockout (KO) versus Wildtype (W) mice.

Motion compensation for in vivo subcellular optical microscopy.

PubMed

Lucotte, B; Balaban, R S

2014-04-01

In this review, we focus on the impact of tissue motion on attempting to conduct subcellular resolution optical microscopy, in vivo. Our position is that tissue motion is one of the major barriers in conducting these studies along with light induced damage, optical probe loading as well as absorbing and scattering effects on the excitation point spread function and collection of emitted light. Recent developments in the speed of image acquisition have reached the limit, in most cases, where the signal from a subcellular voxel limits the speed and not the scanning rate of the microscope. Different schemes for compensating for tissue displacements due to rigid body and deformation are presented from tissue restriction, gating, adaptive gating and active tissue tracking. We argue that methods that minimally impact the natural physiological motion of the tissue are desirable because the major reason to perform in vivo studies is to evaluate normal physiological functions. Towards this goal, active tracking using the optical imaging data itself to monitor tissue displacement and either prospectively or retrospectively correct for the motion without affecting physiological processes is desirable. Critical for this development was the implementation of near real time image processing in conjunction with the control of the microscope imaging parameters. Clearly, the continuing development of methods of motion compensation as well as significant technological solutions to the other barriers to tissue subcellular optical imaging in vivo, including optical aberrations and overall signal-to-noise ratio, will make major contributions to the understanding of cell biology within the body.

Cancer cell specific cytotoxic gene expression mediated by ARF tumor suppressor promoter constructs

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

Kurayoshi, Kenta; Ozono, Eiko; Iwanaga, Ritsuko

Highlights: • ARF promoter showed higher responsiveness to deregulated E2F activity than the E2F1 promoter. • ARF promoter showed higher cancer cell-specificity than E2F1 promoter to drive gene expression. • HSV-TK driven by ARF promoter showed higher cancer cell-specific cytotoxicity than that driven by E2F1 promoter. - Abstract: In current cancer treatment protocols, such as radiation and chemotherapy, side effects on normal cells are major obstacles to radical therapy. To avoid these side effects, a cancer cell-specific approach is needed. One way to specifically target cancer cells is to utilize a cancer specific promoter to express a cytotoxic gene (suicidemore » gene therapy) or a viral gene required for viral replication (oncolytic virotherapy). For this purpose, the selected promoter should have minimal activity in normal cells to avoid side effects, and high activity in a wide variety of cancers to obtain optimal therapeutic efficacy. In contrast to the AFP, CEA and PSA promoters, which have high activity only in a limited spectrum of tumors, the E2F1 promoter exhibits high activity in wide variety of cancers. This is based on the mechanism of carcinogenesis. Defects in the RB pathway and activation of the transcription factor E2F, the main target of the RB pathway, are observed in almost all cancers. Consequently, the E2F1 promoter, which is mainly regulated by E2F, has high activity in wide variety of cancers. However, E2F is also activated by growth stimulation in normal growing cells, suggesting that the E2F1 promoter may also be highly active in normal growing cells. In contrast, we found that the tumor suppressor ARF promoter is activated by deregulated E2F activity, induced by forced inactivation of pRB, but does not respond to physiological E2F activity induced by growth stimulation. We also found that the deregulated E2F activity, which activates the ARF promoter, is detected only in cancer cell lines. These observations suggest that ARF promoter is activated by E2F only in cancer cells and therefore may be more cancer cell-specific than E2F1 promoter to drive gene expression. We show here that the ARF promoter has lower activity in normal growing fibroblasts and shows higher cancer cell-specificity compared to the E2F1 promoter. We also demonstrate that adenovirus expressing HSV-TK under the control of the ARF promoter shows lower cytotoxicity than that of the E2F1 promoter, in normal growing fibroblasts but has equivalent cytotoxicity in cancer cell lines. These results suggest that the ARF promoter, which is specifically activated by deregulated E2F activity, is an excellent candidate to drive therapeutic cytotoxic gene expression, specifically in cancer cells.« less

The Kölliker-Fuse nucleus: a review of animal studies and the implications for cranial nerve function in humans.

PubMed

Browaldh, Nanna; Bautista, Tara G; Dutschmann, Mathias; Berkowitz, Robert G

2016-11-01

To review the scientific literature on the relationship between Kölliker-Fuse nucleus (KF) and cranial nerve function in animal models, with view to evaluating the potential role of KF maturation in explaining age-related normal physiologic parameters and developmental and acquired impairment of cranial nerve function in humans. Medical databases (Medline and PubMed). Studies investigating evidence of KF activity responsible for a specific cranial nerve function that were based on manipulation of KF activity or the use of neural markers were included. Twenty studies were identified that involved the trigeminal (6 studies), vagus (9), and hypoglossal nerves (5). These pertained specifically to a role of the KF in mediating the dive reflex, laryngeal adductor control, swallowing function and upper airway tone. The KF acts as a mediator of a number of important functions that relate primarily to laryngeal closure, upper airway tone and swallowing. These areas are characterized by a variety of disorders that may present to the otolaryngologist, and hence the importance of understanding the role played by the KF in maintaining normal function.

Oxidation-induced calcium-dependent dehydration of normal human red blood cells.

PubMed

Shcherbachenko, Irina M; Lisovskaya, Irina L; Tikhonov, Vladimir P

2007-05-01

Phenazine-methosulphate (PMS) is a strong oxidant that induces reactive oxygen species (ROS) formation in cells. Though it has been shown that PMS increases the red blood cell (RBC) membrane permeability to K(+), the hypotheses on the mechanism of PMS-induced effects are contradictory and there are no data on volume changes induced by this oxidant. Therefore, the influence of the PMS + ascorbate oxidative system on the volume of normal human RBCs was studied. In a Ca(2 + )-containing medium, PMS + ascorbate caused dehydration (shrinking) of RBCs judged by: (1) changes in the density and osmotic resistance distributions of RBCs, and (2) a decrease in their low-angle scattering assessed by FACS analysis. The dehydration resulted from activation of the Gardos channels, was PMS and ascorbate concentration-dependent, was associated with broadening of the density and osmotic resistance distributions of the RBCs, and decreased in the presence of the taxifolin and rutin antioxidants. These findings contribute to a better understanding of the physiology and pathology of oxidatively-modified RBCs and may be of practical significance in estimating the antioxidant activity of various substances.

Microbial production of metabolites and associated enzymatic reactions under high pressure.

PubMed

Dong, Yongsheng; Jiang, Hua

2016-11-01

High environmental pressure exerts an external stress on the survival of microorganisms that are commonly found under normal pressure. In response, many growth traits alter, including cell morphology and physiology, cellular structure, metabolism, physical and chemical properties, the reproductive process, and defense mechanisms. The high-pressure technology (HP) has been industrially utilized in pressurized sterilization, synthesis of stress-induced products, and microbial/enzymatic transformation of chemicals. This article reviews current research on pressure-induced production of metabolites in normal-pressure microbes and their enzymatic reactions. Factors that affect the production of such metabolites are summarized, as well as the effect of pressure on the performance of microbial fermentation and the yield of flavoring compounds, different categories of induced enzymatic reactions and their characteristics in the supercritical carbon dioxide fluid, effects on enzyme activity, and the selection of desirable bacterial strains. Technological challenges are discussed, and future research directions are proposed. Information presented here will benefit the research, development, and application of the HP technology to improve microbial fermentation and enzymatic production of biologically active substances, thereby help to meet their increasing demand from the ever-expanding market.

NF-κB Signaling Pathway and its Potential as a Target for Therapy in Lymphoid Neoplasms

PubMed Central

Yu, Li; Li, Ling; Medeiros, L. Jeffrey; Young, Ken H.

2016-01-01

The NF-κB pathway, a critical regulator of apoptosis, plays a key role in many normal cellular functions. Genetic alterations and other mechanisms leading to constitutive activation of the NF-κB pathway contribute to cancer development, progression and therapy resistance by activation of downstream anti-apoptotic pathways, unfavorable microenvironment interactions, and gene dysregulation. Not surprisingly, given its importance to normal and cancer cell function, the NF-κB pathway has emerged as a target for therapy. In the review, we present the physiologic role of the NF-κB pathway and recent advances in better understanding of the pathologic roles of the NF-κB pathway in major types of lymphoid neoplasms. We also provide an update of clinical trials that use NF-κB pathway inhibitors. These trials are exploring the clinical efficiency of combining NF-κB pathway inhibitors with various agents that target diverse mechanisms of action with the goal being to optimize novel therapeutic opportunities for targeting oncogenic pathways to eradicate cancer cells. PMID:27773462

Space flight and bone formation.

PubMed

Doty, St B

2004-12-01

Major physiological changes which occur during spaceflight include bone loss, muscle atrophy, cardiovascular and immune response alterations. When trying to determine the reason why bone loss occurs during spaceflight, one must remember that all these other changes in physiology and metabolism may also have impact on the skeletal system. For bone, however, the role of normal weight bearing is a major concern and we have found no adequate substitute for weight bearing which can prevent bone loss. During the study of this problem, we have learned a great deal about bone physiology and increased our knowledge about how normal bone is formed and maintained. Presently, we do not have adequate ground based models which can mimic the tissue loss that occurs in spaceflight but this condition closely resembles the bone loss seen with osteoporosis. Although a normal bone structure will respond to application of mechanical force and weight bearing by forming new bone, a weakened osteoporotic bone may have a tendency to fracture. The study of the skeletal system during weightless conditions will eventually produce preventative measures and form a basis for protecting the crew during long term space flight. The added benefit from these studies will be methods to treat bone loss conditions which occur here on earth.

Space flight and bone formation

NASA Technical Reports Server (NTRS)

Doty, St B.

2004-01-01

Major physiological changes which occur during spaceflight include bone loss, muscle atrophy, cardiovascular and immune response alterations. When trying to determine the reason why bone loss occurs during spaceflight, one must remember that all these other changes in physiology and metabolism may also have impact on the skeletal system. For bone, however, the role of normal weight bearing is a major concern and we have found no adequate substitute for weight bearing which can prevent bone loss. During the study of this problem, we have learned a great deal about bone physiology and increased our knowledge about how normal bone is formed and maintained. Presently, we do not have adequate ground based models which can mimic the tissue loss that occurs in spaceflight but this condition closely resembles the bone loss seen with osteoporosis. Although a normal bone structure will respond to application of mechanical force and weight bearing by forming new bone, a weakened osteoporotic bone may have a tendency to fracture. The study of the skeletal system during weightless conditions will eventually produce preventative measures and form a basis for protecting the crew during long term space flight. The added benefit from these studies will be methods to treat bone loss conditions which occur here on earth.

MicroRNA-200c: A Novel Way to Attack Breast Cancer Metastases by Restoring the Epithelial Phenotype

DTIC Science & Technology

2012-02-01

complex relationships and reveal the extent to whichmiRNAs are involved with SHRs in normal physiology and the pathobiology of steroid hormoneene regulation...proges- terone counteracts estrogen-mediated proliferation. To determine whethermiRNAs play a physiological role inmodulating hormonal control of gene...effect on uterine physiology to ate is the finding that P4/PGR affects uterine contractility during abor via regulation of ZEB1 and the miR-200 family

Observation of arterial blood pressure of the primate

NASA Technical Reports Server (NTRS)

Meehan, J. P.; Henry, J. P.

1973-01-01

The developments are reported in physiological instrumentation, surgical procedures, measurement and data analysis techniques, and the definition of flight experiments to determine the effects of prolonged weightlessness on the cardiovascular system of subhuman primates. The development of an implantable telemetric data acquisition system is discussed along with cardiovascular research applications in renal hemodynamics. It is concluded that the implant technique permits a valid interpretation, free of emotional response, for the manipulated variable on physiological functions. It also allows a better definition of normal physiological baseline conditions.

Improved throughput traction microscopy reveals pivotal role for matrix stiffness in fibroblast contractility and TGF-β responsiveness

PubMed Central

Marinković, Aleksandar; Mih, Justin D.; Park, Jin-Ah; Liu, Fei

2012-01-01

Lung fibroblast functions such as matrix remodeling and activation of latent transforming growth factor-β1 (TGF-β1) are associated with expression of the myofibroblast phenotype and are directly linked to fibroblast capacity to generate force and deform the extracellular matrix. However, the study of fibroblast force-generating capacities through methods such as traction force microscopy is hindered by low throughput and time-consuming procedures. In this study, we improved at the detail level methods for higher-throughput traction measurements on polyacrylamide hydrogels using gel-surface-bound fluorescent beads to permit autofocusing and automated displacement mapping, and transduction of fibroblasts with a fluorescent label to streamline cell boundary identification. Together these advances substantially improve the throughput of traction microscopy and allow us to efficiently compute the forces exerted by lung fibroblasts on substrates spanning the stiffness range present in normal and fibrotic lung tissue. Our results reveal that lung fibroblasts dramatically alter the forces they transmit to the extracellular matrix as its stiffness changes, with very low forces generated on matrices as compliant as normal lung tissue. Moreover, exogenous TGF-β1 selectively accentuates tractions on stiff matrices, mimicking fibrotic lung, but not on physiological stiffness matrices, despite equivalent changes in Smad2/3 activation. Taken together, these results demonstrate a pivotal role for matrix mechanical properties in regulating baseline and TGF-β1-stimulated contraction of lung fibroblasts and suggest that stiff fibrotic lung tissue may promote myofibroblast activation through contractility-driven events, whereas normal lung tissue compliance may protect against such feedback amplification of fibroblast activation. PMID:22659883

Thrombin-stimulated platelet aggregation is inhibited by kallikrein in a time- and concentration-dependent manner.

PubMed

Veloso, D

2003-01-01

Many in vitro studies have shown that activation of prekallikrein (PK) to kallikrein (KAL) in normal plasma triggers rapid activation of the coagulation cascade. In agreement, the coagulation activation is impaired in PK-deficient plasma. Paradoxically, PK-deficient patients show a tendency to thrombosis. To investigate the discrepancy between the in vitro and in vivo findings, we analyzed the effect of KAL on the rate of platelet aggregation. For this research, physiologic concentrations of washed human platelets were incubated for 5 and/or 10 min with approximately 2.2 to 88 nM human plasma KAL (< 1/100 to approximately 1/3 of PK concentrations in plasma) prior to the addition of high concentrations of alpha-thrombin (54 nM) or fibrinogen plus ADP. KAL concentrations were arbitrarily selected on the assumption that concentrations of free KAL (the enzymatically active species) were minute in normal plasma and higher when KAL production was enhanced, and/or inhibitors were depleted. Full platelet aggregation was that seen in the absence of KAL or PK. Inhibition of platelet aggregation stimulated by thrombin was markedly increased with increased KAL concentrations and incubation times. The degree of inhibition by KAL was smaller when ADP was the agonist. The data suggest that KAL may play a role in the modulation of platelet aggregation in vivo under normal conditions as well as when prolonged, high concentrations of KAL occur in blood. The data may also help to explain the intriguing observation that PK-deficient patients show a tendency to thrombotic episodes and myocardial infarction whereas in vitro assays predict bleeding.

ERBB2 Deficiency Alters an E2F-1-Dependent Adaptive Stress Response and Leads to Cardiac Dysfunction

PubMed Central

Perry, Marie-Claude; Dufour, Catherine R.; Eichner, Lillian J.; Tsang, David W. K.; Deblois, Geneviève; Muller, William J.

2014-01-01

The tyrosine kinase receptor ERBB2 is required for normal development of the heart and is a potent oncogene in breast epithelium. Trastuzumab, a monoclonal antibody targeting ERBB2, improves the survival of breast cancer patients, but cardiac dysfunction is a major side effect of the drug. The molecular mechanisms underlying how ERBB2 regulates cardiac function and why trastuzumab is cardiotoxic remain poorly understood. We show here that ERBB2 hypomorphic mice develop cardiac dysfunction that mimics the side effects observed in patients treated with trastuzumab. We demonstrate that this phenotype is related to the critical role played by ERBB2 in cardiac homeostasis and physiological hypertrophy. Importantly, genetic and therapeutic reduction of ERBB2 activity in mice, as well as ablation of ERBB2 signaling by trastuzumab or siRNAs in human cardiomyocytes, led to the identification of an impaired E2F-1-dependent genetic program critical for the cardiac adaptive stress response. These findings demonstrate the existence of a previously unknown mechanistic link between ERBB2 and E2F-1 transcriptional activity in heart physiology and trastuzumab-induced cardiac dysfunction. PMID:25246633

Circadian rhythms and fractal fluctuations in forearm motion

NASA Astrophysics Data System (ADS)

Hu, Kun; Hilton, Michael F.

2005-03-01

Recent studies have shown that the circadian pacemaker --- an internal body clock located in the brain which is normally synchronized with the sleep/wake behavioral cycles --- influences key physiologic functions such as the body temperature, hormone secretion and heart rate. Surprisingly, no previous studies have investigated whether the circadian pacemaker impacts human motor activity --- a fundamental physiologic function. We investigate high-frequency actigraph recordings of forearm motion from a group of young and healthy subjects during a forced desynchrony protocol which allows to decouple the sleep/wake cycles from the endogenous circadian cycle while controlling scheduled behaviors. We investigate both static properties (mean value, standard deviation), dynamical characteristics (long-range correlations), and nonlinear features (magnitude and Fourier-phase correlations) in the fluctuations of forearm acceleration across different circadian phases. We demonstrate that while the static properties exhibit significant circadian rhythms with a broad peak in the afternoon, the dynamical and nonlinear characteristics remain invariant with circadian phase. This finding suggests an intrinsic multi-scale dynamic regulation of forearm motion the mechanism of which is not influenced by the circadian pacemaker, thus suggesting that increased cardiac risk in the early morning hours is not related to circadian-mediated influences on motor activity.

Experimental investigation of the effects of aromatic hydrocarbons on a sediment food web. University research initiative. Final draft report

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

Carman, K.R.; Fleeger, J.W.; Pomarico, S.M.

1994-07-01

The influence of polynuclear aromatic hydrocarbons (PAH) on a sedimentary salt-marsh food web was examined using microcosm and laboratory experiments that simulated natural conditions. Microcosms were dosed with concentrations of PAH-contaminated sediment collected from a produced water site at Pass Fourchon, LA. Bacterial activity and abundance were not influenced by PAH, but microalgal activity and physiological condition were. Grazing by copepods on benthic microalgae was not significantly influenced by PAH concentration, nor was the physiological condition of copepods. Meiofaunal community composition was influenced by PAH, as nematodes became disproportionally abundant, and the nauplius/copepod ratio increased in high-PAH treatments. Overall, sublethalmore » effects of PAH were not pronounced at the concentrations (0.3 to 3.0 ppm) we examined. Fish-predation studies indicated that Leiostomus xanthurus could not detect PAH-contaminated sediments, and continued to feed normally when exposed to them. PAH contamination did not decrease the number of feeding strikes or sediment processing time. This lack of ability to discriminate between contaminated and uncontaminated sediments could have serious implications in terms of bioaccumulation of PAH (or other contaminants) by these bottom-feeding fish.« less

Changes in oxygen consumption and respiratory enzymes as stress indicators in an estuarine edible crab Scylla serrata exposed to naphthalene.

PubMed

Vijayavel, K; Balasubramanian, M P

2006-06-01

The sublethal effect of naphthalene was studied on the physiology of a mud crab Scylla serrata. The 96 h acute toxicity of naphthalene was determined and found to be 28 mg 1(-1) (LC100), 18 mg 1(-1) (LC50), 10 mg 1(-1) (LC0) respectively. The 30 days sublethal effect (LC0) 9 mg 1(-1), 8 mg 1(-1), 10 mg 1(-1), of naphthalene was investigated in the crab S. serrata with reference to oxygen consumption and changes in the activity of respiratory enzymes. The results indicated that naphthalene caused disturbance in the normal physiology of the crab. The bioaccumulation of naphthalene was also investigated in gills, hepatopancreas, haemolymph and ovary. The consumption of oxygen increased in the naphthalene medium when compared with that of the crabs exposed to naphthalene free medium. A decreased trend in the activity of respiratory enzymes such as lactate dehydrogenase (LDH), isocitrate dehydrogenase (ICDH), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), alpha-ketoglutarate dehydrogenase (alpha-KDH) and glutathione (GSH) were recorded in the hepatopancreas, ovary and gills of S. serrata for all the tested concentrations of naphthalene and the results were analyzed for their significance.

A mini review on immune role of chemokines and its receptors in snakehead murrel Channa striatus.

PubMed

Bhatt, Prasanth; Kumaresan, Venkatesh; Palanisamy, Rajesh; Ravichandran, Gayathri; Mala, Kanchana; Amin, S M Nurul; Arshad, Aziz; Yusoff, Fatimah Md; Arockiaraj, Jesu

2018-01-01

Chemokines are ubiquitous cytokine molecules involved in migration of cells during inflammation and normal physiological processes. Though the study on chemokines in mammalian species like humans have been extensively studied, characterization of chemokines in teleost fishes is still in the early stage. The present review provides an overview of chemokines and its receptors in a teleost fish, Channa striatus. C. striatus is an air breathing freshwater carnivore, which has enormous economic importance. This species is affected by an oomycete fungus, Aphanomyces invadans and a Gram negative bacteria Aeromonas hydrophila is known to cause secondary infection. These pathogens impose immune changes in the host organism, which in turn mounts several immune responses. Of these, the role of cytokines in the immune response is immense, due to their involvement in several activities of inflammation such as cell trafficking to the site of inflammation and antigen presentation. Given that importance, chemokines in fishes do have significant role in the immunological and other physiological functions of the organism, hence there is a need to understand the characteristics, activities and performace of these small molecules in details. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pineal melatonin synthesis in Syrian hamsters: A summary

NASA Astrophysics Data System (ADS)

Rollag, M. D.

1982-12-01

During the past decade there has been ample documentation of the proposition that the pineal gland mediates photoperiodic influences upon reproductive behavior of hamsters. It is commonly hypothesized that the pineal gland expresses its activity by transformation of photoperiodic information into an hormonal output, that hormone being melatonin. If this hypothesis is correct, there must be some essential diffrence in melatonin's output when hamsters are exposed to different photoperiodic environments. The experiments summarized in this communication analyze pineal melatonin contents in Syrian hamsters maintained in a variety of photoperiodic conditions during different physiological states. The results demonstrate that adult hamsters have a daily surge in pineal melatonin content throughout their lifetime when exposed to simulated annual photoperiodic cycles. There is some fluctuation in the amount of pineal melatonin produced during different physiological states and photoperiodic environments, but these fluctuations seem small when compared to those normally found for other regulatory hormones. When hamsters are exposed to different photoperiodic regimens, the daily melatonin surge maintains a relatively constant phase relationship with respect to the onset of daily activity. There is a concomitant change in its phase relationship with respect to light-dark transitions.

Dynamics of large-scale brain activity in normal arousal states and epileptic seizures

NASA Astrophysics Data System (ADS)

Robinson, P. A.; Rennie, C. J.; Rowe, D. L.

2002-04-01

Links between electroencephalograms (EEGs) and underlying aspects of neurophysiology and anatomy are poorly understood. Here a nonlinear continuum model of large-scale brain electrical activity is used to analyze arousal states and their stability and nonlinear dynamics for physiologically realistic parameters. A simple ordered arousal sequence in a reduced parameter space is inferred and found to be consistent with experimentally determined parameters of waking states. Instabilities arise at spectral peaks of the major clinically observed EEG rhythms-mainly slow wave, delta, theta, alpha, and sleep spindle-with each instability zone lying near its most common experimental precursor arousal states in the reduced space. Theta, alpha, and spindle instabilities evolve toward low-dimensional nonlinear limit cycles that correspond closely to EEGs of petit mal seizures for theta instability, and grand mal seizures for the other types. Nonlinear stimulus-induced entrainment and seizures are also seen, EEG spectra and potentials evoked by stimuli are reproduced, and numerous other points of experimental agreement are found. Inverse modeling enables physiological parameters underlying observed EEGs to be determined by a new, noninvasive route. This model thus provides a single, powerful framework for quantitative understanding of a wide variety of brain phenomena.

Update on the slow delayed rectifier potassium current (I(Ks)): role in modulating cardiac function.

PubMed

Liu, Zhenzhen; Du, Lupei; Li, Minyong

2012-01-01

The slow delayed rectifier current (I(Ks)) is the slow component of cardiac delayed rectifier current and is critical for the late phase repolarization of cardiac action potential. This current is also an important target for Sympathetic Nervous System (SNS) to regulate the cardiac electivity to accommodate to heart rate alterations in response to exercise or emotional stress and can be up-regulated by β- adrenergic or other signal molecules. I(Ks) channel is originated by the co-assembly of pore-forming KCNQ1 α-subunit and accessory KCNE1 β-subunit. Mutations in any subunit can bring about severe long QT syndrome (LQT-1, LQT-5) as characterized by deliquium, seizures and sudden death. This review summarizes the normal physiological functions and molecular basis of I(Ks) channels, as well as illustrates up-to-date development on its blockers and activators. Therefore, the current extensive survey should generate fundamental understanding of the role of I(Ks) channel in modulating cardiac function and donate some instructions to the progression of I(Ks) blockers and activators as potential antiarrhythmic agents or pharmacological tools to determine the physiological and pathological function of I(Ks).

GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function.

PubMed

Horvath, Tamas L; Erion, Derek M; Elsworth, John D; Roth, Robert H; Shulman, Gerald I; Andrews, Zane B

2011-07-01

Guanidinopropionic acid (GPA) increases AMPK activity, mitochondrial function and biogenesis in muscle and improves physiological function, for example during aging. Mitochondrial dysfunction is a major contributor to the pathogenesis of Parkinson's disease. Here we tested whether GPA prevents neurodegeneration of the nigrostriatal dopamine system in MPTP-treated mice. Mice were fed a diet of 1% GPA or normal chow for 4 weeks and then treated with either MPTP or saline. Indices of nigrostriatal function were examined by HPLC, immunohistochemistry, stereology, electron microscopy and mitochondrial respiration. MPTP intoxication decreased TH neurons in the SNpc of normal chow-fed mice; however GPA-fed mice remarkably exhibited no loss of TH neurons in the SNpc. MPTP caused a decrease in striatal dopamine of both normal chow- and GPA-fed mice, although this effect was significantly attenuated in GPA-fed mice. GPA-fed mice showed increased AMPK activity, mitochondrial respiration and mitochondrial number in nigrostriatal TH neurons, suggesting that the neuroprotective effects of GPA involved AMPK-dependent increases in mitochondrial function and biogenesis. MPTP treatment produced a decrease in mitochondrial number and volume in normal chow-fed mice but not GPA-fed mice. Our results show the neuroprotective properties of GPA in a mouse model of Parkinson's disease are partially mediated by AMPK and mitochondrial function. Mitochondrial dysfunction is a common problem in neurodegeneration and thus GPA may slow disease progression in other models of neurodegeneration. Copyright © 2011 Elsevier Inc. All rights reserved.

MELATONIN ENHANCES JUNCTIONAL TRANSFER IN NORMAL C3H/1OT1/2 CELLS

EPA Science Inventory

There is strong evidence that pineal melatonin is involved in controlling neoplastic processes. e have reported that physiological, but not pharmacological or subphysiological, concentrations of melatonin enhance intercellular communication in normal C3H/1OT1/2 fibroblasts. ap ju...

The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide

PubMed Central

Soscia, Stephanie J.; Kirby, James E.; Washicosky, Kevin J.; Tucker, Stephanie M.; Ingelsson, Martin; Hyman, Bradley; Burton, Mark A.; Goldstein, Lee E.; Duong, Scott; Tanzi, Rudolph E.; Moir, Robert D.

2010-01-01

Background The amyloid β-protein (Aβ) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Aβ is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Aβ has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities. Methodology/Principal Findings Here, we provide data supporting an in vivo function for Aβ as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of Aβ and LL-37, an archetypical human AMP. Findings reveal that Aβ exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue Aβ levels. Consistent with Aβ-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Aβ antibodies. Conclusions/Significance Our findings suggest Aβ is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Aβ-mediated pathology and has important implications for ongoing and future AD treatment strategies. PMID:20209079

Factor XII (Hageman factor) is a missing link between stress and hypercoagulability and plays an important role in the pathophysiology of ischemic stroke.

PubMed

Eggers, Arnold E

2006-01-01

A new hypothesis is presented on the function of factor XII, which is postulated to be a "missing link" between acute stress and transient hypercoagulability. The implications of this idea are developed to show how chronic stress, which involves activation of hypertension and migraine as well as hypercoagulability, can cause of cerebrovascular disease. "Acute stress" is defined as "the normal short-term physiological response to the perception of major threats or demands". "Chronic stress" is "the abnormal ongoing physiological response to the continuing perception of unresolvable major threats or demands". The factor XII hypothesis is as follows: Acute stress includes release of epinephrine by the adrenal medulla. Epinephrine activates platelets by binding to alpha-2A adrenergic receptors. Activated platelets convert pre-bound factor XII to its active form, which then initiates the intrinsic coagulation cascade. This can be called the "activated platelet initiation pathway" for coagulation. Neither tissue factor nor pre-formed thrombin is required. Thrombosis proceeds to completion, but only a minute amount of thrombin is formed, and the process normally stops at this point. In people who lapse into a state of chronic stress, essential hypertension, which is also a manifestation of stress, synergizes with hypercoagulability: there is both a baseline rise in blood pressure and systemic platelet activation as well as superimposed labile rises of both. Upregulation of these two stress parameters is atherogenic: epinephrine-activated platelets stimulating thrombin formation interact with endothelial cells activated by angiotensin II to cause, first, smooth muscle cell proliferation, which is a histological hallmark of atherosclerosis, and, lastly, a symptomatic thrombotic occlusion-the stroke. The migraine symptoms which often accompany this process are a marker of chronic stress and ongoing pathophysiologic damage. Therapeutic predictions are made regarding novel ways of blocking stress-induced hypercoagulability and hypertension. Hypercoagulability could be targeted by monoclonal antibodies directed against the platelet-specific alpha-2 adrenergic receptor or the (putative) platelet receptor for Factor XII; hypertension could be treated with monoclonal antibodies directed against the beta-adrenergic receptor in the juxtaglomerular apparatus or by surgical denervation of the kidneys, either of which would decrease the renin release which helps drive the hypertension.

EG-VEGF, BV8, and their receptor expression in human bronchi and their modification in cystic fibrosis: Impact of CFTR mutation (delF508).

PubMed

Chauvet, Sylvain; Traboulsi, Wael; Thevenon, Laura; Kouadri, Amal; Feige, Jean-Jacques; Camara, Boubou; Alfaidy, Nadia; Benharouga, Mohamed

2015-08-01

Enhanced lung angiogenesis has been reported in cystic fibrosis (CF). Recently, two highly homologous ligands, endocrine gland vascular endothelial growth factor (EG-VEGF) and mammalian Bv8, have been described as new angiogenic factors. Both ligands bind and activate two closely related G protein-coupled receptors, the prokineticin receptor (PROKR) 1 and 2. Yet, the expression, regulation, and potential role of EG-VEGF, BV8, and their receptors in normal and CF lung are still unknown. The expression of the receptors and their ligands was examined using molecular, biochemical, and immunocytochemistry analyses in lungs obtained from CF patients vs. control and in normal and CF bronchial epithelial cells. Cystic fibrosis transmembrane conductance regulator (CFTR) activity was evaluated in relation to both ligands, and concentrations of EG-VEGF were measured by ELISA. At the mRNA level, EG-VEGF, BV8, and PROKR2 gene expression was, respectively, approximately five, four, and two times higher in CF lungs compared with the controls. At the cellular level, both the ligands and their receptors showed elevated expressions in the CF condition. Similar results were observed at the protein level. The EG-VEGF secretion was apical and was approximately two times higher in CF compared with the normal epithelial cells. This secretion was increased following the inhibition of CFTR chloride channel activity. More importantly, EG-VEGF and BV8 increased the intracellular concentration of Ca(2+) and cAMP and stimulated CFTR-chloride channel activity. Altogether, these data suggest local roles for epithelial BV8 and EG-VEGF in the CF airway peribronchial vascular remodeling and highlighted the role of CFTR activity in both ligand biosynthesis and secretion. Copyright © 2015 the American Physiological Society.

Neuroendocrine Consequences of Androgen Excess in Female Rodents

PubMed Central

Foecking, Eileen M.; McDevitt, Melissa A.; Acosta-Martínez, Maricedes; Horton, Teresa H.; Levine, Jon E.

2008-01-01

Androgens exert significant organizational and activational effects on the nervous system and behavior. Despite the fact that female mammals generally produce low levels of androgens, relative to the male of the same species, increasing evidence suggests that androgens can exert profound effects on the normal physiology and behavior of females during fetal, neonatal, and adult stages of life. This review examines the effects of exposure to androgens at three stages of development – as an adult, during early postnatal life and as a fetus, on reproductive hormone secretions in female rats. We examine the effects of androgen exposure both as a model of neuroendocrine sexual differentiation and with respect to the role androgens play in the normal female. We then discuss the hypothesis that androgens may cause epigenetic modification of estrogen target genes in the brain. Finally we consider the clinical consequences of excess androgen exposure in women. PMID:18374922

Selected retinoids: determination by isocratic normal-phase HPLC.

PubMed

Klvanova, J; Brtko, J

2002-09-01

Retinol (ROL), retinal (RAL) and retinoic acid (RA) are physiologically active forms of vitamin A. All-trans retinoic acid (ATRA) can be formed by oxidation from all-trans retinal (ATRAL). Isomerization of RA is considered to be an important metabolic pathway of retinoids. RA isomers transactivate various response pathways via their cognate nuclear receptors that act as ligand inducible transcription factors. The aim of this study was to establish a rapid and simple method for determination of ATRA, 13-cis retinoic acid (13CRA) and ATRAL by HPLC. In our laboratory, we slightly modified the method of Miyagi et al. (2001) and separated ATRA, 13CRA and ATRAL by simple isocratic normal phase HPLC. Both retinoic acid isomers and ATRAL were eluted within 13 min and all components were well resolved. The coefficients of variation (C.V.) for RAs and RAL were from 3.0 to 5.4 %.

Cardiovascular Adjustments to Gravitational Stress

NASA Technical Reports Server (NTRS)

Blomqvist, C. Gunnar; Stone, H. Lowell

1991-01-01

The effects of gravity on the cardiovascular system must be taken into account whenever a hemodynamic assessment is made. All intravascular pressure have a gravity-dependent hydrostatic component. The interaction between the gravitational field, the position of the body, and the functional characteristics of the blood vessels determines the distribution of intravascular volume. In turn this distribution largely determines cardiac pump function. Multiple control mechanisms are activated to preserve optimal tissue perfusion when the magnitude of the gravitational field or its direction relative to the body changes. Humans are particularly sensitive to such changes because of the combination of their normally erect posture and the large body mass and blood volume below the level of the heart. Current aerospace technology also exposes human subjects to extreme variations in the gravitational forces that range from zero during space travel to as much an nine-times normal during operation of high-performance military aircraft. This chapter therefore emphasizes human physiology.

Physiology of the motor cortex in polio survivors.

PubMed

Lupu, Vitalie D; Danielian, Laura; Johnsen, Jacqueline A; Vasconcelos, Olavo M; Prokhorenko, Olga A; Jabbari, Bahman; Campbell, William W; Floeter, Mary Kay

2008-02-01

We hypothesized that the corticospinal system undergoes functional changes in long-term polio survivors. Central motor conduction times (CMCTs) to the four limbs were measured in 24 polio survivors using transcranial magnetic stimulation (TMS). Resting motor thresholds and CMCTs were normal. In 17 subjects whose legs were affected by polio and 13 healthy controls, single- and paired-pulse TMS was used to assess motor cortex excitability while recording from tibialis anterior (TA) muscles at rest and following maximal contraction until fatigue. In polio survivors the slope of the recruitment curve was normal, but maximal motor evoked potentials (MEPs) were larger than in controls. MEPs were depressed after fatiguing exercise. Three patients with central fatigue by twitch interpolation had a trend toward slower recovery. There was no association with symptoms of post-polio syndrome. These changes occurring after polio may allow the motor cortex to activate a greater proportion of the motor neurons innervating affected muscles.

[The influence of the LK-92 "Adeli" treatment loading suit on electro-neuro-myographic characteristics in patients with infantile cerebral paralysis].

PubMed

Semenova, K A; Antonova, L V

1998-01-01

Treatment-loading costume (LK-92 "Adely") was investigated in terms of its influence on functional state of neuromotor apparatus in 25 children with infantile cerebral paralysis in the form of spastic diplegia. Improvement of motor functions observed may be conditioned by a decrease of an amplitude of bioelectric activity in spastic muscles at physiologic rest and by an increase of an amplitude of agonists' biopotentials at arbitrary movements. Improvement of motor functions may be also caused by normalization of both the coefficients characterizing coordinated muscules' interactions and functional state of spinal motoneurons as well as of the mechanisms of their suprasegmental regulation. It is suggested that such effect may be, realized because of the afferentation normalization as well as by means of the influence of LK-92 "Adely" on both central and segmentary structures of motor analyzer including neuromediator systems.

The cerebral hemodynamics of normotensive hypovolemia during lower-body negative pressure

NASA Technical Reports Server (NTRS)

Giller, C. A.; Levine, B. D.; Meyer, Y.; Buckey, J. C.; Lane, L. D.; Borchers, D. J.

1992-01-01

Although severe hypovolemia can lead to hypotension and neurological decline, many patients with neurosurgical disorders experience a significant hypovolemia while autonomic compensatory mechanisms maintain a normal blood pressure. To assess the effects of normotensive hypovolemia upon cerebral hemodynamics, transcranial Doppler ultrasound monitoring of 13 healthy volunteers was performed during graded lower-body negative pressure of up to -50 mm Hg, an accepted laboratory model for reproducing the physiological effects of hypovolemia. Middle cerebral artery flow velocity declined by 16% +/- 4% (mean +/- standard error of the mean) and the ratio between transcranial Doppler ultrasound pulsatility and systemic pulsatility rose 22% +/- 8%, suggesting cerebral small-vessel vasoconstriction in response to the sympathetic activation unmasked by lower-body negative pressure. This vasoconstriction may interfere with the autoregulatory response to a sudden fall in blood pressure, and may explain the common observation of neurological deficit during hypovolemia even with a normal blood pressure.

A pilot study on disturbed gastric myoelectric activity in obstructed defecation syndrome.

PubMed

Farid, Mohamed; Emile, Sameh Hany; Haleem, Magdy; El-Hak, Nabil Gad

2018-07-01

Electrogastrography (EGG) is a noninvasive technique for recording gastric myoelectric activity. The aim of this study was to measure and record gastric myoelectric activity in patients with obstructed defecation syndrome (ODS) and to compare their results with those of normal individuals. Forty-two patients (22 male) with ODS and a mean age of 41.02 y were enrolled in this prospective study after thorough clinical and physiologic assessment. Eleven normal subjects (six female) with a mean age of 39.2 ± 8.4 y were assigned to the control group. Both patients and controls were subjected to surface EGG in fasting and postprandial states. Data were recorded and analyzed via a computer system to reveal the EGG pattern in both groups. Abnormalities in the EGG were found in 24 (57.1%) of the 42 patients with ODS. EGG in ODS patients showed alterations in the fasting state in the form of a significant decrease of the normal gastric slow wave (P = 0.03) and a nonsignificant increase in gastric dysrhythmias. The EGG alterations of ODS patients were significantly improved in the postprandial state as the normal gastric slow waves significantly (P = 0.006) increased and the gastric bradycardia declined significantly (P = 0.02). No significant differences were observed in the power distribution between the ODS patients and the healthy controls. Patients with ODS showed an altered EGG pattern compared with that of healthy control subjects. The alterations in ODS patients were more clearly observed during the fasting state and improved significantly after eating. Copyright © 2018 Elsevier Inc. All rights reserved.

Eppur Si Muove: The Dynamic Nature of Physiological Control of Renal Blood Flow by the Renal Sympathetic Nerves

PubMed Central

Schiller, Alicia M.; Pellegrino, Peter Ricci; Zucker, Irving H.

2016-01-01

Tubuloglomerular feedback and the myogenic response are widely appreciated as important regulators of renal blood flow, but the role of the sympathetic nervous system in physiological renal blood flow control remains controversial. Where classic studies using static measures of renal blood flow failed, dynamic approaches have succeeded in demonstrating sympathetic control of renal blood flow under normal physiological conditions. This review focuses on transfer function analysis of renal pressure-flow, which leverages the physical relationship between blood pressure and flow to assess the underlying vascular control mechanisms. Studies using this approach indicate that the renal nerves are important in the rapid regulation of the renal vasculature. Animals with intact renal innervation show a sympathetic signature in the frequency range associated with sympathetic vasomotion that is eliminated by renal denervation. In conscious rabbits, this sympathetic signature exerts vasoconstrictive, baroreflex control of renal vascular conductance, matching well with the rhythmic, baroreflex-influenced control of renal sympathetic nerve activity and complementing findings from other studies employing dynamic approaches to study renal sympathetic vascular control. In this light, classic studies reporting that nerve stimulation and renal denervation do not affect static measures of renal blood flow provide evidence for the strength of renal autoregulation rather than evidence against physiological renal sympathetic control of renal blood flow. Thus, alongside tubuloglomerular feedback and the myogenic response, renal sympathetic outflow should be considered an important physiological regulator of renal blood flow. Clinically, renal sympathetic vasomotion may be important for solving the problems facing the field of therapeutic renal denervation. PMID:27514571

Eppur Si Muove: The dynamic nature of physiological control of renal blood flow by the renal sympathetic nerves.

PubMed

Schiller, Alicia M; Pellegrino, Peter Ricci; Zucker, Irving H

2017-05-01

Tubuloglomerular feedback and the myogenic response are widely appreciated as important regulators of renal blood flow, but the role of the sympathetic nervous system in physiological renal blood flow control remains controversial. Where classic studies using static measures of renal blood flow failed, dynamic approaches have succeeded in demonstrating sympathetic control of renal blood flow under normal physiological conditions. This review focuses on transfer function analysis of renal pressure-flow, which leverages the physical relationship between blood pressure and flow to assess the underlying vascular control mechanisms. Studies using this approach indicate that the renal nerves are important in the rapid regulation of the renal vasculature. Animals with intact renal innervation show a sympathetic signature in the frequency range associated with sympathetic vasomotion that is eliminated by renal denervation. In conscious rabbits, this sympathetic signature exerts vasoconstrictive, baroreflex control of renal vascular conductance, matching well with the rhythmic, baroreflex-influenced control of renal sympathetic nerve activity and complementing findings from other studies employing dynamic approaches to study renal sympathetic vascular control. In this light, classic studies reporting that nerve stimulation and renal denervation do not affect static measures of renal blood flow provide evidence for the strength of renal autoregulation rather than evidence against physiological renal sympathetic control of renal blood flow. Thus, alongside tubuloglomerular feedback and the myogenic response, renal sympathetic outflow should be considered an important physiological regulator of renal blood flow. Clinically, renal sympathetic vasomotion may be important for solving the problems facing the field of therapeutic renal denervation. Copyright © 2016 Elsevier B.V. All rights reserved.

Migratory Behavior and Physiological Development as Potential Determinants of Life History Diversity in Fall Chinook Salmon in the Clearwater River

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

Tiffan, Kenneth F.; Kock, Tobias J.; Connor, William P.

We studied the influence of behavior, water velocity, and physiological development on the downstream movement of subyearling fall Chinook Salmon Oncorhynchus tshawytscha in free-flowing and impounded reaches of the Clearwater and Snake rivers as potential mechanisms that might explain life history diversity in this stock. Movement rates and the percentage of radio-tagged fish that moved faster than the average current velocity were highest in the free-flowing Clearwater River compared to impounded reaches. This provided support for our hypothesis that water velocity is a primary determinant of downstream movement regardless of a fish’s physiological development. In contrast, movement rates slowed andmore » detections became fewer in impounded reaches where velocities were much lower. The percentage of fish that moved faster than the average current velocity continued to decline and reached zero in the lower-most reach of Lower Granite Reservoir suggesting that behavioral disposition to move downstream was low. These findings contrast those of a similar, previous study of Snake River subyearlings in spite of hydrodynamic conditions being similar. Physiological differences between Snake and Clearwater river migrants shed light on this disparity. Subyearlings from the Clearwater River were parr-like in their development and never showed an increase in gill Na+/K+-ATPase activity as did smolts from the Snake River. The later emergence timing and cooler rearing temperatures in the Clearwater River may suppress normal physiological development that causes many fish to delay downstream movement and adopt a yearling life history strategy.« less

Sugar for the brain: the role of glucose in physiological and pathological brain function

PubMed Central

Mergenthaler, Philipp; Lindauer, Ute; Dienel, Gerald A.; Meisel, Andreas

2013-01-01

The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We aim at synthesizing these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation which lead to disease. PMID:23968694

Chronic orthostatic and antiorthostatic restraint induce neuroendocrine, immune and neurophysiological disorders in rats

NASA Astrophysics Data System (ADS)

Assenmacher, I.; Mekaouche, M.; Maurel, D.; Barbanel, G.; Givalois, L.; Boissin, J.; Malaval, F.; Ixart, G.

The tail-cast suspension rat model has been developed in ground laboratories interested in space physiology for extensive study of mechanisms causing the pathophysiological syndrome associated with space flights. We used individually-caged male rats to explore the effects of acute and chronic (7d) orthostatic restraint (OR) and head-down anti-orthostatic restraint (AOR) on a series of physiological variables. The acute restraint study showed that (1) the installation of the OR device induced an acute reaction for 2 days, with a substantial rise in ACTH (x2) and CORT (x6), and that (2) the head-down tilt from OR to AOR induced (i) within 10 min and lasting 60 min a 2-fold rise in the intra-cerebro-ventricular pressure (Picv) monitored with an icv telemetric recording system, which receded to normal between 60 and 120 min; and (ii) within 30 min a short-lived 4-fold rise in plasma ACTH and CORT levels. Chronic OR induced (1) the suppression of the diurnal ACTH/CORT rhythm, with increased mean levels, especially for ACTH, (2) a degraded circadian locomotor activity rhythm manifested by a significant reduction in the spectral power of the 24h periodicity and a concomitant emergence of shorter (ultradian) periodicities, (3) an associated, but less pronounced alteration of the diurnal rhythm in body temperature; and (4) a marked increase in baseline plasma levels of IL-1β and an increased reactivity in cytokine release following an E. coli endotoxin (LPS) challenge. AOR induced (1) a similar obliteration of the circadian ACTH/CORT rhythm, (2) the loss of close correlation between ACTH and CORT, (3) a generalized increase in baseline plasma IL-1β levels and (4) more extensive degradation of the arcadian periodicity for both locomotor activity and, to a lesser extent, body temperature, replaced by dominant spectral powers for ultradian periodicities (3 to 10h). In conclusion, both experimental paradigms — but AOR more than OR — caused a blockade of the arcadian rhythmicity of major physiological variables, the loss of normal correlations between ACTH and CORT, and inflammatory-immune hyperreactivity. These pathophysiological disorders may all be parts of a complex chronic stress syndrome.

Altered cardiovascular reactivity and osmoregulation during hyperosmotic stress in adult rats developmentally exposed to polybrominated diphenyl ethers (PBDEs)

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

Shah, Ashini; Coburn, Cary G.; Watson-Siriboe, Abena

2011-10-15

Polybrominated diphenyl ethers (PBDEs) and the structurally similar chemicals polychlorinated biphenyls (PCBs) disrupt the function of multiple endocrine systems. PCBs and PBDEs disrupt the secretion of vasopressin (VP) from the hypothalamus during osmotic activation. Since the peripheral and central vasopressinergic axes are critical for osmotic and cardiovascular regulation, we examined whether perinatal PBDE exposure could impact these functions during physiological activation. Rats were perinatally dosed with a commercial PBDE mixture, DE-71. Dams were given 0 (corn oil control), 1.7 (low dose) or 30.6 mg/kg/day (high dose) in corn oil from gestational day (GD) 6 through postnatal day (PND) 21 bymore » oral gavage. In the male offspring exposed to high dose PBDE plasma thyroxine and triiodothyronine levels were reduced at PND 21 and recovered to control levels by PND 60 when thyroid stimulating hormone levels were elevated. At 14-18 months of age, cardiovascular responses were measured in four groups of rats: Normal (Oil, normosmotic condition), Hyper (Oil, hyperosmotic stress), Hyper PBDE low (1.7 mg/kg/day DE-71 perinatally, hyperosmotic stress), and Hyper PBDE high (30.6 mg/kg/day DE-71 perinatally, hyperosmotic stress). Systolic blood pressure (BP), diastolic BP, and heart rate (HR) were determined using tail cuff sphygmomanometry and normalized to pretreatment values (baseline) measured under basal conditions. Hyperosmotic treatment yielded significant changes in systolic BP in PBDE exposed rats only. Hyper PBDE low and high dose rats showed 36.1 and 64.7% greater systolic BP responses at 3 h post hyperosmotic injection relative to pretreatment baseline, respectively. No treatment effects were measured for diastolic BP and HR. Hyper and Hyper PBDE rats showed increased mean plasma osmolality values by 45 min after injection relative to normosmotic controls. In contrast to Hyper rats, Hyper PBDE (high) rats showed a further increase in mean plasma osmolality at 3 h (358.3 {+-} 12.4 mOsm/L) relative to 45 min post hyperosmotic injection (325.1 {+-} 11.4 mOsm/L). Impaired osmoregulation in PBDE-treated animals could not be attributed to decreased levels of plasma vasopressin. Our findings suggest that developmental exposure to PBDEs may disrupt cardiovascular reactivity and osmoregulatory responses to physiological activation in late adulthood. - Highlights: > We examined whether PBDE exposure could impact osmotic and cardiovascular regulation. > Hyperosmotic treatment yielded significant changes in systolic BP in PBDE exposed rats only. > PBDEs may disrupt cardiovascular and osmoregulatory responses to physiological activation.« less

Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration.

PubMed

Morley, Wendy A; Seneff, Stephanie

2014-01-01

The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly reduce the bioavailability of neuro-critical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional. Their diminished capacity triggers physiological and biochemical 'work around' processes that result in undesirable downstream consequences. Exposure to certain environmental chemicals, particularly glyphosate, the active ingredient in the herbicide, Roundup(®), may disrupt the body's innate switching mechanism, which normally turns off the immune response to brain injury once danger has been removed. Deficiencies in serotonin, due to disruption of the shikimate pathway, may lead to impaired melatonin supply, which reduces the resiliency of the brain through reduced antioxidant capacity and alterations in the cerebrospinal fluid, reducing critical protective buffering mechanisms in impact trauma. Depletion of certain rare minerals, overuse of sunscreen and/or overprotection from sun exposure, as well as overindulgence in heavily processed, nutrient deficient foods, further compromise the brain's resilience. Modifications to lifestyle practices, if widely implemented, could significantly reduce this trend of neurological damage.

Physiologic mechanisms of circulatory and body fluid losses in weightlessness identified by mathematical modeling

NASA Technical Reports Server (NTRS)

Simanonok, K. E.; Srinivasan, R. S.; Charles, J. B.

1993-01-01

Central volume expansion due to fluid shifts in weightlessness is believed to activate adaptive reflexes which ultimately result in a reduction of the total circulating blood volume. However, the flight data suggests that a central volume overdistention does not persist, in which case some other factor or factors must be responsible for body fluid losses. We used a computer simulation to test the hypothesis that factors other than central volume overdistention are involved in the loss of blood volume and other body fluid volumes observed in weightlessness and in weightless simulations. Additionally, the simulation was used to identify these factors. The results predict that atrial volumes and pressures return to their prebedrest baseline values within the first day of exposure to head down tilt (HDT) as the blood volume is reduced by an elevated urine formation. They indicate that the mechanisms for large and prolonged body fluid losses in weightlessness is red cell hemoconcentration that elevates blood viscosity and peripheral resistance, thereby lowering capillary pressure. This causes a prolonged alteration of the balance of Starling forces, depressing the extracellular fluid volume until the hematocrit is returned to normal through a reduction of the red cell mass, which also allows some restoration of the plasma volume. We conclude that the red cell mass becomes the physiologic driver for a large 'undershoot' of the body fluid volumes after the normalization of atrial volumes and pressures.

Design-Optimization and Material Selection for a Proximal Radius Fracture-Fixation Implant

NASA Astrophysics Data System (ADS)

Grujicic, M.; Xie, X.; Arakere, G.; Grujicic, A.; Wagner, D. W.; Vallejo, A.

2010-11-01

The problem of optimal size, shape, and placement of a proximal radius-fracture fixation-plate is addressed computationally using a combined finite-element/design-optimization procedure. To expand the set of physiological loading conditions experienced by the implant during normal everyday activities of the patient, beyond those typically covered by the pre-clinical implant-evaluation testing procedures, the case of a wheel-chair push exertion is considered. Toward that end, a musculoskeletal multi-body inverse-dynamics analysis is carried out of a human propelling a wheelchair. The results obtained are used as input to a finite-element structural analysis for evaluation of the maximum stress and fatigue life of the parametrically defined implant design. While optimizing the design of the radius-fracture fixation-plate, realistic functional requirements pertaining to the attainment of the required level of the devise safety factor and longevity/lifecycle were considered. It is argued that the type of analyses employed in the present work should be: (a) used to complement the standard experimental pre-clinical implant-evaluation tests (the tests which normally include a limited number of daily-living physiological loading conditions and which rely on single pass/fail outcomes/decisions with respect to a set of lower-bound implant-performance criteria) and (b) integrated early in the implant design and material/manufacturing-route selection process.

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

Maher, Jonathan; Yamamoto, Masayuki, E-mail: masi@mail.tains.tohoku.ac.j

Organisms have evolved sophisticated and redundant mechanisms to manage oxidative and electrophilic challenges that arise from internal metabolism or xenobiotic challenge for survival. NF-E2-related factor 2 (Nrf2) is a transcription factor that has evolved over millennia from primitive origins, with homologues traceable back to invertebrate Caenorhabditis and Drosophila species. The ancestry of Nrf2 clearly has deep-seated roots in hematopoiesis, yet has diversified into a transcription factor that can mediate a multitude of antioxidant signaling and detoxification genes. In higher organisms, a more sophisticated means of tightly regulating Nrf2 activity was introduced via the cysteine-rich kelch-like ECH-associated protein 1 (Keap1), thusmore » suggesting a need to modulate Nrf2 activity. This is evidenced in Keap1{sup -/-} mice, which succumb to juvenile mortality due to hyperkeratosis of the gastrointestinal tract. Although Nrf2 activation protects against acute toxicity and prevents or attenuates several disease states, constitutive activation in some tumors leads to poor clinical outcomes, suggesting Nrf2 has evolved in response to a multitude of selective pressures. The purpose of this review is to examine the origins of Nrf2, while highlighting the versatility and protective abilities elicited upon activation. Various model systems in which Nrf2 is normally beneficial but in which exaggerated pharmacology exacerbates a physiological or pathological condition will be addressed. Although Darwinian principles have selected Nrf2 activity for maximal beneficial effect based on environmental and oxidative challenge, both sub- or super-physiological effects have been noted to be detrimental. The functions of Nrf2 thus suggest a hormetic factor that has evolved empirically over time.« less

A Circuit for Motor Cortical Modulation of Auditory Cortical Activity

PubMed Central

Nelson, Anders; Schneider, David M.; Takatoh, Jun; Sakurai, Katsuyasu; Wang, Fan

2013-01-01

Normal hearing depends on the ability to distinguish self-generated sounds from other sounds, and this ability is thought to involve neural circuits that convey copies of motor command signals to various levels of the auditory system. Although such interactions at the cortical level are believed to facilitate auditory comprehension during movements and drive auditory hallucinations in pathological states, the synaptic organization and function of circuitry linking the motor and auditory cortices remain unclear. Here we describe experiments in the mouse that characterize circuitry well suited to transmit motor-related signals to the auditory cortex. Using retrograde viral tracing, we established that neurons in superficial and deep layers of the medial agranular motor cortex (M2) project directly to the auditory cortex and that the axons of some of these deep-layer cells also target brainstem motor regions. Using in vitro whole-cell physiology, optogenetics, and pharmacology, we determined that M2 axons make excitatory synapses in the auditory cortex but exert a primarily suppressive effect on auditory cortical neuron activity mediated in part by feedforward inhibition involving parvalbumin-positive interneurons. Using in vivo intracellular physiology, optogenetics, and sound playback, we also found that directly activating M2 axon terminals in the auditory cortex suppresses spontaneous and stimulus-evoked synaptic activity in auditory cortical neurons and that this effect depends on the relative timing of motor cortical activity and auditory stimulation. These experiments delineate the structural and functional properties of a corticocortical circuit that could enable movement-related suppression of auditory cortical activity. PMID:24005287

Scytonemin Plays a Potential Role in Stabilizing the Exopolysaccharidic Matrix in Terrestrial Cyanobacteria.

PubMed

Gao, Xiang

2017-02-01

Cyanobacteria are photosynthetic oxygen-evolving prokaryotes that are distributed in diverse habitats. They synthesize the ultraviolet (UV)-screening pigments, scytonemin (SCY) and mycosporine-like amino acids (MAAs), located in the exopolysaccharide (EPS) matrix. Multiple roles for both pigments have gradually been recognized, such as sunscreen ability, antioxidant activity, and heat dissipation from absorbed UV radiation. In this study, a filamentous terrestrial cyanobacterium Nostoc flagelliforme was used to evaluate the potential stabilizing role of SCY on the EPS matrix. SCY (∼3.7 %) was partially removed from N. flagelliforme filaments by rinsing with 100 % acetone for 5 s. The physiological damage to cells resulting from this treatment, in terms of photosystem II activity parameter Fv/Fm, was repaired after culturing the sample for 40 h. The physiologically recovered sample was further desiccated by natural or rapid drying and then allowed to recovery for 24 h. Compared with the normal sample, a relatively slower Fv/Fm recovery was observed in the SCY-partially removed sample, suggesting that the decreased SCY concentration in the EPS matrix caused cells to suffer further damage upon desiccation. In addition, the SCY-partially removed sample could allow the release of MAAs (∼25 %) from the EPS matrix, while the normal sample did not. Therefore, damage caused by drying of the former resulted from at least the reduction of structural stability of the EPS matrix as well as the loss of partial antioxidant compounds. Considering that an approximately 4 % loss of SCY led to this significant effect, the structurally stabilizing potential of SCY on the EPS matrix is crucial for terrestrial cyanobacteria survival in complex environments.

Time courses of changes of para-, meta-, and ortho-tyrosine in septic patients: A pilot study.

PubMed

Szélig, Lívia; Kun, Szilárd; Woth, Gábor; Molnár, Gergő A; Zrínyi, Zita; Kátai, Emese; Lantos, János; Wittmann, István; Bogár, Lajos; Miseta, Attila; Csontos, Csaba

2016-07-01

Sepsis is associated with oxidative stress. Due to oxidative stress, three tyrosine isoforms, para-, meta-, and ortho-tyrosine (p-, m-, and o-Tyr), can be formed non-enzymatically in smaller amounts. p-Tyr is mainly formed physiologically in the kidneys through the activity of the phenylalanine hydroxylase enzyme. The three tyrosine isoforms may undergo different renal handling. Twenty septic patients were involved in the study and 25 healthy individuals served as controls. Blood and urine levels of p-, m-, and o-Tyr were measured on admission and four consecutive days. Serum m-Tyr levels were higher in septic patients than in controls on days 2 (P = 0.031) and 3 (P = 0.035). Serum p-Tyr levels were lower in the cases than in controls on days 1 (P = 0.005) and 2 (P = 0.040), and subsequently normalized due to a day-by-day elevation (P = 0.002). The tendency of urinary m-Tyr concentration was decreasing (P = 0.041), while that of urinary p-Tyr concentration was increasing (P = 0.001). Fractional excretion of m-Tyr (FEm-Tyr) showed a decreasing tendency (P = 0.009), and was, on all days, higher than FEp-Tyr, which remained near-normal, less than 4%. Procalcitonin showed significant correlation with FEm-Tyr (r = 0.454; P < 0.001). Our data suggest that the oxidative stress marker m-Tyr and physiologic p-Tyr may be handled differently in septic patients. The excretion of m-Tyr correlates with inflammation. m-Tyr may be actively secreted or produced in the kidney in some patients, whereas the decreased serum level of p-Tyr is a consequence of diminished renal production and not of renal loss.

Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release

PubMed Central

Zorov, Dmitry B.; Juhaszova, Magdalena; Sollott, Steven J.

2014-01-01

Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo. PMID:24987008

Use of telomerase to create bioengineered tissues.

PubMed

Shay, Jerry W; Wright, Woodring E

2005-12-01

Telomeres are repetitive DNA (TTAGGG) elements at the ends of chromosomes. Telomerase is a ribonucleoprotein complex that catalyzes the addition of telomeric sequences to the ends of chromosomes. The catalytic protein component of telomerase (hTERT) is expressed only in specific germ line cells, proliferative stem cells of renewal tissues, and cancer cells. The expression of hTERT in normal cells reconstitutes telomerase activity and circumvents the induction of senescence. Telomeres shorten with each cell division, eventually leading to senescence (aging), due to incomplete lagging DNA strand synthesis and end-processing events, and because telomerase activity is not detected in most somatic tissues. There are specific tissues and locations in which replicative senescence likely contributes to the decline in human physiological function with increased age and with chronic illnesses. While expressing hTERT in cells results in the maintenance of telomere length and greatly extended life span, blocking replicative aging systemically would be predicted to increase the potential for tumor formation. However, there are many situations in which the transient rejuvenation of cells could be beneficial. Ectopic expression of hTERT has been shown to immortalize human skin keratinocytes, dermal fibroblasts, muscle satellite (stem), and vascular endothelial, myometrial, retinal-pigmented, and breast epithelial cells. In addition, human bronchial, corneal and skin cells expressing hTERT can be used to form organotypic (3D) cultures (bioengineered tissues) that express differentiation-specific proteins, demonstrating that hTERT by itself does not alter normal physiology. The production of hTERT-engineered tissues offers the possibility of producing tissues to treat a variety of chronic diseases and age-related medical conditions that are due to telomere-based replicative senescence.

A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS.

PubMed

Amodeo, Valeria; A, Deli; Betts, Joanne; Bartesaghi, Stefano; Zhang, Ying; Richard-Londt, Angela; Ellis, Matthew; Roshani, Rozita; Vouri, Mikaella; Galavotti, Sara; Oberndorfer, Sarah; Leite, Ana Paula; Mackay, Alan; Lampada, Aikaterini; Stratford, Eva Wessel; Li, Ningning; Dinsdale, David; Grimwade, David; Jones, Chris; Nicotera, Pierluigi; Michod, David; Brandner, Sebastian; Salomoni, Paolo

2017-07-11

Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Long-term memory deficits in Pavlovian fear conditioning in Ca2+/calmodulin kinase kinase alpha-deficient mice.

PubMed

Blaeser, Frank; Sanders, Matthew J; Truong, Nga; Ko, Shanelle; Wu, Long Jun; Wozniak, David F; Fanselow, Michael S; Zhuo, Min; Chatila, Talal A

2006-12-01

Signaling by the Ca(2+)/calmodulin kinase (CaMK) cascade has been implicated in neuronal gene transcription, synaptic plasticity, and long-term memory consolidation. The CaM kinase kinase alpha (CaMKKalpha) isoform is an upstream component of the CaMK cascade whose function in different behavioral and learning and memory paradigms was analyzed by targeted gene disruption in mice. CaMKKalpha mutants exhibited normal long-term spatial memory formation and cued fear conditioning but showed deficits in context fear during both conditioning and long-term follow-up testing. They also exhibited impaired activation of the downstream kinase CaMKIV/Gr and its substrate, the transcription factor cyclic AMP-responsive element binding protein (CREB) upon fear conditioning. Unlike CaMKIV/Gr-deficient mice, the CaMKKalpha mutants exhibited normal long-term potentiation and normal levels of anxiety-like behavior. These results demonstrate a selective role for CaMKKalpha in contextual fear memory and suggest that different combinations of upstream and downstream components of the CaMK cascade may serve distinct physiological functions.

Obesity-programmed mice are rescued by early genetic intervention

PubMed Central

Bumaschny, Viviana F.; Yamashita, Miho; Casas-Cordero, Rodrigo; Otero-Corchón, Verónica; de Souza, Flávio S.J.; Rubinstein, Marcelo; Low, Malcolm J.

2012-01-01

Obesity is a chronic metabolic disorder affecting half a billion people worldwide. Major difficulties in managing obesity are the cessation of continued weight loss in patients after an initial period of responsiveness and rebound to pretreatment weight. It is conceivable that chronic weight gain unrelated to physiological needs induces an allostatic regulatory state that defends a supranormal adipose mass despite its maladaptive consequences. To challenge this hypothesis, we generated a reversible genetic mouse model of early-onset hyperphagia and severe obesity by selectively blocking the expression of the proopiomelanocortin gene (Pomc) in hypothalamic neurons. Eutopic reactivation of central POMC transmission at different stages of overweight progression normalized or greatly reduced food intake in these obesity-programmed mice. Hypothalamic Pomc rescue also attenuated comorbidities such as hyperglycemia, hyperinsulinemia, and hepatic steatosis and normalized locomotor activity. However, effectiveness of treatment to normalize body weight and adiposity declined progressively as the level of obesity at the time of Pomc induction increased. Thus, our study using a novel reversible monogenic obesity model reveals the critical importance of early intervention for the prevention of subsequent allostatic overload that auto-perpetuates obesity. PMID:23093774

Evidence for a vagal pathophysiology for bulimia nervosa and the accompanying depressive symptoms.

PubMed

Faris, Patricia L; Eckert, Elke D; Kim, Suck-Won; Meller, William H; Pardo, Jose V; Goodale, Robert L; Hartman, Boyd K

2006-05-01

The bilateral vagus nerves (Cranial X) provide both afferent and efferent connections between the viscera and the caudal medulla. The afferent branches increasingly are being recognized as providing significant input to the central nervous system for modulation of complex behaviors. In this paper, we review evidence from our laboratory that increases in vagal afferent activity are involved in perpetuating binge-eating and vomiting in bulimia nervosa. Preliminary findings are also presented which suggest that a subgroup of depressions may have a similar pathophysiology. Two main approaches were used to study the role of vagal afferents. Ondansetron (ONDAN), a 5-HT3 antagonist, was used as a pharmacological tool for inhibiting or reducing vagal afferent neurotransmission. Second, somatic pain detection thresholds were assessed for monitoring a physiological process known to be modulated by vagal afferents, including the gastric branches involved in meal termination and satiety. High levels of vagal activity result in an increase in pain detection thresholds. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Positron Emission Tomography (PET) was used to identify higher cortical brain areas activated by vagal stimulation produced by proximal gastric distention in normal eating subjects. Double-blind treatment of severe bulimia nervosa subjects with ONDAN resulted in a rapid and significant decrease in binge-eating and vomiting compared to placebo controls. The decrease in abnormal eating episodes was accompanied by a return of normal satiety. Pain detection thresholds measured weekly over the course of the treatment protocol were found to dynamically fluctuate in association with bulimic episodes. Thresholds were the most elevated during periods of short-term abstinence from the behaviors, suggesting that not engaging in a binge/vomit episode is accompanied by an increase in vagal activity. ONDAN also resulted in abolition of the fluctuations in pain thresholds. Depressive symptoms in these subjects also were reduced by ONDAN. Like pain thresholds, depressive symptoms varied dynamically with the bulimic behaviors, with BDI scores increasing (more depressed) as more time elapsed since the last bulimic episode. PET studies indicated that mechanical distention of the stomach with a balloon (a non-nutritive stimulus) was associated with the activation of several brain loci, including those associated with vagal activation (parabrachial nucleus), emotive aspects of eating (lateral inferior frontal and orbitofrontal), and depressive symptoms (anterior cingulate). The results of the ONDAN study in bulimia nervosa subjects suggest that cyclic increases in vagal activity drive the urge to binge-eat and vomit. The alterations in vagal firing patterns are possibly a physiological adaptation to the high levels of vagal stimulation initially provided by voluntarily binge-eating and vomiting for weight control. The depressive symptoms that occur in association with the urge to binge-eat are also likely due to the cyclic increase in vagal activity. This suggestion is supported by the reduction of depressive symptoms during ONDAN treatment in bulimia subjects and PET imaging studies in normal eating subjects showing that brain loci classically involved in depression are activated by vagal stimulation administered by mechanical gastric distention. In normal eating individuals, depressions accompanying visceral diseases may also be vagally mediated. Ondansetron and other drugs known to modulate vagal activity may be helpful in treating depressions of this origin.

Vitamin A Metabolism: An Update

PubMed Central

D’Ambrosio, Diana N.; Clugston, Robin D.; Blaner, William S.

2011-01-01

Retinoids are required for maintaining many essential physiological processes in the body, including normal growth and development, normal vision, a healthy immune system, normal reproduction, and healthy skin and barrier functions. In excess of 500 genes are thought to be regulated by retinoic acid. 11-cis-retinal serves as the visual chromophore in vision. The body must acquire retinoid from the diet in order to maintain these essential physiological processes. Retinoid metabolism is complex and involves many different retinoid forms, including retinyl esters, retinol, retinal, retinoic acid and oxidized and conjugated metabolites of both retinol and retinoic acid. In addition, retinoid metabolism involves many carrier proteins and enzymes that are specific to retinoid metabolism, as well as other proteins which may be involved in mediating also triglyceride and/or cholesterol metabolism. This review will focus on recent advances for understanding retinoid metabolism that have taken place in the last ten to fifteen years. PMID:21350678

Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine

PubMed Central

Zylka, Mark J.; Sowa, Nathaniel A.; Taylor-Blake, Bonnie; Twomey, Margaret A.; Herrala, Annakaisa; Voikar, Vootele; Vihko, Pirkko

2008-01-01

SUMMARY Thiamine monophosphatase (TMPase, also known as Fluoride-Resistant Acid Phosphatase) is a classic histochemical marker of small-diameter dorsal root ganglia neurons. The molecular identity of TMPase is currently unknown. We found that TMPase is identical to the transmembrane isoform of Prostatic Acid Phosphatase (PAP), an enzyme with unknown molecular and physiological functions. We then found that PAP knockout mice have normal acute pain sensitivity but enhanced sensitivity in chronic inflammatory and neuropathic pain models. In gain-of-function studies, intraspinal injection of PAP protein has potent anti-nociceptive, anti-hyperalgesic and anti-allodynic effects that last longer than the opioid analgesic morphine. PAP suppresses pain by functioning as an ecto-5’-nucleotidase. Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. Our studies reveal molecular and physiological functions for PAP in purine nucleotide metabolism and nociception and suggest a novel use for PAP in the treatment of chronic pain. PMID:18940592

Hemodynamic, ventilatory, and biochemical responses of panic patients and normal controls with sodium lactate infusion and spontaneous panic attacks.

PubMed

Gaffney, F A; Fenton, B J; Lane, L D; Lake, C R

1988-01-01

Hemodynamic, ventilatory, and biochemical variables were measured in ten healthy adults and ten panic patients during infusion of 0.5 mol/L of sodium lactate. Physical activity, fitness level, and ambulatory electrocardiograms were also recorded. Lactate infusion doubled cardiac output, increased blood lactate levels by sixfold, and produced hypernatremia, hypocalcemia, and decreased serum bicarbonate levels in both groups but raised arterial pressure only in the patients. The patients hyperventilated before and during the infusion. Physiological responses and somatic complaints with the infusion differed little between the groups, but emotional complaints were six times more frequent among the panic patients. Eight patients but no control subjects interpreted their symptoms as a panic attack. Heart rate increased with only 14 of 31 recorded spontaneous outpatient panic attacks. Sodium lactate infusions appear to produce panic by mimicking the physiology of spontaneous panic. Treatment with cardioactive agents is not indicated in the absence of cardiopulmonary or autonomic nervous system abnormalities.

A novel mitochondria-targeted two-photon fluorescent probe for dynamic and reversible detection of the redox cycles between peroxynitrite and glutathione.

PubMed

Sun, Chunlong; Du, Wen; Wang, Peng; Wu, Yang; Wang, Baoqin; Wang, Jun; Xie, Wenjun

2017-12-16

Redox homeostasis is important for maintenance of normal physiological functions within cells. Redox state of cells is primarily a consequence of precise balance between levels of reducing equivalents and reactive oxygen species. Redox homeostasis between peroxynitrite (ONOO - ) and glutathione (GSH) is closely associated with physiological and pathological processes, such as prolonged relaxation in vascular tissues and smooth muscle preparations, attenuation of hepatic necrosis, and activation of matrix metalloproteinase-2. We report a two-photon fluorescent probe (TP-Se) based on water-soluble carbazole-based compound, which integrates with organic selenium, to monitor changes in ONOO - /GSH levels in cells. This probe can reversibly respond to ONOO - and GSH and exhibits high selectivity, sensitivity, and mitochondrial targeting. The probe was successfully applied to visualize changes in redox cycles during ONOO - outbreak and antioxidant GSH repair in cells. The probe will lead to significant development on redox events involved in cellular redox regulation. Copyright © 2017 Elsevier Inc. All rights reserved.

Chaperonin polymers in archaea: The cytoskeleton of prokaryotes?

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

Trent, J.D.; Kagawa, H.K.; Zaluzec, N.J.

Chaperonins are protein complexes that play a critical role in folding nascent polypeptides under normal conditions and refolding damaged proteins under stress conditions. In all organisms these complexes are composed of evolutionarily conserved 60-kDa proteins arranged in double-ring structures with between 7 and 9 protein subunits per ring. These double ring structures are assumed to be the functional units in vivo, although they have never been observed inside cells. Here the authors show that the purified chaperonin from the hyperthermophilic archaeon Sulfolobus shibatae, which is closely related to chaperonins in eukaryotes, has a double ring structure at low concentrations (0.1more » mg/ml), but at more physiological concentrations, the rings stack end to end to form polymers. The polymers are stable at physiological temperatures (75 C) and closely resemble structures observed inside unfixed S. shibatae cells. The authors suggest that in vivo chaperonin activity may be regulated by polymerization and that chaperonin polymers may act as a cytoskeleton-like structure in archaea and bacteria.« less

Biomolecular filters for improved separation of output signals in enzyme logic systems applied to biomedical analysis.

PubMed

Halámek, Jan; Zhou, Jian; Halámková, Lenka; Bocharova, Vera; Privman, Vladimir; Wang, Joseph; Katz, Evgeny

2011-11-15

Biomolecular logic systems processing biochemical input signals and producing "digital" outputs in the form of YES/NO were developed for analysis of physiological conditions characteristic of liver injury, soft tissue injury, and abdominal trauma. Injury biomarkers were used as input signals for activating the logic systems. Their normal physiological concentrations were defined as logic-0 level, while their pathologically elevated concentrations were defined as logic-1 values. Since the input concentrations applied as logic 0 and 1 values were not sufficiently different, the output signals being at low and high values (0, 1 outputs) were separated with a short gap making their discrimination difficult. Coupled enzymatic reactions functioning as a biomolecular signal processing system with a built-in filter property were developed. The filter process involves a partial back-conversion of the optical-output-signal-yielding product, but only at its low concentrations, thus allowing the proper discrimination between 0 and 1 output values.

Mechanisms for Selective Single-Cell Reactivation during Offline Sharp-Wave Ripples and Their Distortion by Fast Ripples.

PubMed

Valero, Manuel; Averkin, Robert G; Fernandez-Lamo, Ivan; Aguilar, Juan; Lopez-Pigozzi, Diego; Brotons-Mas, Jorge R; Cid, Elena; Tamas, Gabor; Menendez de la Prida, Liset

2017-06-21

Memory traces are reactivated selectively during sharp-wave ripples. The mechanisms of selective reactivation, and how degraded reactivation affects memory, are poorly understood. We evaluated hippocampal single-cell activity during physiological and pathological sharp-wave ripples using juxtacellular and intracellular recordings in normal and epileptic rats with different memory abilities. CA1 pyramidal cells participate selectively during physiological events but fired together during epileptic fast ripples. We found that firing selectivity was dominated by an event- and cell-specific synaptic drive, modulated in single cells by changes in the excitatory/inhibitory ratio measured intracellularly. This mechanism collapses during pathological fast ripples to exacerbate and randomize neuronal firing. Acute administration of a use- and cell-type-dependent sodium channel blocker reduced neuronal collapse and randomness and improved recall in epileptic rats. We propose that cell-specific synaptic inputs govern firing selectivity of CA1 pyramidal cells during sharp-wave ripples. Copyright © 2017 Elsevier Inc. All rights reserved.

Ubiquitinated Sirtuin 1 (SIRT1) Function Is Modulated during DNA Damage-induced Cell Death and Survival*

PubMed Central

Peng, Lirong; Yuan, Zhigang; Li, Yixuan; Ling, Hongbo; Izumi, Victoria; Fang, Bin; Fukasawa, Kenji; Koomen, John; Chen, Jiandong; Seto, Edward

2015-01-01

Downstream signaling of physiological and pathological cell responses depends on post-translational modification such as ubiquitination. The mechanisms regulating downstream DNA damage response (DDR) signaling are not completely elucidated. Sirtuin 1 (SIRT1), the founding member of Class III histone deacetylases, regulates multiple steps in DDR and is closely associated with many physiological and pathological processes. However, the role of post-translational modification or ubiquitination of SIRT1 during DDR is unclear. We show that SIRT1 is dynamically and distinctly ubiquitinated in response to DNA damage. SIRT1 was ubiquitinated by the MDM2 E3 ligase in vitro and in vivo. SIRT1 ubiquitination under normal conditions had no effect on its enzymatic activity or rate of degradation; hypo-ubiquitination, however, reduced SIRT1 nuclear localization. Ubiquitination of SIRT1 affected its function in cell death and survival in response to DNA damage. Our results suggest that ubiquitination is required for SIRT1 function during DDR. PMID:25670865

Chaperonin Polymers in Archaea: The Cytoskeleton of Prokaryotes?

DOE R&D Accomplishments Database

Trent, J. D.; Kagawa, H. K.; Zaluzec, N. J.

1997-07-01

Chaperonins are protein complexes that play a critical role in folding nascent polypeptides under normal conditions and refolding damaged proteins under stress conditions. In all organisms these complexes are composed of evolutionarily conserved 60-kDa proteins arranged in double-ring structures with between 7 and 9 protein subunits per ring. These double ring structures are assumed to be the functional units in vivo, although they have never been observed inside cells. Here the authors show that the purified chaperonin from the hyperthermophilic archaeon Sulfolobus shibatae, which is closely related to chaperonins in eukaryotes, has a double ring structure at low concentrations (0.1 mg/ml), but at more physiological concentrations, the rings stack end to end to form polymers. The polymers are stable at physiological temperatures (75 C) and closely resemble structures observed inside unfixed S. shibatae cells. The authors suggest that in vivo chaperonin activity may be regulated by polymerization and that chaperonin polymers may act as a cytoskeleton-like structure in archaea and bacteria.

Voluntary EMG-to-force estimation with a multi-scale physiological muscle model

PubMed Central

2013-01-01

Background EMG-to-force estimation based on muscle models, for voluntary contraction has many applications in human motion analysis. The so-called Hill model is recognized as a standard model for this practical use. However, it is a phenomenological model whereby muscle activation, force-length and force-velocity properties are considered independently. Perreault reported Hill modeling errors were large for different firing frequencies, level of activation and speed of contraction. It may be due to the lack of coupling between activation and force-velocity properties. In this paper, we discuss EMG-force estimation with a multi-scale physiology based model, which has a link to underlying crossbridge dynamics. Differently from the Hill model, the proposed method provides dual dynamics of recruitment and calcium activation. Methods The ankle torque was measured for the plantar flexion along with EMG measurements of the medial gastrocnemius (GAS) and soleus (SOL). In addition to Hill representation of the passive elements, three models of the contractile parts have been compared. Using common EMG signals during isometric contraction in four able-bodied subjects, torque was estimated by the linear Hill model, the nonlinear Hill model and the multi-scale physiological model that refers to Huxley theory. The comparison was made in normalized scale versus the case in maximum voluntary contraction. Results The estimation results obtained with the multi-scale model showed the best performances both in fast-short and slow-long term contraction in randomized tests for all the four subjects. The RMS errors were improved with the nonlinear Hill model compared to linear Hill, however it showed limitations to account for the different speed of contractions. Average error was 16.9% with the linear Hill model, 9.3% with the modified Hill model. In contrast, the error in the multi-scale model was 6.1% while maintaining a uniform estimation performance in both fast and slow contractions schemes. Conclusions We introduced a novel approach that allows EMG-force estimation based on a multi-scale physiology model integrating Hill approach for the passive elements and microscopic cross-bridge representations for the contractile element. The experimental evaluation highlights estimation improvements especially a larger range of contraction conditions with integration of the neural activation frequency property and force-velocity relationship through cross-bridge dynamics consideration. PMID:24007560

Stimulation of the Nonneuronal Cholinergic System by Highly Diluted Acetylcholine in Keratinocytes.

PubMed

Uberti, Francesca; Bardelli, Claudio; Morsanuto, Vera; Ghirlanda, Sabrina; Cochis, Andrea; Molinari, Claudio

2017-01-01

The physiological effects of acetylcholine on keratinocytes depend on the presence of nicotinic and muscarinic receptors. The role of nonneuronal acetylcholine in keratinocytes could have important clinical implications for patients with various skin disorders such as nonhealing wounds. In order to evaluate the efficacy of highly diluted acetylcholine solutions obtained by sequential kinetic activation, we aimed to investigate the effects of these solutions on normal human keratinocytes. Two different concentrations (10 fg/mL and 1 pg/mL) and formulations (kinetically activated and nonkinetically activated) of acetylcholine were used to verify keratinocyte viability, proliferation, and migration and the intracellular pathways involved using MTT, crystal violet, wound healing, and Western blot compared to 147 ng/mL acetylcholine. The activated formulations (1 pg/mL and 10 fg/mL) revealed a significant capacity to increase migration, cell viability, and cell proliferation compared to 147 ng/mL acetylcholine, and these effects were more evident after a single administration. Sequential kinetic activation resulted in a statistically significant decrease in reactive oxygen species production accompanied by an increase in mitochondrial membrane potential and a decrease in oxygen consumption compared to 147 ng/mL acetylcholine. The M1 muscarinic receptor was involved in these effects. Finally, the involvement of ERK/mitogen-activated protein kinases (MAPK) and KI67 confirmed the effectiveness of the single treatment on cell proliferation. The intracellular pathways of calcium were investigated as well. Our results indicate for the first time that highly diluted and kinetically activated acetylcholine seems to play an active role in an in vitro model of wound healing. Moreover, the administration of acetylcholine within the physiological range may not only be effective but is also likely to be safe. © 2016 S. Karger AG, Basel.

The autodigestion hypothesis: Proteolytic receptor cleavage in rheological and cardiovascular cell dysfunction1

PubMed Central

Schmid-Schönbein, Geert W.

2017-01-01

Transformation of circulating leukocytes from a dormant into an activated state with changing rheological properties leads to a major shift of their behavior in the microcirculation. Low levels of pseudopod formation or expression of adhesion molecules facilitate relatively free passage through microvessels while activated leukocytes with pseudopods and enhanced levels of adhesion membrane proteins become trapped in microvessels, attach to the endothelium and migrate into the tissue. The transformation of leukocytes into an activated state is seen in many diseases. While mechanisms for activation due to infections, tissue trauma, as well as non-physiological biochemical or biophysical exposures are well recognized, the mechanisms for activation in many diseases have not been conclusively liked to these traditional mechanisms and remain unknown. We summarize our recent evidence suggesting a major and surprising role of digestive enzymes in the small intestine as root causes for leukocyte activation and microvascular disturbances. During normal digestion of food digestive enzymes are compartmentalized in the lumen of the intestine by the mucosal epithelial barrier. When permeability of this barrier increases, these powerful degrading enzymes leak into the wall of the intestine and into the systemic circulation. Leakage of digestive enzymes occurs for example in physiological shock and multi-organ failure. Entry of digestive enzymes into the wall of the small intestine leads to degradation of the intestinal tissue in an autodigestion process. The digestive enzymes and tissue/food fragments generate not only activate leukocytes but also cause numerous cell dysfunctions. For example, proteolytic destruction of membrane receptors, plasma proteins and other biomolecules occurs. We conclude that escape of digestive enzymes from the intestinal track serves as a major source of cell dysfunction, morbidity and even mortality, including abnormal leukocyte activation seen in rheological studies. PMID:28269737

The glutathione-dependent system of antioxidant defense is not modulated by temperature acclimation in muscle tissues from striped bass, Morone saxatilis.

PubMed

Grim, Jeffrey M; Simonik, Elizabeth A; Semones, Molly C; Kuhn, Donald E; Crockett, Elizabeth L

2013-02-01

Cold temperature generally induces an enhancement of oxidative capacities, a greater content of intracellular lipids, and a remodeling of lipids in biological membranes. These physiological responses may pose a heightened risk of lipid peroxidation (LPO), while warm temperature could result in greater risk of LPO since rates involving reactive oxygen species and LPO will be elevated. The current study examines responses of the glutathione system of antioxidant defense after temperature acclimation. We measured total glutathione (tGSH), and protein levels of GPx1, GPx4, and GST (cardiac and skeletal muscles), and enzymatic activity (skeletal muscle) of glutathione-dependent antioxidants (GPx, GPx4, and GST) in tissues from striped bass (Morone saxatilis) acclimated for six weeks to 7 °C or 25 °C. tGSH of cardiac muscle from cold-acclimated animals was 1.2-times higher than in warm-bodied counterparts, but unchanged with temperature acclimation in skeletal muscle. A second low molecular weight antioxidant, ascorbate was 1.4- and 1.5-times higher in cardiac and skeletal muscle, respectively in warm- than cold-acclimated animals. Despite 1.2-times higher oxidative capacities (as indicated by citrate synthase activity), in skeletal muscle from cold- versus warm-acclimated fish, levels and activities of antioxidant enzymes were similar between acclimation groups. Lipid peroxidation products (as indicated by TBARS), normalized to tissue wet weight, were more than 2-times higher in skeletal muscle from cold- than warm-acclimated animals, however, when normalized to phospholipid content there was no statistical difference between acclimation groups. Our results demonstrate that the physiological changes, associated with acclimation to low temperature in the eurythermal striped bass, are not accompanied by an enhanced antioxidant defense in the glutathione-dependent system. Copyright © 2012 Elsevier Inc. All rights reserved.

Bioactivities in the tamarind seed extracts: A preliminary study

NASA Astrophysics Data System (ADS)

Garg, Sukant; Muangman, Thanchanok; Huifu, He; Ling, Li; Kaul, Sunil C.; Wadhwa, Renu

2018-01-01

Stress is a state that triggers change in normal physiology and recognized by human body and brain as an unfavorable event causing concern, worry or anxiety. It may vary from physical, metabolic, physiological or emotional often culminating into wide range of ailments that may range from common cold, decline in functional efficacy of body systems or even cancer. Skin is the largest tissue of the body and makes the first interface with the environment. Skin color and characteristics are highly influenced by environment stress. A variety of natural compounds have been used for anti-stress and disease preventive potentials in worldwide traditional home medicine systems. They have recently attracted attention in research laboratories to dissect their mode of action to promote safe and economic drug development. We have earlier identified anti-stress and anti-aging activities in Withania somnifera, Helicteres angustifolia and honeybee propolis using human cultured normal and cancer cells. In the present study, we explored the effect of tamarind seed extracts prepared in water or 95% ethanol. In cell-based assays, we found that the extracts were safe to use in viable cells (in the range of 0.01-1.0%, for at least 4 weeks). Consistently, molecular studies revealed no effect on the expression/activity of cancer promoting proteins. We recruited oxidative stress models, such as, hydrogen peroxide (H2O2), ultraviolet radiation (UV) and diacylglycerol 1-oleoyl-2-acetyl-sn-glycerol (OAG). Investigation on anti-stress potential of the extracts revealed that they do not offer remarkable protection against stress caused by either H2O2 or UV, however, significantly compromised OAG-induced melanogenesis. The preliminary data warrant further investigations on the active components and mechanism of action to develop useful natural compounds/extracts for manipulation of melanogenesis that plays important role in response of cells to UV and its consequences including DNA damage, oxidative stress and related diseases.

[Features of cholecalciferol hydroxylation in the liver of rats in conditions of D-hypervitaminosis and activity of alpha-tocopherol].

PubMed

Velykyĭ, M M; Apukhovs'ka, L I; Vasylevs'ka, V M; Lotots'ka, O Iu; Besusiak, A I; Khomenko, A V

2010-01-01

It is shown, that hepatocytes contain two (microsomal and mitochondrial) vitamin D3 25-hydroxylase enzymes, which differ as to their activity and function with maximal activity at different concentrations to substrate, namely at 15 microM and 100 microM of vitamin D3, accordingly. Activity of vitamin D3 25-hydroxylase enzymes of hepatocytes is regulated by cholecalciferol and alpha-tocopherol. The general and microsomal vitamin D3 25-hydroxylase enzymes activity of hepatocytes is lowered, but mitochondrial isoform is increased under D-hypervitaminosis conditions. Vitamin E increases microsomal vitamin D3 25-hydroxylase activity and decreases mitochondrial isoform activity of rats hepatocytes under D-hypervitaminosis conditions. It is established that D-hypervitaminosis is accompanied by expressed hypercalcemia and hyperphosphatemia, by decreased contents of mineral components in the bone tissue and high activity of alkaline phosphatase in the blood serum. The physiological doses of vitamin E under these conditions normalized the mineral metabolism, contents of calcium, phosphates and activity of alkaline phosphatase isoform in the blood serum.

Visualising Androgen Receptor Activity in Male and Female Mice

PubMed Central

Dart, D. Alwyn; Waxman, Jonathan; Aboagye, Eric O.; Bevan, Charlotte L.

2013-01-01

Androgens, required for normal development and fertility of males and females, have vital roles in the reproductive tract, brain, cardiovascular system, smooth muscle and bone. Androgens function via the androgen receptor (AR), a ligand-dependent transcription factor. To assay and localise AR activity in vivo we generated the transgenic “ARE-Luc” mouse, expressing a luciferase reporter gene under the control of activated endogenous AR. In vivo imaging of androgen-mediated luciferase activity revealed several strongly expressing tissues in the male mouse as expected and also in certain female tissues. In males the testes, prostate, seminal vesicles and bone marrow all showed high AR activity. In females, strong activity was seen in the ovaries, uterus, omentum tissue and mammary glands. In both sexes AR expression and activity was also found in salivary glands, the eye (and associated glands), adipose tissue, spleen and, notably, regions of the brain. Luciferase protein expression was found in the same cell layers as androgen receptor expression. Additionally, mouse AR expression and activity correlated well with AR expression in human tissues. The anti-androgen bicalutamide reduced luciferase signal in all tissues. Our model demonstrates that androgens can act in these tissues directly via AR, rather than exclusively via androgen aromatisation to estrogens and activation of the estrogen receptor. Additionally, it visually demonstrates the fundamental importance of AR signalling outside the normal role in the reproductive organs. This model represents an important tool for physiological and developmental analysis of androgen signalling, and for characterization of known and novel androgenic or antiandrogenic compounds. PMID:23940781

Monitoring ATP dynamics in electrically active white matter tracts

PubMed Central

Trevisiol, Andrea; Saab, Aiman S; Winkler, Ulrike; Marx, Grit; Imamura, Hiromi; Möbius, Wiebke; Kusch, Kathrin; Nave, Klaus-Armin; Hirrlinger, Johannes

2017-01-01

In several neurodegenerative diseases and myelin disorders, the degeneration profiles of myelinated axons are compatible with underlying energy deficits. However, it is presently impossible to measure selectively axonal ATP levels in the electrically active nervous system. We combined transgenic expression of an ATP-sensor in neurons of mice with confocal FRET imaging and electrophysiological recordings of acutely isolated optic nerves. This allowed us to monitor dynamic changes and activity-dependent axonal ATP homeostasis at the cellular level and in real time. We find that changes in ATP levels correlate well with compound action potentials. However, this correlation is disrupted when metabolism of lactate is inhibited, suggesting that axonal glycolysis products are not sufficient to maintain mitochondrial energy metabolism of electrically active axons. The combined monitoring of cellular ATP and electrical activity is a novel tool to study neuronal and glial energy metabolism in normal physiology and in models of neurodegenerative disorders. DOI: http://dx.doi.org/10.7554/eLife.24241.001 PMID:28414271

Antioxidant activity of hydrated carboxylated nanodiamonds and its influence on water γ-radiolysis

NASA Astrophysics Data System (ADS)

Santacruz-Gomez, Karla; Sarabia-Sainz, A.; Acosta-Elias, M.; Sarabia-Sainz, M.; Janetanakit, Woraphong; Khosla, Nathan; Melendrez, R.; Pedroza Montero, Martin; Lal, Ratnesh

2018-03-01

Water radiolysis involves chemical decomposition of the water molecule into free radicals after exposure to ionizing radiation. These free radicals have deleterious effects on normal cell physiology. Carboxylated nanodiamonds (cNDs) appear to modulate the deleterious effects of γ-irradiation on the pathophysiology of red blood cells (RBCs). In the present work, the antioxidant activity of hydrated cNDs (h-cNDs) on limiting oxidative damage (the water radiolysis effect) by γ-irradiation was confirmed. Our results show that h-cNDs have remarkable free radical scavenging ability and preserve the enzymatic activity of catalase after γ-irradiation. The underlying mechanism through which nanodiamonds exhibit antioxidant activity appears to depend on their colloidal stability. This property of detonation synthesized nanodiamonds is improved after carboxylation, which in turn influences changes in the hydrogen bond strength in water. The observed stability of h-cNDs in water and their antioxidant activity correlates with their protective effect on RBCs against γ-irradiation.

Phosphorylation of basic helix-loop-helix transcription factor Twist in development and disease.

PubMed

Xue, Gongda; Hemmings, Brian A

2012-02-01

The transcription factor Twist plays vital roles during embryonic development through regulating/controlling cell migration. However, postnatally, in normal physiological settings, Twist is either not expressed or inactivated. Increasing evidence shows a strong correlation between Twist reactivation and both cancer progression and malignancy, where the transcriptional activities of Twist support cancer cells to disseminate from primary tumours and subsequently establish a secondary tumour growth in distant organs. However, it is largely unclear how this signalling programme is reactivated or what signalling pathways regulate its activity. The present review discusses recent advances in Twist regulation and activity, with a focus on phosphorylation-dependent Twist activity, potential upstream kinases and the contribution of these factors in transducing biological signals from upstream signalling complexes. The recent advances in these areas have shed new light on how phosphorylation-dependent regulation of the Twist proteins promotes or suppresses Twist activity, leading to differential regulation of Twist transcriptional targets and thereby influencing cell fate.

Neuronal regulation of homeostasis by nutrient sensing.

PubMed

Lam, Tony K T

2010-04-01

In type 2 diabetes and obesity, the homeostatic control of glucose and energy balance is impaired, leading to hyperglycemia and hyperphagia. Recent studies indicate that nutrient-sensing mechanisms in the body activate negative-feedback systems to regulate energy and glucose homeostasis through a neuronal network. Direct metabolic signaling within the intestine activates gut-brain and gut-brain-liver axes to regulate energy and glucose homeostasis, respectively. In parallel, direct metabolism of nutrients within the hypothalamus regulates food intake and blood glucose levels. These findings highlight the importance of the central nervous system in mediating the ability of nutrient sensing to maintain homeostasis. Futhermore, they provide a physiological and neuronal framework by which enhancing or restoring nutrient sensing in the intestine and the brain could normalize energy and glucose homeostasis in diabetes and obesity.

A time dependent anatomically detailed model of cardiac conduction

NASA Technical Reports Server (NTRS)

Saxberg, B. E.; Grumbach, M. P.; Cohen, R. J.

1985-01-01

In order to understand the determinants of transitions in cardiac electrical activity from normal patterns to dysrhythmias such as ventricular fibrillation, we are constructing an anatomically and physiologically detailed finite element simulation of myocardial electrical propagation. A healthy human heart embedded in paraffin was sectioned to provide a detailed anatomical substrate for model calculations. The simulation of propagation includes anisotropy in conduction velocity due to fiber orientation as well as gradients in conduction velocities, absolute and relative refractory periods, action potential duration and electrotonic influence of nearest neighbors. The model also includes changes in the behaviour of myocardial tissue as a function of the past local activity. With this model, we can examine the significance of fiber orientation and time dependence of local propagation parameters on dysrhythmogenesis.

Neural control of renal function in health and disease.

PubMed

DiBona, G F

1994-04-01

The renal sympathetic innervation of the kidney exerts significant effects on multiple aspects of renal function, including renal haemodynamics, tubular sodium and water reabsorption and renin secretion. These effects constitute an important control system which is important in the physiological regulation of arterial pressure and total body fluid and sodium homeostasis. Abnormalities in this regulatory mechanism have pathophysiological consequences and are manifest in clinically relevant human disease states. Decreased renal sympathetic nerve activity results in impaired renin secretion, the inability to conserve sodium normally and an attenuated ability to dispose of both acute and chronic sodium loads. Increased renal sympathetic nerve activity contributes significantly to the excess renal sodium retention and related renal abnormalities observed in both hypertension and oedema forming conditions, such as cardiac failure, cirrhosis and nephrotic syndrome.