Dioxins and Cardiovascular Mortality: A Review (EHP)

EPA Science Inventory

In spite of its large public health burden, the risk factors for cardiovascular disease remain incompletely understood. Here we review the association of cardiovascular disease (CVD) mortality with exposure to dioxin, a pollutant resulting from the production and combustion of ch...

Matrix Gla Protein polymorphism, but not concentrations, is associated with radiographic hand osteoarthritis

USDA-ARS?s Scientific Manuscript database

Objective. Factors associated with mineralization and osteophyte formation in osteoarthritis (OA) are incompletely understood. Genetic polymorphisms of matrix Gla protein (MGP), a mineralization inhibitor, have been associated clinically with conditions of abnormal calcification. We therefore evalua...

Programming of Essential Hypertension: What Pediatric Cardiologists Need to Know.

PubMed

Morgado, Joana; Sanches, Bruno; Anjos, Rui; Coelho, Constança

2015-10-01

Hypertension is recognized as one of the major contributing factors to cardiovascular disease, but its etiology remains incompletely understood. Known genetic and environmental influences can only explain a small part of the variability in cardiovascular disease risk. The missing heritability is currently one of the most important challenges in blood pressure and hypertension genetics. Recently, some promising approaches have emerged that move beyond the DNA sequence and focus on identification of blood pressure genes regulated by epigenetic mechanisms such as DNA methylation, histone modification and microRNAs. This review summarizes information on gene-environmental interactions that lead toward the developmental programming of hypertension with specific reference to epigenetics and provides pediatricians and pediatric cardiologists with a more complete understanding of its pathogenesis.

Interleukin-22 Signaling in the Regulation of Intestinal Health and Disease

PubMed Central

Parks, Olivia B.; Pociask, Derek A.; Hodzic, Zerina; Kolls, Jay K.; Good, Misty

2016-01-01

Interleukin (IL)-22 is a member of the IL-10 family of cytokines that has been extensively studied since its discovery in 2000. This review article aims to describe the cellular sources and signaling pathways of this cytokine as well as the functions of IL-22 in the intestine. In addition, this article describes the roles of IL-22 in the pathogenesis of several gastrointestinal diseases, including inhibition of inflammation and barrier defense against pathogens within the intestine. Since many of the functions of IL-22 in the intestine are incompletely understood, this review is meant to assess our current understanding of the roles of IL-22 and provide new opportunities for inquiry to improve human intestinal health and disease. PMID:26793707

Precursors of hexoneogenesis within the human mammary gland

USDA-ARS?s Scientific Manuscript database

The human mammary gland is capable of de novo synthesis of glucose and galactose (hexoneogenesis); however, the carbon source is incompletely understood. In this study, we investigated the role of acetate, glutamine, lactate and glycerol as potential carbon sources for hexoneogenesis. Healthy breast...

Sequestration of mitochondrial iron by silica particles initiates a biological effect.

EPA Science Inventory

Summary Inhalation of particulate matter has presented a challenge to human health for thousands of years. The underlying mechanism for biological effect following particle exposure is incompletely understood. We tested the postulate that particle sequestration of cell and mit...

SUPEROXIDE-DEPENDENT IRON UPTAKE: A NEW ROLE FOR ANION EXCHANGE PROTEIN 2

EPA Science Inventory

Lung cells import iron across the plasma membrane as ferrous (Fe2+) ion by incompletely understood mechanisms. We tested the hypothesis that human bronchial epithelial (HBE) cells import non-transferrin-bound iron (NTBI) using superoxide-dependent ferri-reductase activity involvi...

The Arabidopsis sickle mutant exhibits altered circadian clock responses to cool tempatures and tempature-dependent alternative splicing

USDA-ARS?s Scientific Manuscript database

The circadian clock allows plants to anticipate and respond to daily changes in ambient temperature. Mechanisms establishing the timing of circadian rhythms in Arabidopsis thaliana through temperature entrainment remain unclear. Also incompletely understood is the temperature compensation mechanism ...

Case of Primary Central Nervous System Lymphoma Arising at Site of Remote Herpes Encephalitis.

PubMed

Li, Victor; Levine, Adrian B; Gooderham, Peter A; Yip, Stephen; Chew, Jason

2018-05-01

Primary central nervous system lymphoma (PCNSL) is a rare malignancy that usually arises in the context of severe immunosuppression but has incompletely understood etiology, limiting effective treatments. We present the case of an 81-year-old immunocompetent man who developed a PCNSL in the right temporal lobe, at the site of a remote episode of herpes simplex virus (HSV) encephalitis 8 years prior. There are numerous viruses with known oncogenic associations; however, to our knowledge, this is the first reported case of PCNSL with an antecedent HSV infection. We discuss this case in the context of our current understandings of the pathogenesis of HSV encephalitis and PCNSL and postulate mechanisms through which the 2 could be associated. Copyright © 2018 Elsevier Inc. All rights reserved.

Bacterial vaginosis and preterm birth.

PubMed

Manns-James, Laura

2011-01-01

Although it has been clear for more than 2 decades that bacterial vaginosis increases the risk for preterm birth in some women, it is not yet fully understood why this association exists or how best to modify the risk. Incomplete understanding of this polymicrobial condition and difficulties in classification contribute to the challenge. The relationship between altered vaginal microflora and preterm birth is likely mediated by host immune responses. Because treatment of bacterial vaginosis during pregnancy does not improve preterm birth rates, and may in fact increase them, screening and treatment of asymptomatic pregnant women is discouraged. Symptomatic women should be treated for symptom relief. This article reviews the pathophysiology of bacterial vaginosis and controversy surrounding management during pregnancy. Agents currently recommended for treatment of this condition are reviewed. © 2011 by the American College of Nurse-Midwives.

OGLE-2012-BLG-0455/MOA-2012-BLG-206: Microlensing Event with Ambiguity in Planetary Interpretations Caused by Incomplete Coverage of Planetary Signal

NASA Astrophysics Data System (ADS)

Park, H.; Han, C.; Gould, A.; Udalski, A.; Sumi, T.; Fouqué, P.; Choi, J.-Y.; Christie, G.; Depoy, D. L.; Dong, Subo; Gaudi, B. S.; Hwang, K.-H.; Jung, Y. K.; Kavka, A.; Lee, C.-U.; Monard, L. A. G.; Natusch, T.; Ngan, H.; Pogge, R. W.; Shin, I.-G.; Yee, J. C.; μFUN Collaboration; Szymański, M. K.; Kubiak, M.; Soszyński, I.; Pietrzyński, G.; Poleski, R.; Ulaczyk, K.; Pietrukowicz, P.; Kozłowski, S.; Skowron, J.; Wyrzykowski, Ł.; OGLE Collaboration; Abe, F.; Bennett, D. P.; Bond, I. A.; Botzler, C. S.; Chote, P.; Freeman, M.; Fukui, A.; Fukunaga, D.; Harris, P.; Itow, Y.; Koshimoto, N.; Ling, C. H.; Masuda, K.; Matsubara, Y.; Muraki, Y.; Namba, S.; Ohnishi, K.; Rattenbury, N. J.; Saito, To.; Sullivan, D. J.; Sweatman, W. L.; Suzuki, D.; Tristram, P. J.; Wada, K.; Yamai, N.; Yock, P. C. M.; Yonehara, A.; MOA Collaboration

2014-05-01

Characterizing a microlensing planet is done by modeling an observed lensing light curve. In this process, it is often confronted that solutions of different lensing parameters result in similar light curves, causing difficulties in uniquely interpreting the lens system, and thus understanding the causes of different types of degeneracy is important. In this work, we show that incomplete coverage of a planetary perturbation can result in degenerate solutions even for events where the planetary signal is detected with a high level of statistical significance. We demonstrate the degeneracy for an actually observed event OGLE-2012-BLG-0455/MOA-2012-BLG-206. The peak of this high-magnification event (A max ~ 400) exhibits very strong deviation from a point-lens model with Δχ2 >~ 4000 for data sets with a total of 6963 measurements. From detailed modeling of the light curve, we find that the deviation can be explained by four distinct solutions, i.e., two very different sets of solutions, each with a twofold degeneracy. While the twofold (so-called close/wide) degeneracy is well understood, the degeneracy between the radically different solutions is not previously known. The model light curves of this degeneracy differ substantially in the parts that were not covered by observation, indicating that the degeneracy is caused by the incomplete coverage of the perturbation. It is expected that the frequency of the degeneracy introduced in this work will be greatly reduced with the improvement of the current lensing survey and follow-up experiments and the advent of new surveys.

Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management

PubMed Central

Chaudhury, Arun; Duvoor, Chitharanjan; Reddy Dendi, Vijaya Sena; Kraleti, Shashank; Chada, Aditya; Ravilla, Rahul; Marco, Asween; Shekhawat, Nawal Singh; Montales, Maria Theresa; Kuriakose, Kevin; Sasapu, Appalanaidu; Beebe, Alexandria; Patil, Naveen; Musham, Chaitanya K.; Lohani, Govinda Prasad; Mirza, Wasique

2017-01-01

Type 2 diabetes mellitus (T2DM) is a global pandemic, as evident from the global cartographic picture of diabetes by the International Diabetes Federation (http://www.diabetesatlas.org/). Diabetes mellitus is a chronic, progressive, incompletely understood metabolic condition chiefly characterized by hyperglycemia. Impaired insulin secretion, resistance to tissue actions of insulin, or a combination of both are thought to be the commonest reasons contributing to the pathophysiology of T2DM, a spectrum of disease originally arising from tissue insulin resistance and gradually progressing to a state characterized by complete loss of secretory activity of the beta cells of the pancreas. T2DM is a major contributor to the very large rise in the rate of non-communicable diseases affecting developed as well as developing nations. In this mini review, we endeavor to outline the current management principles, including the spectrum of medications that are currently used for pharmacologic management, for lowering the elevated blood glucose in T2DM. PMID:28167928

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

PubMed Central

Mora, Ana L.; Rojas, Mauricio; Pardo, Annie; Selman, Moises

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches. PMID:29081515

Scleroderma: nomenclature, etiology, pathogenesis, prognosis, and treatments: facts and controversies.

PubMed

Fett, Nicole

2013-01-01

Scleroderma refers to a heterogeneous group of autoimmune fibrosing disorders. The nomenclature of scleroderma has changed dramatically in recent years, with morphea (localized scleroderma), limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis sine scleroderma encompassing the currently accepted disease subtypes. Major advances have been made in the molecular studies of morphea and systemic sclerosis; however, their etiologies and pathogenesis remain incompletely understood. Although morphea and systemic sclerosis demonstrate activation of similar inflammatory and fibrotic pathways, important differences in signaling pathways and gene signatures indicate they are likely biologically distinct processes. Morphea can cause significant morbidity but does not affect mortality, whereas systemic sclerosis has the highest disease-specific mortality of all autoimmune connective tissue diseases. Treatment recommendations for morphea and systemic sclerosis are based on limited data and largely expert opinions. Current collaborative efforts in morphea and systemic sclerosis research will hopefully lead to better understanding of the etiology and pathogenesis of these rare and varied diseases and improved treatment options. Published by Elsevier Inc.

An overview of structure, mechanical properties, and treatment for age-related tendinopathy.

PubMed

Zhou, B; Zhou, Y; Tang, K

2014-04-01

Tendons transfer tensile loads from muscle to bone, which enable joint motions and stabilize joints. Tendons sustain large mechanical loads in vivo and as a result, tendons were frequently injured. Aging has been confirmed as a predisposing factor of tendinopathy and bad recovery quality following tendon repair. Current treatment methods are generally not effective and involve either symptomatic relief with non-steroidal antiinflammatory drugs and physical therapy or surgery when conservative treatments failed. The limitation in treatment options is due to our incomplete knowledge of age-related tendinopathy. Studies over the past decades have uncovered a number of important mechanical and cellular changes of aging tendon. However, the basis of aging as a major risk factor for tendon injury and impaired tendon healing remained poorly understood. The objectives of this review are to provide an overview of the current knowledge about the aging-associated changes of structure, mechanical properties and treatment in tendon and highlight causes and therapies for age-related tendinopathy.

The Effect of Cleft Lip on Socio-Emotional Functioning in School-Aged Children

ERIC Educational Resources Information Center

Murray, Lynne; Arteche, Adriane; Bingley, Caroline; Hentges, Francoise; Bishop, Dorothy V. M.; Dalton, Louise; Goodacre, Tim; Hill, Jonathan

2010-01-01

Background: Children with cleft lip are known to be at raised risk for socio-emotional difficulties, but the nature of these problems and their causes are incompletely understood; longitudinal studies are required that include comprehensive assessment of child functioning, and consideration of developmental mechanisms. Method: Children with cleft…

Chapter 13: Recent Advances on the Genomics of Litter- and Soil-Inhabiting Agaricomycetes

Treesearch

Phil Kersten; Dan Cullen

2013-01-01

Woody biomass makes up the major portion of terrestrial carbon, and forest ecosystems contain enormous reservoirs of lignocellulose belowground, in dead trees, and litter. Decomposition of this recalcitrant material and mobilization of nutrients are essential for forest health [reviewed by Boddy and Watkinson (1995)]. Although mechanisms are incompletely understood,...

The Class I HDAC Inhibitor RGFP963 Enhances Consolidation of Cued Fear Extinction

ERIC Educational Resources Information Center

Bowers, Mallory E.; Xia, Bing; Carreiro, Samantha; Ressler, Kerry J.

2015-01-01

Evidence indicates that broad, nonspecific histone deacetylase (HDAC) inhibition enhances learning and memory, however, the contribution of the various HDACs to specific forms of learning is incompletely understood. Here, we show that the Class I HDAC inhibitor, RGFP963, enhances consolidation of cued fear extinction. However, RGFP966, a strong…

The role of reduced oxygen in the developmental physiology of growth and metamorphosis initiation in Drosophila

USDA-ARS?s Scientific Manuscript database

Rearing oxygen level is known to affect final body size in a variety of insects, but the physiological mechanisms by which oxygen affects size are incompletely understood. In Manduca and Drosophila, the larval size at which metamorphosis is initiated largely determines adult size, and metamorphosis ...

Dynamic variation in sapwood specific conductivity in six woody species.

Treesearch

J.C. Domec; F.C. Meinzer; B.L. Gartner; J. Housset

2007-01-01

Relationships between pressure gradients and flow rates in the xylem are incompletely understood because steady-state conductivity coefficients are inadequate for predicting and interpreting flow under the non-steady-state conditions more prevalent in intact trees. The goal of this study was to determine the magnitude of deviation of trunk sapwood specific conductivity...

Dopamine modulates hemocyte phagocytosis via a D1-like receptor in the rice stem borer, Chilo suppressalis

USDA-ARS?s Scientific Manuscript database

Dopamine (DA) is a signal moiety bridging the nervous and immune systems. DA dysregulation is linked to serious human diseases, including addiction, schizophrenia, and Parkinson's disease. However, DA actions in the immune system remain incompletely understood. In this study, we found that DA modula...

Internal Structure of Mini-CEX Scores for Internal Medicine Residents: Factor Analysis and Generalizability

ERIC Educational Resources Information Center

Cook, David A.; Beckman, Thomas J.; Mandrekar, Jayawant N.; Pankratz, V. Shane

2010-01-01

The mini-CEX is widely used to rate directly observed resident-patient encounters. Although several studies have explored the reliability of mini-CEX scores, the dimensionality of mini-CEX scores is incompletely understood. Objective: Explore the dimensionality of mini-CEX scores through factor analysis and generalizability analysis. Design:…

Enhanced mammary progesterone receptor-A isoform activity in the promotion of mammary tumor progression by dietary soy in rats

USDA-ARS?s Scientific Manuscript database

Dietary contribution to breast cancer risk, recurrence, and progression remains incompletely understood. Increased consumption of soy and soy isoflavones is associated with reduced mammary cancer susceptibility in women and in rodent models of carcinogenesis. In rats treated with N-Methyl-N-Nitrosou...

Treatment of Intravenous Leiomyomatosis with Cardiac Extension following Incomplete Resection.

PubMed

Doyle, Mathew P; Li, Annette; Villanueva, Claudia I; Peeceeyen, Sheen C S; Cooper, Michael G; Hanel, Kevin C; Fermanis, Gary G; Robertson, Greg

2015-01-01

Aim. Intravenous leiomyomatosis (IVL) with cardiac extension (CE) is a rare variant of benign uterine leiomyoma. Incomplete resection has a recurrence rate of over 30%. Different hormonal treatments have been described following incomplete resection; however no standard therapy currently exists. We review the literature for medical treatments options following incomplete resection of IVL with CE. Methods. Electronic databases were searched for all studies reporting IVL with CE. These studies were then searched for reports of patients with inoperable or incomplete resection and any further medical treatments. Our database was searched for patients with medical therapy following incomplete resection of IVL with CE and their results were included. Results. All studies were either case reports or case series. Five literature reviews confirm that surgery is the only treatment to achieve cure. The uses of progesterone, estrogen modulation, gonadotropin-releasing hormone antagonism, and aromatase inhibition have been described following incomplete resection. Currently no studies have reviewed the outcomes of these treatments. Conclusions. Complete surgical resection is the only means of cure for IVL with CE, while multiple hormonal therapies have been used with varying results following incomplete resection. Aromatase inhibitors are the only reported treatment to prevent tumor progression or recurrence in patients with incompletely resected IVL with CE.

Treatment of Intravenous Leiomyomatosis with Cardiac Extension following Incomplete Resection

PubMed Central

Doyle, Mathew P.; Li, Annette; Villanueva, Claudia I.; Peeceeyen, Sheen C. S.; Cooper, Michael G.; Hanel, Kevin C.; Fermanis, Gary G.; Robertson, Greg

2015-01-01

Aim. Intravenous leiomyomatosis (IVL) with cardiac extension (CE) is a rare variant of benign uterine leiomyoma. Incomplete resection has a recurrence rate of over 30%. Different hormonal treatments have been described following incomplete resection; however no standard therapy currently exists. We review the literature for medical treatments options following incomplete resection of IVL with CE. Methods. Electronic databases were searched for all studies reporting IVL with CE. These studies were then searched for reports of patients with inoperable or incomplete resection and any further medical treatments. Our database was searched for patients with medical therapy following incomplete resection of IVL with CE and their results were included. Results. All studies were either case reports or case series. Five literature reviews confirm that surgery is the only treatment to achieve cure. The uses of progesterone, estrogen modulation, gonadotropin-releasing hormone antagonism, and aromatase inhibition have been described following incomplete resection. Currently no studies have reviewed the outcomes of these treatments. Conclusions. Complete surgical resection is the only means of cure for IVL with CE, while multiple hormonal therapies have been used with varying results following incomplete resection. Aromatase inhibitors are the only reported treatment to prevent tumor progression or recurrence in patients with incompletely resected IVL with CE. PMID:26783463

Proviral Latency, Persistent Human Immunodeficiency Virus Infection, and the Development of Latency Reversing Agents

PubMed Central

Archin, Nancie M.

2017-01-01

Abstract Quiescent proviral genomes that persist during human immunodeficiency virus type 1 (HIV-1) infection despite effective antiretroviral therapy (ART) can fuel rebound viremia after ART interruption and is a central obstacle to the cure of HIV infection. The induction of quiescent provirus is the goal of a new class of potential therapeutics, latency reversing agents (LRAs). The discovery, development, and testing of HIV LRAs is a key part of current efforts to develop latency reversal and viral clearance strategies to eradicate established HIV infection. The development of LRAs is burdened by many uncertainties that make drug discovery difficult. The biology of HIV latency is complex and incompletely understood. Potential targets for LRAs are host factors, and the potential toxicities of host-directed therapies in individuals that are otherwise clinically stable may be unacceptable. Assays to measure latency reversal and assess the effectiveness of potential therapeutics are complex and incompletely validated. Despite these obstacles, novel LRAs are under development and beginning to enter combination testing with viral clearance strategies. It is hoped that the steady advances in the development of LRAs now being paired with emerging immunotherapeutics to clear persistently infected cells will soon allow measurable clinical advances toward an HIV cure. PMID:28520964

Inflammation: A novel target of current therapies for hepatic encephalopathy in liver cirrhosis.

PubMed

Luo, Ming; Guo, Jian-Yang; Cao, Wu-Kui

2015-11-07

Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome that most commonly occurs in decompensated liver cirrhosis and incorporates a spectrum of manifestations that ranges from mild cognitive impairment to coma. Although the etiology of HE is not completely understood, it is believed that multiple underlying mechanisms are involved in the pathogenesis of HE, and one of the main factors is thought to be ammonia; however, the ammonia hypothesis in the pathogenesis of HE is incomplete. Recently, it has been increasingly demonstrated that inflammation, including systemic inflammation, neuroinflammation and endotoxemia, acts in concert with ammonia in the pathogenesis of HE in cirrhotic patients. Meanwhile, a good number of studies have found that current therapies for HE, such as lactulose, rifaximin, probiotics and the molecular adsorbent recirculating system, could inhibit different types of inflammation, thereby improving the neuropsychiatric manifestations and preventing the progression of HE in cirrhotic patients. The anti-inflammatory effects of these current therapies provide a novel therapeutic approach for cirrhotic patients with HE. The purpose of this review is to describe the inflammatory mechanisms behind the etiology of HE in cirrhosis and discuss the current therapies that target the inflammatory pathogenesis of HE.

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

Schreck, S.; Sant, T.; Micallef, D.

Wind turbine structures and components suffer excessive loads and premature failures when key aerodynamic phenomena are not well characterized, fail to be understood, or are inaccurately predicted. Turbine blade rotational augmentation remains incompletely characterized and understood, thus limiting robust prediction for design. Pertinent rotational augmentation research including experimental, theoretical, and computational work has been pursued for some time, but large scale wind tunnel testing is a relatively recent development for investigating wind turbine blade aerodynamics. Because of their large scale and complementary nature, the MEXICO and UAE Phase VI wind tunnel experiments offer unprecedented synergies to better characterize and understandmore » rotational augmentation of blade aerodynamics.« less

Steps in Prostate Cancer Progression that lead to Bone Metastasis

PubMed Central

Jin, Jung-Kang; Dayyani, Farshid; Gallick, Gary E.

2011-01-01

Prostate cancer is a complex disease in which metastasis to the bone is the main cause of death. Initial stages of metastasis are generally similar to those for most solid tumors; however, the mechanisms that underlie the homing of prostate tumor cells to the bone remain incompletely understood. Prostate cancer bone metastasis is also a microenvironment-driven disease, involving bi-directional interactions between the tumor and the bone microenvironment. In this review, we discuss the current understanding of the biologic processes and regulatory factors involved in the metastasis of prostate cancer cells, and their specific properties that promote growth in bone. Although many of these processes still need to be fully elucidated, a better understanding of the complex tumor/microenvironment interplay is slowly leading to more effective therapies for patients with prostate cancer bone metastases. PMID:21365645

DNA curvature and flexibility in vitro and in vivo

PubMed Central

Peters, Justin P.; Maher, L. James

2014-01-01

It has been more than 50 years since the elucidation of the structure of double-helical DNA. Despite active research and progress in DNA biology and biochemistry, much remains to be learned in the field of DNA biophysics. Predicting the sequence-dependent curvature and flexibility of DNA is difficult. Applicability of the conventional worm-like chain polymer model of DNA has been challenged. The fundamental forces responsible for the remarkable resistance of DNA to bending and twisting remain controversial. The apparent “softening” of DNA measured in vivo in the presence of kinking proteins and superhelical strain is incompletely understood. New methods and insights are being applied to these problems. This review places current work on DNA biophysics in historical context and illustrates the ongoing interplay between theory and experiment in this exciting field. PMID:20478077

Visualizing uncertainty about the future.

PubMed

Spiegelhalter, David; Pearson, Mike; Short, Ian

2011-09-09

We are all faced with uncertainty about the future, but we can get the measure of some uncertainties in terms of probabilities. Probabilities are notoriously difficult to communicate effectively to lay audiences, and in this review we examine current practice for communicating uncertainties visually, using examples drawn from sport, weather, climate, health, economics, and politics. Despite the burgeoning interest in infographics, there is limited experimental evidence on how different types of visualizations are processed and understood, although the effectiveness of some graphics clearly depends on the relative numeracy of an audience. Fortunately, it is increasingly easy to present data in the form of interactive visualizations and in multiple types of representation that can be adjusted to user needs and capabilities. Nonetheless, communicating deeper uncertainties resulting from incomplete or disputed knowledge--or from essential indeterminacy about the future--remains a challenge.

Characterization of apple replant disease-associated microbial communities over multiple growth periods using next-generation sequencing

USDA-ARS?s Scientific Manuscript database

Replant disease in apple occurs as a result of incompletely understood and variable complexes of soil-borne pathogens that can build up over time in orchard soil. This disease limits economic viability of newly established orchards on replant sites and results in reduced productivity for the life of...

Social and Non-Social Cueing of Visuospatial Attention in Autism and Typical Development

ERIC Educational Resources Information Center

Pruett, John R.; LaMacchia, Angela; Hoertel, Sarah; Squire, Emma; McVey, Kelly; Todd, Richard D.; Constantino, John N.; Petersen, Steven E.

2011-01-01

Three experiments explored attention to eye gaze, which is incompletely understood in typical development and is hypothesized to be disrupted in autism. Experiment 1 (n = 26 typical adults) involved covert orienting to box, arrow, and gaze cues at two probabilities and cue-target times to test whether reorienting for gaze is endogenous, exogenous,…

Such Stuff as Habits Are Made on: A Reply to Cooper and Shallice (2006)

ERIC Educational Resources Information Center

Botvinick, Matthew M.; Plaut, David C.

2006-01-01

The representations and mechanisms guiding everyday routine sequential action remain incompletely understood. In recent work, the authors proposed a computational model of routine sequential behavior that took the form of a recurrent neural network (M. Botvinick & D. C. Plaut, 2004). Subsequently, R. P. Cooper and T. Shallice (2006) put forth a…

The Origins of Mass

ScienceCinema

Lincoln, Don

2018-01-16

The Higgs boson was discovered in July of 2012 and is generally understood to be the origin of mass. While those statements are true, they are incomplete. It turns out that the Higgs boson is responsible for only about 2% of the mass of ordinary matter. In this dramatic new video, Dr. Don Lincoln of Fermilab tells us the rest of the story.

OGLE-2012-BLG-0455/MOA-2012-BLG-206: Microlensing event with ambiguity in planetary interpretations caused by incomplete coverage of planetary signal

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

Park, H.; Han, C.; Choi, J.-Y.

2014-05-20

Characterizing a microlensing planet is done by modeling an observed lensing light curve. In this process, it is often confronted that solutions of different lensing parameters result in similar light curves, causing difficulties in uniquely interpreting the lens system, and thus understanding the causes of different types of degeneracy is important. In this work, we show that incomplete coverage of a planetary perturbation can result in degenerate solutions even for events where the planetary signal is detected with a high level of statistical significance. We demonstrate the degeneracy for an actually observed event OGLE-2012-BLG-0455/MOA-2012-BLG-206. The peak of this high-magnification eventmore » (A {sub max} ∼ 400) exhibits very strong deviation from a point-lens model with Δχ{sup 2} ≳ 4000 for data sets with a total of 6963 measurements. From detailed modeling of the light curve, we find that the deviation can be explained by four distinct solutions, i.e., two very different sets of solutions, each with a twofold degeneracy. While the twofold (so-called close/wide) degeneracy is well understood, the degeneracy between the radically different solutions is not previously known. The model light curves of this degeneracy differ substantially in the parts that were not covered by observation, indicating that the degeneracy is caused by the incomplete coverage of the perturbation. It is expected that the frequency of the degeneracy introduced in this work will be greatly reduced with the improvement of the current lensing survey and follow-up experiments and the advent of new surveys.« less

Extragalactic circuits, transmission lines, and CR particle acceleration

NASA Astrophysics Data System (ADS)

Kronberg, Philipp P.; Lovelace, Richard V. E.

2015-08-01

A non-negligible fraction of a Supermassive Black Hole's (SMBH) rest mass energy gets transported into extragalactic space by a remarkable process in jets which are incompletely understood. What are the physical processes which transport this energy? It is likely that the energy flows electromagnetically, rather than via a particle beam flux. The deduced electromagnetic fields may produce particles of energy as high as ˜ 1020 eV. The energetics of SMBH accretion disk models and the electromagnetic energy transfer imply that a SMBH should generate a 1018 - 1019 Ampères current close to the black hole and its accretion disk. We describe the so far best observation-based estimate of the magnitude of the current flow along the axis of the jet extending from the nucleus of the active galaxy in 3C303. The current is measured to be I ˜ 1018 Ampères at ˜ 40 kpc away from the AGN. This indicates that organised current flow remains intact over multi-kpc distances. The electric current I transports electromagnetic power into free space, P = I2Z, where Z ˜ 30 Ohms is related to the impedance of free space, and this points to the existence of cosmic electric circuit. The associated electric potential drop, V = IZ, is of the order of that required to generate Ultra High Energy Cosmic Rays (UHECR). We also explore further implications, including disruption/deflection of the power flow and also why such measurements, exemplified by those on 3C303, are currently very difficult to make and to unambiguously interpret. This naturally leads to the topic of how such measurements can be extended and improved in the future. We describe the analogy of electromagnetically dominated jets with transmission lines. High powered jets in vacuo can be understood by approximate analogy with a waveguide. The importance of inductance, impedance, and other laboratory electrical concepts are discussed in this context.

PD-L2 Elbows out PD-L1 to Rescue T Cell Immunity to Malaria.

PubMed

Crompton, Peter D; Pierce, Susan K

2016-08-16

How early interactions between innate and adaptive immune cells influence outcomes of acute infections is incompletely understood. In this issue of Immunity, Karunarathne et al. (2016) show that dendritic cells help CD4(+) T helper 1 cell immunity against malaria through PD-L2's competition with PD-L1. Published by Elsevier Inc.

Variation in offspring sex ratio of a long-lived sexually dimorphic raptor, the eastern imperial eagle (Aquila heliaca)

Treesearch

Todd E. Katzner; Daniel S. Jackson; Jamie Ivy; Evgeny A. Bragin; Andrew Dewoody

2014-01-01

Sex ratio theory attempts to explain observed variation in offspring sex ratio at both the population and the brood levels. In the context of low-fecundity organisms producing high-investment offspring, the drivers of adaptive variation in sex ratio are incompletely understood. For raptors that display reverse sexual dimorphism (RSD), preferential allocation of...

Chilled in Translation: Adapting to Bacterial Climate Change.

PubMed

Gottesman, Susan

2018-04-19

Cold-shocked bacteria transiently shut down protein translation, but the mechanisms whereby they adaptively restore translation were incompletely understood. Zhang et al. (2018) demonstrate a global increase in mRNA structure after cold shock and that, as structured RNA decreases, translation returns, dependent upon ribonuclease RNase R and cold shock protein CspA and its homologs. Published by Elsevier Inc.

S100A4 is a biomarker and regulator of glioma stem cells that is critical for mesenchymal transition in glioblastoma

USDA-ARS?s Scientific Manuscript database

Glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with canc...

Transcriptome profiling of microRNA by next-gen deep sequencing reveals known and novel miRNA species in the lipid fraction of human breast milk

USDA-ARS?s Scientific Manuscript database

While breast milk has unique health advantages for infants, the mechanisms by which it regulates the physiology of newborns are incompletely understood. miRNAs have been described as functioning transcellularly, and have been previously isolated in cell-free and exosomal form from bodily liquids (se...

Increased Phosphoenolpyruvate Carboxykinase (PEPCK) Gene Expression and Steatosis During Hepatitis C Virus (HCV) Subgenome Replication: Role of Nonstructural Component-5A (NS5A) and CCAAT/Enhancer Binding Protein ß (C/EBPß)

USDA-ARS?s Scientific Manuscript database

Chronic hepatitis C virus (HCV) infection greatly increases the risk for type 2 diabetes and nonalcoholic steatohepatitis; however, the pathogenic mechanisms remain incompletely understood. Here we report gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) transcription and associated tra...

Time-dependent biodistribution and transgene expression of a recombinant human adenovirus serotype 5-luciferase vector as a surrogate agent for rAd5-FMDV vaccines in cattle

USDA-ARS?s Scientific Manuscript database

Replication-defective recombinant adenovirus 5 (rAd5) vectors carrying foot-and-mouth disease virus (FMDV) transgenes elicit a robust immune response to FMDV challenge in cattle; however vaccine function mechanisms are incompletely understood. Recent efforts addressing critical interactions of rAd5 ...

Intrauterine growth restriction and hypospadias: is there a connection?

PubMed Central

2014-01-01

Hypospadias is one of the most common congenital malformations of the genitourinary tract in males. It is an incomplete fusion of urethral folds early in fetal development and may be associated with other malformations of the genital tract. The etiology is poorly understood and may be hormonal, genetic, or environmental, but most often is idiopathic or multifactorial. Among many possible risk factors identified, of particular importance is low birth weight, which is defined in various ways in the literature. No mechanism has been identified for the association of low birth weight and hypospadias, but some authors propose placental insufficiency as a common inciting factor. Currently, there is no standardized approach for evaluating children with hypospadias in the setting of intrauterine growth restriction. We reviewed the available published literature on the association of hypospadias and growth restriction to determine whether it should be considered a separate entity within the category of disorders of sexual differentiation. PMID:25337123

Optical Imaging and Control of Neurons

NASA Astrophysics Data System (ADS)

Song, Yoon-Kyu

Although remarkable progress has been made in our understanding of the function, organization, and development of the brain by various approaches of modern science and technology, how the brain performs its marvelous function remains unsolved or incompletely understood. This is mainly attributed to the insufficient capability of currently available research tools and conceptual frameworks to deal with enormous complexity of the brain. Hence, in the last couple of decades, a significant effort has been made to crack the complexity of brain by utilizing research tools from diverse scientific areas. The research tools include the optical neurotechnology which incorporates the exquisite characteristics of optics, such as multi-parallel access and non-invasiveness, in sensing and stimulating the excitable membrane of a neuron, the basic functional unit of the brain. This chapter is aimed to serve as a short introduction to the optical neurotechnology for those who wish to use optical techniques as one of their brain research tools.

Gender Dysphoria in Adults.

PubMed

Zucker, Kenneth J; Lawrence, Anne A; Kreukels, Baudewijntje P C

2016-01-01

Gender dysphoria (GD), a term that denotes persistent discomfort with one's biologic sex or assigned gender, replaced the diagnosis of gender identity disorder in the Diagnostic and Statistical Manual of Mental Disorders in 2013. Subtypes of GD in adults, defined by sexual orientation and age of onset, have been described; these display different developmental trajectories and prognoses. Prevalence studies conclude that fewer than 1 in 10,000 adult natal males and 1 in 30,000 adult natal females experience GD, but such estimates vary widely. GD in adults is associated with an elevated prevalence of comorbid psychopathology, especially mood disorders, anxiety disorders, and suicidality. Causal mechanisms in GD are incompletely understood, but genetic, neurodevelopmental, and psychosocial factors probably all contribute. Treatment of GD in adults, although largely standardized, is likely to evolve in response to the increasing diversity of persons seeking treatment, demands for greater client autonomy, and improved understanding of the benefits and limitations of current treatment modalities.

The mitochondrial uniporter controls fight or flight heart rate increases.

PubMed

Wu, Yuejin; Rasmussen, Tyler P; Koval, Olha M; Joiner, Mei-Ling A; Hall, Duane D; Chen, Biyi; Luczak, Elizabeth D; Wang, Qiongling; Rokita, Adam G; Wehrens, Xander H T; Song, Long-Sheng; Anderson, Mark E

2015-01-20

Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart rate increases are resistant to current therapies. However, the metabolic mechanisms driving heart rate acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calcium uniporter (MCU) facilitates calcium entry into the mitochondrial matrix to stimulate metabolism. We developed mice with myocardial MCU inhibition by transgenic expression of a dominant-negative (DN) MCU. Here, we show that DN-MCU mice had normal resting heart rates but were incapable of physiological fight or flight heart rate acceleration. We found that MCU function was essential for rapidly increasing mitochondrial calcium in pacemaker cells and that MCU-enhanced oxidative phoshorylation was required to accelerate reloading of an intracellular calcium compartment before each heartbeat. Our findings show that MCU is necessary for complete physiological heart rate acceleration and suggest that MCU inhibition could reduce inappropriate heart rate increases without affecting resting heart rate.

Understanding the cellular basis and pathophysiology of Peyronie’s disease to optimize treatment for erectile dysfunction

PubMed Central

Alzubaidi, Raidh

2017-01-01

Erectile dysfunction (ED) is a common condition that significantly impacts a man’s physical and psychological well-being. ED is often associated with Peyronie’s disease (PD), which is an abnormal curvature of the penis. Delayed treatment of or surgical invention for PD often results in ED and therefore unsatisfied patients. The pathophysiology of PD is incompletely understood, but has been studied extensively and based on our current understanding of PD physiology, many medical treatment options have been proposed. In this paper, we will review what is known about the pathophysiology of PD and the medical treatment options that have been trialed as a result. More investigations in regards to the basic science of PD need to be carried out in order to elucidate the exact mechanisms of the fibrosis, and propose new, more successful treatment options which should be implemented prior to the onset of ED. PMID:28217450

The bioenergetics mechanisms and applications of sulfate-reducing bacteria in remediation of pollutants in drainage: A review.

PubMed

Li, Xin; Lan, Shi-Ming; Zhu, Zhong-Ping; Zhang, Chang; Zeng, Guang-Ming; Liu, Yun-Guo; Cao, Wei-Cheng; Song, Biao; Yang, Hong; Wang, Sheng-Fan; Wu, Shao-Hua

2018-04-20

Sulfate-reducing bacteria (SRB), a group of anaerobic prokaryotes, can use sulfur species as a terminal electron acceptor for the oxidation of organic compounds. They not only have significant ecological functions, but also play an important role in bioremediation of contaminated sites. Although numerous studies on metabolism and applications of SRB have been conducted, they still remain incompletely understood and even controversial. Fully understanding the metabolism of SRB paves the way for allowing the microorganisms to provide more beneficial services in bioremediation. Here we review progress in bioenergetics mechanisms and application of SRB including: (1) electron acceptors and donors for SRB; (2) pathway for sulfate reduction; (3) electron transfer in sulfate reduction; (4) application of SRB for economical and concomitant treatment of heavy metal, organic contaminants and sulfates. Moreover, current knowledge gaps and further research needs are identified. Copyright © 2018 Elsevier Inc. All rights reserved.

Sulfur mustard skin lesions: A systematic review on pathomechanisms, treatment options and future research directions.

PubMed

Rose, Dorothee; Schmidt, Annette; Brandenburger, Matthias; Sturmheit, Tabea; Zille, Marietta; Boltze, Johannes

2018-09-01

Sulfur mustard (SM) is a chemical warfare, which has been used for one hundred years. However, its exact pathomechanisms are still incompletely understood and there is no specific therapy available so far. In this systematic review, studies published between January 2000 and July 2017 involving pathomechanisms and experimental treatments of SM-induced skin lesions were analyzed to summarize current knowledge on SM pathology, to provide an overview on novel treatment options, and to identify promising targets for future research to more effectively counter SM effects. We suggest that future studies should focus on (I) systemic effects of SM intoxication due to its distribution throughout the body, (II) removal of SM depots that continuously release active compound contributing to chronic skin damage, and (III) therapeutic options that counteract the pleiotropic effects of SM. Copyright © 2017 Elsevier B.V. All rights reserved.

Neural Basis of Reinforcement Learning and Decision Making

PubMed Central

Lee, Daeyeol; Seo, Hyojung; Jung, Min Whan

2012-01-01

Reinforcement learning is an adaptive process in which an animal utilizes its previous experience to improve the outcomes of future choices. Computational theories of reinforcement learning play a central role in the newly emerging areas of neuroeconomics and decision neuroscience. In this framework, actions are chosen according to their value functions, which describe how much future reward is expected from each action. Value functions can be adjusted not only through reward and penalty, but also by the animal’s knowledge of its current environment. Studies have revealed that a large proportion of the brain is involved in representing and updating value functions and using them to choose an action. However, how the nature of a behavioral task affects the neural mechanisms of reinforcement learning remains incompletely understood. Future studies should uncover the principles by which different computational elements of reinforcement learning are dynamically coordinated across the entire brain. PMID:22462543

Idiopathic recurrent pericarditis as an immune-mediated disease: current insights into pathogenesis and emerging treatment options.

PubMed

Imazio, Massimo

2014-11-01

Idiopathic recurrent pericarditis affects 30-50% of patients with a previous attack of pericarditis. The etiopathogenesis is incompletely understood and most cases remain idiopathic with a presumed immune-mediated pathogenesis. The mainstay of therapy is aspirin or a nonsteroidal anti-inflammatory drug plus colchicine and the possible adjunct of a low-to-moderate dose of a corticosteroid in more difficult cases. Colchicine as an adjunct to anti-inflammatory therapy reduces by 50% the subsequent recurrent rate. For true refractory cases with failure of standard combination therapies, new and emerging options especially include human intravenous immunoglobulins and biological agents (i.e., anakinra). The outcome of idiopathic recurrent pericarditis is good with a negligible risk of developing constrictive pericarditis. Thus, it is important to reassure patients on their prognosis, explaining the nature of the disease and the likely course. Moreover, therapeutic choices should include less toxic agents and favor cheaper drugs whenever possible.

Current status of achalasia management: a review on diagnosis and treatment.

PubMed

Tuason, Joshua; Inoue, Haruhiro

2017-04-01

Achalasia is a rare esophageal motility disorder that is characterized by loss of peristalsis and failure of relaxation of the lower esophageal sphincter (LES), particularly during swallowing. This review focuses on the diagnosis of esophageal motility disorders as defined by the Chicago Classification ver 3.0, and presents management options with regard to per-oral endoscopic myotomy (POEM) as the treatment of choice. A concise review of literature was performed for articles related to the management of achalasia, and this was contrasted with our institution's current practice. Achalasia is still incompletely understood, and management is focused on establishing a proper diagnosis, and relieving the obstructive symptoms. Achalasia should be considered when dysphagia is present, and not otherwise caused by an obstruction or inflammation, and when criteria is met as per the Chicago Classification ver 3.0. Lowering LES tone and disruption of LES can be accomplished by various methods, most notably pneumatic balloon dilatation and surgical myotomy. POEM has been gaining momentum as a first line therapy for achalasia symptoms, and can be considered an important tool for motility disorders of the esophagus.

Activators of potassium M currents have anticonvulsant actions in two rat models of encephalitis

PubMed Central

Solbrig, Marylou V.; Adrian, Russell; Wechsler, Steven L.; Koob, George F.

2010-01-01

Opioid systems in hippocampus regulate excitability and kappa opioids have a role in anticonvulsant protection, but their mechanisms of action are incompletely understood. We examined the ability of opioid and nonopioid agents with overlapping ionic mechanisms and actions similar to kappa opioid agonists, to block seizures in rat models of encephalitis due to Borna Disease virus and Herpes Simplex Virus Type-1. Naltrindole, a delta antagonist and thus a kappa opioid sparing agent, (10 mg/kg s.c.) blocked spontaneous and naloxone (opioid antagonist)-induced seizures in the models, but produced somatic signs similar to opioid withdrawal. Given that delta antagonists as well as kappa opioid agonists in hippocampus enhance potassium M currents (IM), we tested the effect of the IM augmenter flupirtine. Flupirtine (20 mg/kg i.p.) prevented seizures in Borna and herpes infected rats, without signs of withdrawal, hypotonia or sedation. The results support the efficacy of opioid and nonopioid drugs in modulating naloxone-induced seizures in critical illness due to viral encephalitis and by analogy, opioid withdrawal seizures. PMID:17126318

Complications associated with prone positioning in elective spinal surgery.

PubMed

DePasse, J Mason; Palumbo, Mark A; Haque, Maahir; Eberson, Craig P; Daniels, Alan H

2015-04-18

Complications associated with prone surgical positioning during elective spine surgery have the potential to cause serious patient morbidity. Although many of these complications remain uncommon, the range of possible morbidities is wide and includes multiple organ systems. Perioperative visual loss (POVL) is a well described, but uncommon complication that may occur due to ischemia to the optic nerve, retina, or cerebral cortex. Closed-angle glaucoma and amaurosis have been reported as additional etiologies for vision loss following spinal surgery. Peripheral nerve injuries, such as those caused by prolonged traction to the brachial plexus, are more commonly encountered postoperative events. Myocutaneous complications including pressure ulcers and compartment syndrome may also occur after prone positioning, albeit rarely. Other uncommon positioning complications such as tongue swelling resulting in airway compromise, femoral artery ischemia, and avascular necrosis of the femoral head have also been reported. Many of these are well-understood and largely avoidable through thoughtful attention to detail. Other complications, such as POVL, remain incompletely understood and thus more difficult to predict or prevent. Here, the current literature on the complications of prone positioning for spine surgery is reviewed to increase awareness of the spectrum of potential complications and to inform spine surgeons of strategies to minimize the risk of prone patient morbidity.

Complications associated with prone positioning in elective spinal surgery

PubMed Central

DePasse, J Mason; Palumbo, Mark A; Haque, Maahir; Eberson, Craig P; Daniels, Alan H

2015-01-01

Complications associated with prone surgical positioning during elective spine surgery have the potential to cause serious patient morbidity. Although many of these complications remain uncommon, the range of possible morbidities is wide and includes multiple organ systems. Perioperative visual loss (POVL) is a well described, but uncommon complication that may occur due to ischemia to the optic nerve, retina, or cerebral cortex. Closed-angle glaucoma and amaurosis have been reported as additional etiologies for vision loss following spinal surgery. Peripheral nerve injuries, such as those caused by prolonged traction to the brachial plexus, are more commonly encountered postoperative events. Myocutaneous complications including pressure ulcers and compartment syndrome may also occur after prone positioning, albeit rarely. Other uncommon positioning complications such as tongue swelling resulting in airway compromise, femoral artery ischemia, and avascular necrosis of the femoral head have also been reported. Many of these are well-understood and largely avoidable through thoughtful attention to detail. Other complications, such as POVL, remain incompletely understood and thus more difficult to predict or prevent. Here, the current literature on the complications of prone positioning for spine surgery is reviewed to increase awareness of the spectrum of potential complications and to inform spine surgeons of strategies to minimize the risk of prone patient morbidity. PMID:25893178

Influence of cold storage prior to and after ripening on quality factors and sensory attributes of ‘Hass’ avocados

USDA-ARS?s Scientific Manuscript database

Partially-ripened avocados are often held in cold storage in an attempt to enable the consistent delivery of ripe fruit to food service or retail outlets, although the effect on the quality of such fruit is incompletely understood. ‘Hass’ avocados were ripened to near ripeness (13.3 - 17.8 N) at 20 ...

Switch-Hitting Immune Cells: From Tumor Protection to Metastasis Promotion | Center for Cancer Research

Cancer.gov

The leading cause of death from cancer is not a primary tumor but is the metastases, or invasion of tumor cells into other locations in the body, that result from it. A complex and incompletely understood process, metastatic tumor formation is thought to require several steps in which tumor cells invade the tissue surrounding the primary tumor, enter local blood vessels,

[Gestalt theory of V. v. Weizsäcker from the viewpoint of the psychology emotions].

PubMed

Brunnhuber, S

2001-07-01

The "Gestaltkreis" represents an important part in the psychosomatic theory-discussion, which can be understood as an incomplete contribution towards a general theory of emotions. Especially the relationship between perception and motion requires further consideration. Instead of a causal attribution, cyclic complementaries are important. Furthermore different degrees of organisation within the body-scheme and the affect-apparatus are mentioned.

Incomplete gastric metaplasia in children with insulin-dependent diabetes mellitus and celiac disease. An ultrastructural study

PubMed Central

Bertini, Marina; Sbarbati, Andrea; Valletta, Enrico; Pinelli, Leonardo; Tatò, Luciano

2001-01-01

Background The association of insulin-dependent diabetes mellitus (IDDM) and celiac disease (CD) has been widely reported in children but the relationship between the two conditions is incompletely understood. Moreover, specific studies on intestinal biopsies of patients with the association of the two diseases are still lacking. Methods We studied the ultrastructure of the duodenal mucosa in 12 patients with both IDDM and CD. Results All patients had either total or partial atrophy of duodenal mucosa. In seven subjects, an accumulation of electrondense granules in the apical cytoplasm of groups of enterocytes was found. In four of them, a double population of granules existed (mean diameter: 400-800 nm and 100-200 nm respectively) showing a biphasic pattern. In the other three patients, only smaller granules (100- 200 nm) were found in the enterocytes. Conclusions The present work suggests that patients with IDDM/CD may represent a subgroup in the context of the CD population. Intestinal biopsies of such individuals often show accumulation of electrondense granules in the apical cytoplasm of enterocytes that can be interpreted as incomplete gastric metaplasia. PMID:11466133

Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway* | Office of Cancer Genomics

Cancer.gov

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumors and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood.

Modeling Aggressive Medulloblastoma Using Human Induced Pluripotent Stem Cells

DTIC Science & Technology

2017-09-01

and Myc in turn induces expression of AT1R creating a positive feedback loop and development of aggression tumor phenotype. The therapeutic...strengths are the relevant expertise of the applicant and his collaborating team, the novel paracrine positive feedback loop in EC-tumor cell...to as MYC-driven MB. The molecular mechanisms that drive MYC hyper -activation in MB remain incompletely understood. MB cells in actual tumors interact

GLUTAMATE ABNORMALITIES IN OBSESSIVE COMPULSIVE DISORDER: NEUROBIOLOGY, PATHOPHYSIOLOGY, AND TREATMENT

PubMed Central

Pittenger, Christopher; Bloch, Michael H.; Williams, Kyle

2011-01-01

Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics. PMID:21963369

Leptin is associated with cardiopulmonary fitness independent of body-mass index and insulin sensitivity in adolescents with type 1 diabetes: a brief report from the EMERALD study.

PubMed

Bjornstad, Petter; Cree-Green, Melanie; Baumgartner, Amy; Coe, Gregory; Reyes, Yesenia Garcia; Schafer, Michal; Pyle, Laura; Regensteiner, Judith G; Reusch, Jane E B; Nadeau, Kristen J

2017-05-01

Cardiopulmonary fitness is decreased in type 1 diabetes for reasons that are incompletely understood. In this study, leptin was associated with exercise capacity independent of insulin sensitivity (IS) and body mass index (BMI), suggesting that leptin may relate to cardiopulmonary fitness by mechanisms beyond IS and/or obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

A high-fat diet containing whole walnuts (Juglans regia) reduces tumour size and growth along with plasma insulin-like growth factor 1 in the transgenic adenocarcinoma of the mouse prostate model

USDA-ARS?s Scientific Manuscript database

Dietary fat is linked to prostate cancer (PCa), the most commonly diagnosed male cancer, but the nature and strength of the relationships between total fat, n-6 and n-3 fatty acids and PCa remain incompletely understood. Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice (N=10-12 per grou...

Myotubularin related protein-2 and its phospholipid substrate PIP2 control Piezo2-mediated mechanotransduction in peripheral sensory neurons

PubMed Central

Narayanan, Pratibha; Hütte, Meike; Kudryasheva, Galina; Taberner, Francisco J; Lechner, Stefan G; Rehfeldt, Florian; Gomez-Varela, David

2018-01-01

Piezo2 ion channels are critical determinants of the sense of light touch in vertebrates. Yet, their regulation is only incompletely understood. We recently identified myotubularin related protein-2 (Mtmr2), a phosphoinositide (PI) phosphatase, in the native Piezo2 interactome of murine dorsal root ganglia (DRG). Here, we demonstrate that Mtmr2 attenuates Piezo2-mediated rapidly adapting mechanically activated (RA-MA) currents. Interestingly, heterologous Piezo1 and other known MA current subtypes in DRG appeared largely unaffected by Mtmr2. Experiments with catalytically inactive Mtmr2, pharmacological blockers of PI(3,5)P2 synthesis, and osmotic stress suggest that Mtmr2-dependent Piezo2 inhibition involves depletion of PI(3,5)P2. Further, we identified a PI(3,5)P2 binding region in Piezo2, but not Piezo1, that confers sensitivity to Mtmr2 as indicated by functional analysis of a domain-swapped Piezo2 mutant. Altogether, our results propose local PI(3,5)P2 modulation via Mtmr2 in the vicinity of Piezo2 as a novel mechanism to dynamically control Piezo2-dependent mechanotransduction in peripheral sensory neurons. PMID:29521261

Obsessive-compulsive disorder and its related disorders: a reappraisal of obsessive-compulsive spectrum concepts.

PubMed

Murphy, Dennis L; Timpano, Kiara R; Wheaton, Michael G; Greenberg, Benjamin D; Miguel, Euripedes C

2010-01-01

Obsessive-compulsive disorder (OCD) is a clinical syndrome whose hallmarks are excessive, anxiety-evoking thoughts and compulsive behaviors that are generally recognized as unreasonable, but which cause significant distress and impairment. When these are the exclusive symptoms, they constitute uncomplicated OCD. OCD may also occur in the context of other neuropsychiatric disorders, most commonly other anxiety and mood disorders. The question remains as to whether these combinations of disorders should be regarded as independent, cooccurring disorders or as different manifestations of an incompletely understood constellation of OCD spectrum disorders with a common etiology. Additional considerations are given here to two potential etiology-based subgroups: (i) an environmentally based group in which OCD occurs following apparent causal events such as streptococcal infections, brain injury, or atypical neuroleptic treatment; and (ii) a genomically based group in which OCD is related to chromosomal anomalies or specific genes. Considering the status of current research, the concept of OCD and OCD-related spectrum conditions seems fluid in 2010, and in need of ongoing reappraisal.

Oxidant/Antioxidant Imbalance in Alzheimer's Disease: Therapeutic and Diagnostic Prospects

PubMed Central

2018-01-01

Alzheimer's disease (AD) is the most common cause of dementia and a great socioeconomic burden in the aging society. Compelling evidence demonstrates that molecular change characteristics for AD, such as oxidative stress and amyloid β (Aβ) oligomerization, precede by decades the onset of clinical dementia and that the disease represents a biological and clinical continuum of stages, from asymptomatic to severely impaired. Nevertheless, the sequence of the early molecular alterations and the interplay between them are incompletely understood. This review presents current knowledge about the oxidative stress-induced impairments and compromised oxidative stress defense mechanisms in AD brain and the cross-talk between various pathophysiological insults, with the focus on excessive reactive oxygen species (ROS) generation and Aβ overproduction at the early stages of the disease. Prospects for AD therapies targeting oxidant/antioxidant imbalance are being discussed, as well as for the development of novel oxidative stress-related, blood-based biomarkers for early, noninvasive AD diagnostics. PMID:29636850

Interferon lambda: opportunities, risks, and uncertainties in the fight against HCV.

PubMed

Laidlaw, Stephen M; Dustin, Lynn B

2014-01-01

Innate immunity is key to the fight against the daily onslaught from viruses that our bodies are subjected to. Essential to this response are the interferons (IFNs) that prime our cells to block viral pathogens. Recent evidence suggests that the Type III (λ) IFNs are intimately associated with the immune response to hepatitis C virus (HCV) infection. Genome-wide association studies have identified polymorphisms within the IFN-λ gene locus that correlate with response to IFNα-based antiviral therapy and with spontaneous clearance of HCV infection. The mechanisms for these correlations are incompletely understood. Restricted expression of the IFN-λ receptor, and the ability of IFN-λ to induce IFN-stimulated genes in HCV-infected cells, suggest potential roles for IFN-λ in HCV therapy even in this era of directly acting antivirals. This review summarizes our current understanding of the IFN-λ family and the role of λ IFNs in the natural history of HCV infection.

Scientific Evidence of Rice By-Products for Cancer Prevention: Chemopreventive Properties of Waste Products from Rice Milling on Carcinogenesis In Vitro and In Vivo

PubMed Central

Tan, Bee Ling

2017-01-01

Cancer is a significant global health concern affecting men and women worldwide. Although current chemopreventive drugs could inhibit the growth of cancer cells, they exert many adverse side effects. Dietary factor plays a crucial role in the management of cancers and has drawn the attention of researchers to be used as an option to combat this disease. Both in vitro and in vivo studies showed that rice and its by-products display encouraging results in the prevention of this disease. The mechanism of anticancer effect is suggested partly through potentiation of bioactive compounds like vitamin E, phytic acid, γ-aminobutyric acid (GABA), γ-oryzanol, and phenolics. Nevertheless, the bioactivity of rice and its by-products is still incompletely understood. In this review, we present the findings from a preclinical study both in in vitro and in animal experiments on the promising role of rice by-products with focus on cancer prevention. PMID:28210630

Ketamine: 50 Years of Modulating the Mind

PubMed Central

Li, Linda; Vlisides, Phillip E.

2016-01-01

Ketamine was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically fascinating. With considerably diverse molecular targets and neurophysiological properties, ketamine’s effects on the central nervous system remain incompletely understood. Investigators have leveraged the unique characteristics of ketamine to explore the invariant, fundamental mechanisms of anesthetic action. Emerging evidence indicates that ketamine-mediated anesthesia may occur via disruption of corticocortical information transfer in a frontal-to-parietal (“top down”) distribution. This proposed mechanism of general anesthesia has since been demonstrated with anesthetics in other pharmacological classes as well. Ketamine remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia. Furthermore, there may be an emerging role for ketamine in treatment of refractory depression and Post-Traumatic Stress Disorder. In this article, we review the history of ketamine, its pharmacology, putative mechanisms of action and current clinical applications. PMID:27965560

The molecular basis of herpes simplex virus latency

PubMed Central

Nicoll, Michael P; Proença, João T; Efstathiou, Stacey

2012-01-01

Herpes simplex virus type 1 is a neurotropic herpesvirus that establishes latency within sensory neurones. Following primary infection, the virus replicates productively within mucosal epithelial cells and enters sensory neurones via nerve termini. The virus is then transported to neuronal cell bodies where latency can be established. Periodically, the virus can reactivate to resume its normal lytic cycle gene expression programme and result in the generation of new virus progeny that are transported axonally back to the periphery. The ability to establish lifelong latency within the host and to periodically reactivate to facilitate dissemination is central to the survival strategy of this virus. Although incompletely understood, this review will focus on the mechanisms involved in the regulation of latency that centre on the functions of the virus-encoded latency-associated transcripts (LATs), epigenetic regulation of the latent virus genome and the molecular events that precipitate reactivation. This review considers current knowledge and hypotheses relating to the mechanisms involved in the establishment, maintenance and reactivation herpes simplex virus latency. PMID:22150699

Technical aspects of neurostimulation: Focus on equipment, electric field modeling, and stimulation protocols.

PubMed

Klooster, D C W; de Louw, A J A; Aldenkamp, A P; Besseling, R M H; Mestrom, R M C; Carrette, S; Zinger, S; Bergmans, J W M; Mess, W H; Vonck, K; Carrette, E; Breuer, L E M; Bernas, A; Tijhuis, A G; Boon, P

2016-06-01

Neuromodulation is a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies for the purpose of improving quality of life and functioning of humans. Brain neuromodulation involves different neurostimulation techniques: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), which are being used both to study their effects on cognitive brain functions and to treat neuropsychiatric disorders. The mechanisms of action of neurostimulation remain incompletely understood. Insight into the technical basis of neurostimulation might be a first step towards a more profound understanding of these mechanisms, which might lead to improved clinical outcome and therapeutic potential. This review provides an overview of the technical basis of neurostimulation focusing on the equipment, the present understanding of induced electric fields, and the stimulation protocols. The review is written from a technical perspective aimed at supporting the use of neurostimulation in clinical practice. Copyright © 2016 Elsevier Ltd. All rights reserved.

FOREST ECOLOGY. Pervasive drought legacies in forest ecosystems and their implications for carbon cycle models.

PubMed

Anderegg, W R L; Schwalm, C; Biondi, F; Camarero, J J; Koch, G; Litvak, M; Ogle, K; Shaw, J D; Shevliakova, E; Williams, A P; Wolf, A; Ziaco, E; Pacala, S

2015-07-31

The impacts of climate extremes on terrestrial ecosystems are poorly understood but important for predicting carbon cycle feedbacks to climate change. Coupled climate-carbon cycle models typically assume that vegetation recovery from extreme drought is immediate and complete, which conflicts with the understanding of basic plant physiology. We examined the recovery of stem growth in trees after severe drought at 1338 forest sites across the globe, comprising 49,339 site-years, and compared the results with simulated recovery in climate-vegetation models. We found pervasive and substantial "legacy effects" of reduced growth and incomplete recovery for 1 to 4 years after severe drought. Legacy effects were most prevalent in dry ecosystems, among Pinaceae, and among species with low hydraulic safety margins. In contrast, limited or no legacy effects after drought were simulated by current climate-vegetation models. Our results highlight hysteresis in ecosystem-level carbon cycling and delayed recovery from climate extremes. Copyright © 2015, American Association for the Advancement of Science.

MODELS OF INSULIN RESISTANCE AND HEART FAILURE

PubMed Central

Velez, Mauricio; Kohli, Smita; Sabbah, Hani N.

2013-01-01

The incidence of heart failure (HF) and diabetes mellitus is rapidly increasing and is associated with poor prognosis. In spite of the advances in therapy, HF remains a major health problem with high morbidity and mortality. When HF and diabetes coexist, clinical outcomes are significantly worse. The relationship between these two conditions has been studied in various experimental models. However, the mechanisms for this interrelationship are complex, incompletely understood, and have become a matter of considerable clinical and research interest. There are only few animal models that manifest both HF and diabetes. However, the translation of results from these models to human disease is limited and new models are needed to expand our current understanding of this clinical interaction. In this review, we discuss mechanisms of insulin signaling and insulin resistance, the clinical association between insulin resistance and HF and its proposed pathophysiologic mechanisms. Finally, we discuss available animal models of insulin resistance and HF and propose requirements for future new models. PMID:23456447

Inside-out neuropharmacology of nicotinic drugs

PubMed Central

Henderson, Brandon J.; Lester, Henry A.

2015-01-01

Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as “inside-out pharmacology”. This term contrasts with the better-known, acute, “outside-in” effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology. PMID:25660637

Scientific Evidence of Rice By-Products for Cancer Prevention: Chemopreventive Properties of Waste Products from Rice Milling on Carcinogenesis In Vitro and In Vivo.

PubMed

Tan, Bee Ling; Norhaizan, Mohd Esa

2017-01-01

Cancer is a significant global health concern affecting men and women worldwide. Although current chemopreventive drugs could inhibit the growth of cancer cells, they exert many adverse side effects. Dietary factor plays a crucial role in the management of cancers and has drawn the attention of researchers to be used as an option to combat this disease. Both in vitro and in vivo studies showed that rice and its by-products display encouraging results in the prevention of this disease. The mechanism of anticancer effect is suggested partly through potentiation of bioactive compounds like vitamin E, phytic acid, γ -aminobutyric acid (GABA), γ -oryzanol, and phenolics. Nevertheless, the bioactivity of rice and its by-products is still incompletely understood. In this review, we present the findings from a preclinical study both in in vitro and in animal experiments on the promising role of rice by-products with focus on cancer prevention.

HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

PubMed Central

Zhong, Peng; Vickstrom, Casey R; Liu, Xiaojie; Hu, Ying; Yu, Laikang; Yu, Han-Gang

2018-01-01

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors. PMID:29256865

An Overview of Biofield Devices

PubMed Central

Muehsam, David; Chevalier, Gaétan; Barsotti, Tiffany

2015-01-01

Advances in biophysics, biology, functional genomics, neuroscience, psychology, psychoneuroimmunology, and other fields suggest the existence of a subtle system of “biofield” interactions that organize biological processes from the subatomic, atomic, molecular, cellular, and organismic to the interpersonal and cosmic levels. Biofield interactions may bring about regulation of biochemical, cellular, and neurological processes through means related to electromagnetism, quantum fields, and perhaps other means of modulating biological activity and information flow. The biofield paradigm, in contrast to a reductionist, chemistry-centered viewpoint, emphasizes the informational content of biological processes; biofield interactions are thought to operate in part via low-energy or “subtle” processes such as weak, nonthermal electromagnetic fields (EMFs) or processes potentially related to consciousness and nonlocality. Biofield interactions may also operate through or be reflected in more well-understood informational processes found in electroencephalographic (EEG) and electrocardiographic (ECG) data. Recent advances have led to the development of a wide variety of therapeutic and diagnostic biofield devices, defined as physical instruments best understood from the viewpoint of a biofield paradigm. Here, we provide a broad overview of biofield devices, with emphasis on those devices for which solid, peer-reviewed evidence exists. A subset of these devices, such as those based upon EEG- and ECG-based heart rate variability, function via mechanisms that are well understood and are widely employed in clinical settings. Other device modalities, such a gas discharge visualization and biophoton emission, appear to operate through incompletely understood mechanisms and have unclear clinical significance. Device modes of operation include EMF-light, EMF-heat, EMF-nonthermal, electrical current, vibration and sound, physical and mechanical, intentionality and nonlocality, gas and plasma, and other (mode of operation not well-understood). Methodological issues in device development and interfaces for future interdisciplinary research are discussed. Devices play prominent cultural and scientific roles in our society, and it is likely that device technologies will be one of the most influential access points for the furthering of biofield research and the dissemination of biofield concepts. This developing field of study presents new areas of research that have many important implications for both basic science and clinical medicine. PMID:26665041

An Overview of Biofield Devices.

PubMed

Muehsam, David; Chevalier, Gaétan; Barsotti, Tiffany; Gurfein, Blake T

2015-11-01

Advances in biophysics, biology, functional genomics, neuroscience, psychology, psychoneuroimmunology, and other fields suggest the existence of a subtle system of "biofield" interactions that organize biological processes from the subatomic, atomic, molecular, cellular, and organismic to the interpersonal and cosmic levels. Biofield interactions may bring about regulation of biochemical, cellular, and neurological processes through means related to electromagnetism, quantum fields, and perhaps other means of modulating biological activity and information flow. The biofield paradigm, in contrast to a reductionist, chemistry-centered viewpoint, emphasizes the informational content of biological processes; biofield interactions are thought to operate in part via low-energy or "subtle" processes such as weak, nonthermal electromagnetic fields (EMFs) or processes potentially related to consciousness and nonlocality. Biofield interactions may also operate through or be reflected in more well-understood informational processes found in electroencephalographic (EEG) and electrocardiographic (ECG) data. Recent advances have led to the development of a wide variety of therapeutic and diagnostic biofield devices, defined as physical instruments best understood from the viewpoint of a biofield paradigm. Here, we provide a broad overview of biofield devices, with emphasis on those devices for which solid, peer-reviewed evidence exists. A subset of these devices, such as those based upon EEG- and ECG-based heart rate variability, function via mechanisms that are well understood and are widely employed in clinical settings. Other device modalities, such a gas discharge visualization and biophoton emission, appear to operate through incompletely understood mechanisms and have unclear clinical significance. Device modes of operation include EMF-light, EMF-heat, EMF-nonthermal, electrical current, vibration and sound, physical and mechanical, intentionality and nonlocality, gas and plasma, and other (mode of operation not well-understood). Methodological issues in device development and interfaces for future interdisciplinary research are discussed. Devices play prominent cultural and scientific roles in our society, and it is likely that device technologies will be one of the most influential access points for the furthering of biofield research and the dissemination of biofield concepts. This developing field of study presents new areas of research that have many important implications for both basic science and clinical medicine.

Dehydration upon admission is a risk factor for incomplete recovery of renal function in children with haemolytic uremic syndrome.

PubMed

Ojeda, José M; Kohout, Isolda; Cuestas, Eduardo

2013-01-01

Haemolytic uremic syndrome (HUS) is the most common cause of acute renal failure and the second leading cause of chronic renal failure in children. The factors that affect incomplete renal function recovery prior to hospital admission are poorly understood. To analyse the risk factors that determine incomplete recovery of renal function prior to hospitalisation in children with HUS. A retrospective case-control study. age, sex, duration of diarrhoea, bloody stools, vomiting, fever, dehydration, previous use of antibiotics, and incomplete recovery of renal function (proteinuria, hypertension, reduced creatinine clearance, and chronic renal failure during follow-up). Patients of both sexes under 15 years of age were included. Of 36 patients, 23 were males (65.3%; 95%CI: 45.8 to 80.9), with an average age of 2.5 ± 1.4 years. Twenty-one patients required dialysis (58%; 95% CI: 40.8 to 75.8), and 13 (36.1%; 95% CI: 19.0 to 53.1) did not recover renal function. In the bivariate model, the only significant risk factor was dehydration (defined as weight loss >5%) [(OR: 5.3; 95% CI: 1.4 to 12.3; P=.0220]. In the multivariate analysis (Cox multiple regression), only dehydration was marginally significant (HR: 95.823; 95% CI: 93.175 to 109.948; P=.085). Our data suggest that dehydration prior to admission may be a factor that increases the risk of incomplete recovery of renal function during long-term follow-up in children who develop HUS D+. Consequently, in patients with diarrhoea who are at risk of HUS, dehydration should be strongly avoided during outpatient care to preserve long-term renal function. These results must be confirmed by larger prospective studies.

Inflammation and hypoxia in the kidney: friends or foes?

PubMed

Haase, Volker H

2015-08-01

Hypoxic injury is commonly associated with inflammatory-cell infiltration, and inflammation frequently leads to the activation of cellular hypoxia response pathways. The molecular mechanisms underlying this cross-talk during kidney injury are incompletely understood. Yamaguchi and colleagues identify CCAAT/enhancer-binding protein δ as a cytokine- and hypoxia-regulated transcription factor that fine-tunes hypoxia-inducible factor-1 signaling in renal epithelial cells and thus provide a novel molecular link between hypoxia and inflammation in kidney injury.

The intersection of nonalcoholic fatty liver disease and obesity.

PubMed

Woo Baidal, Jennifer A; Lavine, Joel E

2016-01-27

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and recently emerged as the most rapidly increasing indication for liver transplant. Although obesity is a risk factor for NAFLD, overlap between these two entities is incompletely understood. We highlight recent insights into the pathogenesis of human NAFLD in relation to obesity and discuss advances in the diagnosis and treatment of NAFLD. Copyright © 2016, American Association for the Advancement of Science.

Stomach Dysfunction in Diabetes Mellitus: Emerging Technology and Pharmacology

PubMed Central

Szarka, Lawrence A.; Camilleri, Michael

2010-01-01

Gastroparesis and other types of gastric dysfunction result in substantial morbidity in diabetes patients. The pathophysiology of these disorders is incompletely understood. This article reviews techniques applicable to the assessment of gastric function in diabetes patients, including the measurement of emptying, accommodation, and contractility. Available treatment options are also reviewed, including novel yet unapproved serotonin 5-HT4 agonist pharmacological treatments, as well as the role of endoscopic, surgical, and device treatments of gastroparesis. PMID:20167183

COEXISTENCE OF CONSTIPATION AND INCONTINENCE IN CHILDREN AND ADULTS

PubMed Central

Nurko, S; Scott, SM

2011-01-01

The coexistence of constipation and fecal incontinence has long been recognized in pediatric and geriatric populations, but is grossly underappreciated in the rest of the adult population. In children, functional fecal incontinence is usually associated with constipation, stool retention and incomplete evacuation, and is frequently allied to urinary incontinence. Pathophysiology of the incontinence is incompletely understood, although both in children and adults, it is thought to be secondary to overflow, while in adults it may also be related to pelvic floor dysfunction and denervation. Incontinence has an important impact on quality of life and daily functioning, and in children may be associated with behavior problems. The treatment of underlying constipation usually results in improvement in incontinence. This review broadly addresses the epidemiology and pathophysiology of coexistent constipation and incontinence in both children and adults, and also reviews clinical presentation and treatment response in pediatrics. PMID:21382577

Grief following childhood loss of a parent.

PubMed

Johnson, P A; Rosenblatt, P C

1981-07-01

A distinction is drawn between incomplete grief and grief arising from maturational events such as life-cycle milestones. Treating maturational grief as though it were incomplete grief or using expressions of maturational grief as a sign of important childhood roots for a patient's current problems is likely to be unproductive.

Air Force Maintenance Technician Performance Measurement.

DTIC Science & Technology

1979-12-28

R G A N I Z A T IO N N A M E A N D A D R S A R E A P HO R U I T N U M B E R AFIT STUDENT AT: Arizona State Univ II. CONTROLLING OFFICE NAME AND...inflated, or provide incomplete and non -current coverage of maintenance organizations. The performance aopraisal method developed relies on subjective...highly inflated, or provided incomplete and non -current coverage of maintenance organizations. The performance appraisal method developed relied on

Current collection in a magnetoplasma

NASA Technical Reports Server (NTRS)

Laframboise, Jim G.; Sonmor, L. J.

1990-01-01

The authors present a survey of a very incomplete subject, current collection in a magnetoplasma. The best-developed and simplest theories for current collection are steady-state collisionless theories, and these must be understood before departures from them can be analyzed usefully. Thus, the authors begin with a review of them. The authors include some recent numerical results which indicate that steady-state collisionless Laplace-limit currents remain substantially below the Parker-Murphy (1967) canonical upper bound out to very large electrode potentials, and approach it as a limit only very slowly if at all. Attempts to correct this theory for space-charge effects lead to potential disturbances which extend to infinite distance along the electrode's magnetic shadow, unless collisional effects are also taken into account. However, even a small amount of relative plasma drift motion, such as that involved in a typical rocket experiment, can change this conclusion fundamentally. It is widely believed that time-averaged current collection may be increased by effects of plasma turbulence, and the authors review the available evidence for and against this contention. Steady-state collisionless particle dynamics predicts the existence of a toroidal region of trapped orbits which surrounds the electrode. Light emissions from this region have been photographed, indicating that collisional ionization may also occur there, and this, and/or scattering by collisions or possibly turbulent fluctuations in this region, may also increase current collection by the electrode. The authors also discuss effects on particle motions near the electrode, associated with breakdown of magnetic insulation in the region of large electric fields near it.

Diagnoses of Depression and Anxiety Versus Current Symptoms and Quality of Life in Multiple Sclerosis.

PubMed

Marrie, Ruth Ann; Patten, Scott B; Berrigan, Lindsay I; Tremlett, Helen; Wolfson, Christina; Warren, Sharon; Leung, Stella; Fiest, Kirsten M; McKay, Kyla A; Fisk, John D

2018-01-01

Studies assessing the prevalence of depression and anxiety in multiple sclerosis (MS) have used various ascertainment methods that capture different constructs. The relationships between these methods are incompletely understood. Psychiatric comorbidity is associated with lower health-related quality of life (HRQOL) in MS, but the effects of past diagnoses of depression and anxiety on HRQOL are largely unknown. We compared the prevalence of depression and anxiety in persons with MS using administrative data, self-reported physician diagnoses, and symptom-based measures and compared characteristics of persons classified as depressed or anxious by each method. We evaluated whether HRQOL was most affected by previous diagnoses of depression or anxiety or by current symptoms. We linked clinical and administrative data for 859 participants with MS. HRQOL was measured by the Health Utilities Index Mark 3. We classified participants as depressed or anxious using administrative data, self-reported physician diagnoses, and the Hospital Anxiety and Depression Scale. Multivariable linear regression examined whether diagnosed depression or anxiety affected HRQOL after accounting for current symptoms. Lifetime prevalence estimates for depression were approximately 30% regardless of methods used, but 35.8% with current depressive symptoms were not captured by either administrative data or self-reported diagnoses. Prevalence estimates of anxiety ranged from 11% to 19%, but 65.6% with current anxiety were not captured by either administrative data or self-reported diagnoses. Previous diagnoses did not decrease HRQOL after accounting for current symptoms. Depression and, to a greater extent, anxiety remain underdiagnosed and undertreated in MS; both substantially contribute to reduced HRQOL in MS.

Management under uncertainty: guide-lines for incorporating connectivity into the protection of coral reefs

NASA Astrophysics Data System (ADS)

McCook, L. J.; Almany, G. R.; Berumen, M. L.; Day, J. C.; Green, A. L.; Jones, G. P.; Leis, J. M.; Planes, S.; Russ, G. R.; Sale, P. F.; Thorrold, S. R.

2009-06-01

The global decline in coral reefs demands urgent management strategies to protect resilience. Protecting ecological connectivity, within and among reefs, and between reefs and other ecosystems is critical to resilience. However, connectivity science is not yet able to clearly identify the specific measures for effective protection of connectivity. This article aims to provide a set of principles or practical guidelines that can be applied currently to protect connectivity. These ‘rules of thumb’ are based on current knowledge and expert opinion, and on the philosophy that, given the urgency, it is better to act with incomplete knowledge than to wait for detailed understanding that may come too late. The principles, many of which are not unique to connectivity, include: (1) allow margins of error in extent and nature of protection, as insurance against unforeseen or incompletely understood threats or critical processes; (2) spread risks among areas; (3) aim for networks of protected areas which are: (a) comprehensive and spread—protect all biotypes, habitats and processes, etc., to capture as many possible connections, known and unknown; (b) adequate—maximise extent of protection for each habitat type, and for the entire region; (c) representative—maximise likelihood of protecting the full range of processes and spatial requirements; (d) replicated—multiple examples of biotypes or processes enhances risk spreading; (4) protect entire biological units where possible (e.g. whole reefs), including buffers around core areas. Otherwise, choose bigger rather than smaller areas; (5) provide for connectivity at a wide range of dispersal distances (within and between patches), emphasising distances <20-30 km; and (6) use a portfolio of approaches, including but not limited to MPAs. Three case studies illustrating the application of these principles to coral reef management in the Bohol Sea (Philippines), the Great Barrier Reef (Australia) and Kimbe Bay (Papua New Guinea) are described.

Maintaining the continuity of HIV-care records for patients transferring care between centers: challenges, workloads, needs and risks.

PubMed

Gill, M John; Ody, Meagan; Lynch, Tarah; Jessiman-Perreault, Lynn; Krentz, Hartmut B

2016-08-01

With improved life expectancy, the medical records of HIV-infected patients are likely to be transferred repeatedly between HIV caregivers. The challenges, and risk for introducing medical error from incomplete record transfers are poorly understood. We measured number of requests for record transfer, the workload incurred, and explore, using genotypic antiretroviral resistance testing results (GART), the potential risk of incomplete records. Using retrospective database and chart review, we examined all patients followed at the Southern Alberta Clinic between 1 January 2004 and 1 January 2015, and determined how many patients transferred care into and out our program, the associated requests and the workload for record transfer. Using a complete record of all GART tests, the potential importance of absent historic records in current treatment decisions was analyzed. The annual churn rate was 22 ± 3.4%. We received requests for only 70% of patient records who had left our care. Median time for receipt of incoming medical records was 28 days; average clerical time for processing data was 2 hours/record. Of all GART results, 25% exhibited resistance. Of 111 patients with potentially misleading GART results (i.e., documented historical resistance not visible on more recent GART), 34 (30.6%) had moved in from elsewhere. Rigorous maintenance of the continuity of the HIV record is not universally practiced. Resources, costs and logistic challenges as well as a lack of appreciation of risks clearly shown by GART testing, may be relevant barriers. Addressing such issues is pressing as aging and transfers of care are increasingly common.

Getting older can be exhausting.

PubMed

Mittal, Rohit; Ford, Mandy L; Coopersmith, Craig M

2014-07-29

Sepsis is a disease that affects primarily the aged. Although mortality is higher in both older septic patients and aged septic mice, the mechanisms underlying decreased survival in older hosts are incompletely understood. New work by Inoue and colleagues demonstrates persistent inflammation and T-cell exhaustion in older septic patients and aged septic mice. The clinical significance of these findings is manifested not only in increased mortality but also in a marked difference in secondary infections in older patients as long as a month following ICU admission.

Pearling Instabilities of a Viscoelastic Thread

NASA Astrophysics Data System (ADS)

Deblais, A.; Velikov, K. P.; Bonn, D.

2018-05-01

Pearling instabilities of slender viscoelastic threads have received much attention, but remain incompletely understood. We study the instabilities in polymer solutions subject to uniaxial elongational flow. Two distinctly different instabilites are observed: beads on a string and blistering. The beads-on-a-string structure arises from a capillary instability whereas the blistering instability has a different origin: it is due to a coupling between stress and polymer concentration. By varying the temperature to change the solution properties we elucidate the interplay between flow and phase separation.

Perceived poisons.

PubMed

Nañagas, Kristine A; Kirk, Mark A

2005-11-01

Perceived poisoning may manifest in numerous ways; however, all cases share certain characteristics. All are fostered by the wide availability of unreliable information about chemical safety, poor understanding of scientific principles, and ineffective risk communication. Although this problem is still incompletely understood, some approaches have been demonstrated to be useful, such as education about risk, appropriate reassurance, and empathy on the part of the practitioner. Successful management may curtail the spread or exacerbation of symptoms, whereas unsuccessful treatment may cause the problems to escalate, with detrimental effects on both society and patient.

Eddy properties in the Southern California Current System

NASA Astrophysics Data System (ADS)

Chenillat, Fanny; Franks, Peter J. S.; Capet, Xavier; Rivière, Pascal; Grima, Nicolas; Blanke, Bruno; Combes, Vincent

2018-05-01

The California Current System (CCS) is an eastern boundary upwelling system characterized by strong eddies that are often generated at the coast. These eddies contribute to intense, long-distance cross-shelf transport of upwelled water with enhanced biological activity. However, the mechanisms of formation of such coastal eddies, and more importantly their capacity to trap and transport tracers, are poorly understood. Their unpredictability and strong dynamics leave us with an incomplete picture of the physical and biological processes at work, their effects on coastal export, lateral water exchange among eddies and their surrounding waters, and how long and how far these eddies remain coherent structures. Focusing our analysis on the southern part of the CCS, we find a predominance of cyclonic eddies, with a 25-km radius and a SSH amplitude of 6 cm. They are formed near shore and travel slightly northwest offshore for 190 days at 2 km day-1. We then study one particular, representative cyclonic eddy using a combined Lagrangian and Eulerian numerical approach to characterize its kinematics. Formed near shore, this eddy trapped a core made up of 67% California Current waters and 33% California Undercurrent waters. This core was surrounded by other waters while the eddy detached from the coast, leaving the oldest waters at the eddy's core and the younger waters toward the edge. The eddy traveled several months as a coherent structure, with only limited lateral exchange within the eddy.

New insights into the pathogenesis of IgA nephropathy.

PubMed

Yeo, See Cheng; Cheung, Chee Kay; Barratt, Jonathan

2018-05-01

IgA nephropathy is the most common form of glomerulonephritis in many parts of the world and remains an important cause of end-stage renal disease. Current evidence suggests that IgA nephropathy is not due to a single pathogenic insult, but rather the result of multiple sequential pathogenic "hits". An abnormally increased level of circulating poorly O-galactosylated IgA1 and the production of O-glycan-specific antibodies leads to the formation of IgA1-containing immune complexes, and their subsequent mesangial deposition results in inflammation and glomerular injury. While this general framework has formed the foundation of our current understanding of the pathogenesis of IgA nephropathy, much work is ongoing to try to precisely define the genetic, epigenetic, immunological, and molecular basis of IgA nephropathy. In particular, the precise origin of poorly O-galactosylated IgA1 and the inciting factors for the production of O-glycan-specific antibodies continue to be intensely evaluated. The mechanisms responsible for mesangial IgA1 deposition and subsequent renal injury also remain incompletely understood. In this review, we summarize the current understanding of the key steps involved in the pathogenesis of IgA nephropathy. It is hoped that further advances in our understanding of this common glomerulonephritis will lead to novel diagnostic and prognostic biomarkers, and targeted therapies to ameliorate disease progression.

Feeling Heard & Understood in the Hospital Environment: Benchmarking Communication Quality Among Patients with Advanced Cancer Before and After Palliative Care Consultation.

PubMed

Ingersoll, Luke T; Saeed, Fahad; Ladwig, Susan; Norton, Sally A; Anderson, Wendy; Alexander, Stewart C; Gramling, Robert

2018-05-02

Maximizing value in palliative care requires continued development and standardization of communication quality indicators. To describe the basic epidemiology of a newly-adopted patient-centered communication quality indicator for hospitalized palliative care patie9nts with advanced cancer. Cross-sectional analysis of 207 advanced cancer patients who received palliative care consultation at two medical centers in the United States. Participants completed the Heard & Understood quality indicator immediately before and the day following the initial palliative care consultation: "Over the past two days ["24 hours" for the post-consultation version], how much have you felt heard and understood by the doctors, nurses and hospital staff? Completely/Quite a Bit/Moderately/Slightly/Not at All". We categorized "Completely" as indicating ideal quality. Approximately one-third indicated ideal Heard & Understood quality before palliative care consultation. Age, financial security, emotional distress, preferences for comfort-longevity tradeoffs at end-of-life, and prognosis expectations were associated with pre-consultation quality. Among those with less-than-ideal quality at baseline, 56% rated feeling more Heard & Understood the day following palliative care consultation. The greatest pre-post improvement was among people who had unformed end-of-life treatment preferences or who reported having "no idea" about their prognosis at baseline. Most patients felt incompletely heard and understood at the time of referral to palliative care consultation and more than half improved following consultation. Feeling heard and understood is an important quality indicator sensitive to interventions to improve care and key variations in the patient experience. Copyright © 2018. Published by Elsevier Inc.

Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells

PubMed Central

Dai, Haiming; Ding, Husheng; Meng, X. Wei; Peterson, Kevin L.; Schneider, Paula A.; Karp, Judith E.; Kaufmann, Scott H.

2015-01-01

Mitochondrial outer membrane permeabilization (MOMP), a key step in the intrinsic apoptotic pathway, is incompletely understood. Current models emphasize the role of BH3-only BCL2 family members in BAX and BAK activation. Here we demonstrate concentration-dependent BAK autoactivation under cell-free conditions and provide evidence that this autoactivation plays a key role in regulating the intrinsic apoptotic pathway in intact cells. In particular, we show that up to 80% of BAK (but not BAX) in lymphohematopoietic cell lines is oligomerized and bound to anti-apoptotic BCL2 family members in the absence of exogenous death stimuli. The extent of this constitutive BAK oligomerization is diminished by BAK knockdown and unaffected by BIM or PUMA down-regulation. Further analysis indicates that sensitivity of cells to BH3 mimetics reflects the identity of the anti-apoptotic proteins to which BAK is constitutively bound, with extensive BCLXL•BAK complexes predicting navitoclax sensitivity, and extensive MCL1•BAK complexes predicting A1210477 sensitivity. Moreover, high BAK expression correlates with sensitivity of clinical acute myelogenous leukemia to chemotherapy, whereas low BAK levels correlate with resistance and relapse. Collectively, these results inform current understanding of MOMP and provide new insight into the ability of BH3 mimetics to induce apoptosis without directly activating BAX or BAK. PMID:26494789

Obesity hypoventilation syndrome: current theories of pathogenesis.

PubMed

Pierce, Aaron M; Brown, Lee K

2015-11-01

To summarize recent primary publications and discuss the impact these finding have on current understanding on the development of hypoventilation in obesity hypoventilation syndrome (OHS), also known as Pickwickian syndrome. As a result of the significant morbidity and mortality associated with OHS, evidence is building for pre-OHS intermediate states that can be identified earlier and treated sooner, with the goal of modifying disease course. Findings of alterations in respiratory mechanics with obesity remain unchanged; however, elevated metabolism and CO2 production may be instrumental in OHS-related hypercapnia. Ongoing positive airway pressure trials continue to demonstrate that correction of nocturnal obstructive sleep apnea and hypoventilation improves diurnal respiratory physiology, metabolic profiles, quality of life, and morbidity/mortality. Finally, CNS effects of leptin on respiratory mechanics and chemoreceptor sensitivity are becoming better understood; however, characterization remains incomplete. OHS is a complex multiorgan system disease process that appears to be driven by adaptive changes in respiratory physiology and compensatory changes in metabolic processes, both of which are ultimately counter-productive. The diurnal hypercapnia and hypoxia induce pathologic effects that further worsen sleep-related breathing, resulting in a slowly progressive worsening of disease. In addition, leptin resistance in obesity and OHS likely contributes to blunting of ventilatory drive and inadequate chemoreceptor response to hypercarbia and hypoxemia.

A clinical comparison of penetrating and blunt traumatic brain injuries.

PubMed

Santiago, Luis A; Oh, Bryan C; Dash, Pramod K; Holcomb, John B; Wade, Charles E

2012-01-01

Traumatic brain injury (TBI) is a leading cause of injury death and long-term disability in the USA. It commonly results from blunt (closed) or penetrating trauma. The majority of civilian TBI is caused by falls or motor vehicle collisions, whereas military TBI mainly results from explosions. Although penetrating injuries are less common than closed injuries in the civilian population, they are far more lethal. Unfortunately, the pathophysiologic differences between penetrating and closed TBI remain poorly understood due to the lack of studies on the subject. Many studies on the prognostic factors of mortality and functional outcome after TBI exclude penetrating brain injuries from their series because they are believed to have a different pathophysiology. 125 Articles regarding brain injury were reviewed and summarized for this report. Despite the absence of a clear delineation between penetrating and blunt TBI, the current guidelines for penetrating TBI suggest defaulting to management strategies used for closed TBI with limited supportive evidence. Thus, injuries that appear to have different pathophysiologies and outcomes are managed equally and perhaps not optimally. In view of the incomplete understanding of the impact of mechanism of injury on TBI outcomes, as demonstrated in the current review, new research studies are required to improve evidence-based TBI guidelines tailored especially for penetrating injuries.

Molecular phylogeny of the Nearctic and Mesoamerican freshwater mussel genus Megalonaias

USGS Publications Warehouse

Pfeiffer, John M.; Sharpe, Ashley; Johnson, Nathan A.; Emery, Kitty F.; Page, Lawrence M.

2018-01-01

Megalonaias is the most geographically widespread genus of the subfamily Ambleminae and is distributed across much of the eastern half of North America, from Minnesota to Nicaragua. Despite the large geographic distribution, the species-level diversity of Megalonaias is quite depauperate (2 spp.), suggesting the genus may not be constrained by the same physical, ecological, or physiological barriers that limit dispersal in many other amblemines. However, this hypothesis is contingent on the assumption that the current taxonomy of Megalonaiasaccurately reflects its evolutionary history, which remains incompletely understood due to the marginalization of Mesoamerican populations in systematic research. Using one mitochondrial (COI) and one nuclear marker (ITS1) sequenced from 41 individuals distributed across both the Nearctic and Mesoamerican ecoregions, we set out to better understand the species boundaries and genetic diversity within Megalonaias. The reconstructed molecular phylogeny and the observed genetic diversity suggests that Megalonaias is a monotypic genus and that Megalonaias nickliniana, currently considered a federally endangered species, is not a valid species. These results are discussed in the context of their systematic and conservation implications, as well as how the unusual life history strategy of Megalonaias may be influencing its molecular diversity.

A Drosophila Toolkit for the Visualization and Quantification of Viral Replication Launched from Transgenic Genomes

PubMed Central

Wernet, Mathias F.; Klovstad, Martha; Clandinin, Thomas R.

2014-01-01

Arthropod RNA viruses pose a serious threat to human health, yet many aspects of their replication cycle remain incompletely understood. Here we describe a versatile Drosophila toolkit of transgenic, self-replicating genomes (‘replicons’) from Sindbis virus that allow rapid visualization and quantification of viral replication in vivo. We generated replicons expressing Luciferase for the quantification of viral replication, serving as useful new tools for large-scale genetic screens for identifying cellular pathways that influence viral replication. We also present a new binary system in which replication-deficient viral genomes can be activated ‘in trans’, through co-expression of an intact replicon contributing an RNA-dependent RNA polymerase. The utility of this toolkit for studying virus biology is demonstrated by the observation of stochastic exclusion between replicons expressing different fluorescent proteins, when co-expressed under control of the same cellular promoter. This process is analogous to ‘superinfection exclusion’ between virus particles in cell culture, a process that is incompletely understood. We show that viral polymerases strongly prefer to replicate the genome that encoded them, and that almost invariably only a single virus genome is stochastically chosen for replication in each cell. Our in vivo system now makes this process amenable to detailed genetic dissection. Thus, this toolkit allows the cell-type specific, quantitative study of viral replication in a genetic model organism, opening new avenues for molecular, genetic and pharmacological dissection of virus biology and tool development. PMID:25386852

Neuroblastoma: treatment outcome after incomplete resection of primary tumors.

PubMed

Moon, Suk-Bae; Park, Kwi-Won; Jung, Sung-Eun; Youn, Woong-Jae

2009-09-01

For International Neuroblastoma Staging System (INSS) stages III or IV neuroblastoma (intermediate or high risk), complete excision of the primary tumor is not always feasible. Most current studies on the treatment outcome of these patients have reported on the complete excision status. The aim of this study is to review the treatment outcome after the incomplete resection. The medical records of 37 patients that underwent incomplete resection between January 1986 and December 2005 were reviewed retrospectively. Incomplete resection was assessed by review of the operative notes and postoperative computerized tomography. Age, gender, tumor location, INSS stage, N-myc gene copy number, pre- and postoperative therapy, and treatment outcome were reviewed. The treatment outcome was evaluated according to the postoperative treatment protocol in the high-risk group. Intermediate-risk patients were treated with conventional chemotherapy, isotretinoin (ITT) and interleukin-2 (IL-2). High-risk patients were treated with peripheral blood stem cell transplantation (PBSCT), ITT, and IL-2 (N = 11). Before the introduction of PBSCT, the high-risk patients were also treated with the conventional chemotherapy (N = 19). Intermediate-risk patients (N = 5) currently have no evidence of disease (NED). For the high-risk patients (N = 32), 19 patients were treated with chemotherapy alone; 15 patients died of their disease while four patients currently have an NED status. Eight of 11 patients that underwent PBSCT are currently alive. For intermediate risk, conventional chemotherapy appears to be acceptable treatment. However, for high-risk patients, every effort should be made to control residual disease including the use of myeloablative chemotherapy, differentiating agents and immune-modulating agents.

Poorly Understood Aspects of Striated Muscle Contraction

PubMed Central

Månsson, Alf

2015-01-01

Muscle contraction results from cyclic interactions between the contractile proteins myosin and actin, driven by the turnover of adenosine triphosphate (ATP). Despite intense studies, several molecular events in the contraction process are poorly understood, including the relationship between force-generation and phosphate-release in the ATP-turnover. Different aspects of the force-generating transition are reflected in the changes in tension development by muscle cells, myofibrils and single molecules upon changes in temperature, altered phosphate concentration, or length perturbations. It has been notoriously difficult to explain all these events within a given theoretical framework and to unequivocally correlate observed events with the atomic structures of the myosin motor. Other incompletely understood issues include the role of the two heads of myosin II and structural changes in the actin filaments as well as the importance of the three-dimensional order. We here review these issues in relation to controversies regarding basic physiological properties of striated muscle. We also briefly consider actomyosin mutation effects in cardiac and skeletal muscle function and the possibility to treat these defects by drugs. PMID:25961006

Poorly understood aspects of striated muscle contraction.

PubMed

Månsson, Alf; Rassier, Dilson; Tsiavaliaris, Georgios

2015-01-01

Muscle contraction results from cyclic interactions between the contractile proteins myosin and actin, driven by the turnover of adenosine triphosphate (ATP). Despite intense studies, several molecular events in the contraction process are poorly understood, including the relationship between force-generation and phosphate-release in the ATP-turnover. Different aspects of the force-generating transition are reflected in the changes in tension development by muscle cells, myofibrils and single molecules upon changes in temperature, altered phosphate concentration, or length perturbations. It has been notoriously difficult to explain all these events within a given theoretical framework and to unequivocally correlate observed events with the atomic structures of the myosin motor. Other incompletely understood issues include the role of the two heads of myosin II and structural changes in the actin filaments as well as the importance of the three-dimensional order. We here review these issues in relation to controversies regarding basic physiological properties of striated muscle. We also briefly consider actomyosin mutation effects in cardiac and skeletal muscle function and the possibility to treat these defects by drugs.

Mechanisms of Cancer Cell Dormancy--Another Hallmark of Cancer?

PubMed

Yeh, Albert C; Ramaswamy, Sridhar

2015-12-01

Disease relapse in cancer patients many years after clinical remission, often referred to as cancer dormancy, is well documented but remains an incompletely understood phenomenon on the biologic level. Recent reviews have summarized potential models that can explain this phenomenon, including angiogenic, immunologic, and cellular dormancy. We focus on mechanisms of cellular dormancy as newer biologic insights have enabled better understanding of this process. We provide a historical context, synthesize current advances in the field, and propose a mechanistic framework that treats cancer cell dormancy as a dynamic cell state conferring a fitness advantage to an evolving malignancy under stress. Cellular dormancy appears to be an active process that can be toggled through a variety of signaling mechanisms that ultimately downregulate the RAS/MAPK and PI(3)K/AKT pathways, an ability that is preserved even in cancers that constitutively depend on these pathways for their growth and survival. Just as unbridled proliferation is a key hallmark of cancer, the ability of cancer cells to become quiescent may be critical to evolving malignancies, with implications for understanding cancer initiation, progression, and treatment resistance. ©2015 American Association for Cancer Research.

Mechanisms of Cancer Cell Dormancy – Another Hallmark of Cancer?

PubMed Central

Yeh, Albert C.; Ramaswamy, Sridhar

2015-01-01

Disease relapse in cancer patients many years after clinical remission, often referred to as cancer dormancy, is well documented but remains an incompletely understood phenomenon on the biological level. Recent reviews have summarized potential models that can explain this phenomenon, including angiogenic, immunologic, and cellular dormancy. We focus on mechanisms of cellular dormancy as newer biological insights have enabled better understanding of this process. We provide a historical context, synthesize current advances in the field, and propose a mechanistic framework that treats cancer cell dormancy as a dynamic cell state conferring a fitness advantage to an evolving malignancy under stress. Cellular dormancy appears to be an active process that can be toggled through a variety of signaling mechanisms that ultimately down-regulate the Ras/MAPK and PI(3)K/AKT pathways, an ability that is preserved even in cancers that constitutively depend on these pathways for their growth and survival. Just as unbridled proliferation is a key hallmark of cancer, the ability of cancer cells to become quiescent may be critical to evolving malignancies, with implications for understanding cancer initiation, progression, and treatment resistance. PMID:26354021

Cell Cycle Regulation of Stem Cells by MicroRNAs.

PubMed

Mens, Michelle M J; Ghanbari, Mohsen

2018-06-01

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules involved in the regulation of gene expression. They are involved in the fine-tuning of fundamental biological processes such as proliferation, differentiation, survival and apoptosis in many cell types. Emerging evidence suggests that miRNAs regulate critical pathways involved in stem cell function. Several miRNAs have been suggested to target transcripts that directly or indirectly coordinate the cell cycle progression of stem cells. Moreover, previous studies have shown that altered expression levels of miRNAs can contribute to pathological conditions, such as cancer, due to the loss of cell cycle regulation. However, the precise mechanism underlying miRNA-mediated regulation of cell cycle in stem cells is still incompletely understood. In this review, we discuss current knowledge of miRNAs regulatory role in cell cycle progression of stem cells. We describe how specific miRNAs may control cell cycle associated molecules and checkpoints in embryonic, somatic and cancer stem cells. We further outline how these miRNAs could be regulated to influence cell cycle progression in stem cells as a potential clinical application.

The PI3K/Akt pathway is required for LPS activation of microglial cells.

PubMed

Saponaro, Concetta; Cianciulli, Antonia; Calvello, Rosa; Dragone, Teresa; Iacobazzi, Francesco; Panaro, Maria Antonietta

2012-10-01

Upregulation of inflammatory responses in the brain is associated with a number of neurodegenerative diseases. Microglia are activated in neurodegenerative diseases, producing pro-inflammatory mediators. Critically, lipopolysaccharide (LPS)-induced microglial activation causes dopaminergic neurodegeneration in vitro and in vivo. The signaling mechanisms triggered by LPS to stimulate the release of pro-inflammatory mediators in microglial cells are still incompletely understood. To further explore the mechanisms of LPS-mediated inflammatory response of microglial cells, we studied the role of phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathways known to be activated by toll-like receptor-4 signaling through LPS. In the current study, we report that the activation profile of LPS-induced pAkt activation preceded those of LPS-induced NF-κB activation, suggesting a role for PI3K/Akt in the pathway activation of NF-κB-dependent inflammatory responses of activated microglia. These results, providing the first evidence that PI3K dependent signaling is involved in the inflammatory responses of microglial cells following LPS stimulation, may be useful in preventing inflammatory based neurodegenerative processes.

Cardiovascular Consequences of Metabolic Syndrome

PubMed Central

Tune, Johnathan D.; Goodwill, Adam G.; Sassoon, Daniel J.; Mather, Kieren J.

2017-01-01

The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiologic mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review we highlight current knowledge regarding the pathophysiologic consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiologic and molecular mechanisms that may contribute to these adverse outcomes. PMID:28130064

A human-infecting H10N8 influenza virus retains a strong preference for avian-type receptors

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

Zhang, Heng; de Vries, Robert  P.; Tzarum, Netanel

Recent avian-origin H10N8 influenza A viruses that have infected humans pose a potential pandemic threat. Alterations in the viral surface glycoprotein, hemagglutinin (HA), typically are required for influenza A viruses to cross the species barrier for adaptation to a new host, but whether H10N8 contains adaptations supporting human infection remains incompletely understood. In this paper, we investigated whether H10N8 HA can bind human receptors. Sialoside glycan microarray analysis showed that the H10 HA retains a strong preference for avian receptor analogs and negligible binding to human receptor analogs. Crystal structures of H10 HA with avian and human receptor analogs revealedmore » the basis for preferential recognition of avian-like receptors. Furthermore, introduction of mutations into the H10 receptor-binding site (RBS) known to convert other HA subtypes from avian to human receptor specificity failed to switch preference to human receptors. In conclusion, collectively these findings suggest that the current H10N8 human isolates are poorly adapted for efficient human-to-human transmission.« less

The proximal-to-distal sequence in upper-limb motions on multiple levels and time scales.

PubMed

Serrien, Ben; Baeyens, Jean-Pierre

2017-10-01

The proximal-to-distal sequence is a phenomenon that can be observed in a large variety of motions of the upper limbs in both humans and other mammals. The mechanisms behind this sequence are not completely understood and motor control theories able to explain this phenomenon are currently incomplete. The aim of this narrative review is to take a theoretical constraints-led approach to the proximal-to-distal sequence and provide a broad multidisciplinary overview of relevant literature. This sequence exists at multiple levels (brain, spine, muscles, kinetics and kinematics) and on multiple time scales (motion, motor learning and development, growth and possibly even evolution). We hypothesize that the proximodistal spatiotemporal direction on each time scale and level provides part of the organismic constraints that guide the dynamics at the other levels and time scales. The constraint-led approach in this review may serve as a first onset towards integration of evidence and a framework for further experimentation to reveal the dynamics of the proximal-to-distal sequence. Copyright © 2017 Elsevier B.V. All rights reserved.

A human-infecting H10N8 influenza virus retains a strong preference for avian-type receptors

DOE PAGES

Zhang, Heng; de Vries, Robert  P.; Tzarum, Netanel; ...

2015-03-11

Recent avian-origin H10N8 influenza A viruses that have infected humans pose a potential pandemic threat. Alterations in the viral surface glycoprotein, hemagglutinin (HA), typically are required for influenza A viruses to cross the species barrier for adaptation to a new host, but whether H10N8 contains adaptations supporting human infection remains incompletely understood. In this paper, we investigated whether H10N8 HA can bind human receptors. Sialoside glycan microarray analysis showed that the H10 HA retains a strong preference for avian receptor analogs and negligible binding to human receptor analogs. Crystal structures of H10 HA with avian and human receptor analogs revealedmore » the basis for preferential recognition of avian-like receptors. Furthermore, introduction of mutations into the H10 receptor-binding site (RBS) known to convert other HA subtypes from avian to human receptor specificity failed to switch preference to human receptors. In conclusion, collectively these findings suggest that the current H10N8 human isolates are poorly adapted for efficient human-to-human transmission.« less

Advances in IBS 2016: A Review of Current and Emerging Data.

PubMed

Schoenfeld, Philip S

2016-08-01

Irritable bowel syndrome (IBS) is characterized by chronic intermittent abdominal pain and associated diarrhea (IBS-D), constipation (IBS-C), or both. IBS can significantly impact patient function and quality of life. The diagnosis of IBS is based on the presence of characteristic symptoms, the exclusion of concerning features, and selected tests to exclude organic diseases that can mimic IBS. The pathophysiology of IBS remains incompletely understood, and new contributing factors have been identified over the past decade. Altered gut immune activation, intestinal permeability, and the intestinal and colonic microbiome may be important factors. Poorly absorbed carbohydrates have been implicated in triggering IBS symptoms. Increasing evidence supports the benefit of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). Although there are several randomized controlled trials of probiotics in IBS, they are typically poorly designed and have not consistently demonstrated efficacy. Until recently, there were few effective treatments for IBS-D. Data from recent clinical trials support the use of rifaximin, eluxadoline, and peppermint oil. Options for the treatment of IBS-C include lubiprostone and linaclotide.

Advances in IBS 2016: A Review of Current and Emerging Data

PubMed Central

Schoenfeld, Philip S.

2016-01-01

Irritable bowel syndrome (IBS) is characterized by chronic intermittent abdominal pain and associated diarrhea (IBS-D), constipation (IBS-C), or both. IBS can significantly impact patient function and quality of life. The diagnosis of IBS is based on the presence of characteristic symptoms, the exclusion of concerning features, and selected tests to exclude organic diseases that can mimic IBS. The pathophysiology of IBS remains incompletely understood, and new contributing factors have been identified over the past decade. Altered gut immune activation, intestinal permeability, and the intestinal and colonic microbiome may be important factors. Poorly absorbed carbohydrates have been implicated in triggering IBS symptoms. Increasing evidence supports the benefit of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). Although there are several randomized controlled trials of probiotics in IBS, they are typically poorly designed and have not consistently demonstrated efficacy. Until recently, there were few effective treatments for IBS-D. Data from recent clinical trials support the use of rifaximin, eluxadoline, and peppermint oil. Options for the treatment of IBS-C include lubiprostone and linaclotide. PMID:28070176

The maternal womb: a novel target for cancer prevention in the era of the obesity pandemic?

PubMed Central

Simmen, Frank A.; Simmen, Rosalia C.M.

2011-01-01

The dramatic rise in worldwide prevalence of obesity has necessitated the search for more efficacious anti-obesity strategies to counter the increased cancer risks in overweight and obese individuals. The mechanistic pathways linking obesity status with adult chronic diseases such as cancer remain incompletely understood. A growing body of evidence suggests that novel approaches and interventional agents to disrupt the feed-forward cycle of maternal to offspring obesity transfer that is initiated in utero, will be important for stemming both the obesity pandemic and the associated increase in cancer incidence. The convergence of multiple research areas including those encompassing the insulin and insulin-like growth factor (IGF) systems, epigenetics, and stem cell biology is providing insights into the potential for cancer prevention in adult offspring previously exposed to the intrauterine environment of overweight/obese mothers. Here, we review the current state of this nascent research field, with a focus on three major cancers namely breast, colorectal and liver, and suggest some possible future directions to optimize its impact for the health of future generations. PMID:21701386

Co-amplification of phosphoinositide 3-kinase enhancer A and cyclin-dependent kinase 4 triggers glioblastoma progression | Office of Cancer Genomics

Cancer.gov

Glioblastoma (GBM) is the most common primary brain tumor and has a dismal prognosis. Amplification of chromosome 12q13-q15 (Cyclin-dependent kinase 4 (CDK4) amplicon) is frequently observed in numerous human cancers including GBM. Phosphoinositide 3-kinase enhancer (PIKE) is a group of GTP-binding proteins that belong to the subgroup of centaurin GTPase family, encoded by CENTG1 located in CDK4 amplicon. However, the pathological significance of CDK4 amplicon in GBM formation remains incompletely understood.

Bone-Immune Cell Crosstalk: Bone Diseases

PubMed Central

Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta

2015-01-01

Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma. PMID:26000310

Bone-immune cell crosstalk: bone diseases.

PubMed

Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta; Brunetti, Giacomina

2015-01-01

Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma.

Sleep Deprivation.

PubMed

Abrams, Robert M

2015-09-01

Sleep deprivation occurs when inadequate sleep leads to decreased performance, inadequate alertness, and deterioration in health. It is incompletely understood why humans need sleep, although some theories include energy conservation, restoration, and information processing. Sleep deprivation has many deleterious health effects. Residency programs have enacted strict work restrictions because of medically related errors due to sleep deprivation. Because obstetrics is an unpredictable specialty with long irregular hours, enacting a hospitalist program enhances patient safety, decreases malpractice risk, and improves the physician's quality of life by allowing obstetricians to get sufficient rest. Copyright © 2015 Elsevier Inc. All rights reserved.

Lengthening our perspective: morphological, cellular, and molecular responses to eccentric exercise.

PubMed

Hyldahl, Robert D; Hubal, Monica J

2014-02-01

The response of skeletal muscle to unaccustomed eccentric exercise has been studied widely, yet it is incompletely understood. This review is intended to provide an up-to-date overview of our understanding of how skeletal muscle responds to eccentric actions, with particular emphasis on the underlying molecular and cellular mechanisms of damage and recovery. This review begins by addressing the question of whether eccentric actions result in physical damage to muscle fibers and/or connective tissue. We next review the symptomatic manifestations of eccentric exercise (i.e., indirect damage markers, such as delayed onset muscle soreness), with emphasis on their relatively poorly understood molecular underpinnings. We then highlight factors that potentially modify the muscle damage response following eccentric exercise. Finally, we explore the utility of using eccentric training to improve muscle function in populations of healthy and aging individuals, as well as those living with neuromuscular disorders. Copyright © 2013 Wiley Periodicals, Inc.

Finite element simulation of thickness changes in laminate during thermoforming

NASA Astrophysics Data System (ADS)

White, K. D.; Sherwood, J. A.

2017-10-01

This paper discusses a numerical investigation of thickness changes of Dyneema HB80, a cross-ply thermoplastic lamina, during a helmet thermoforming process. The main mode of deformation during the preform phase of manufacture is in-plane shearing of the fabric. A laminate undergoes varying degrees of shear to conform to the geometric variations over the surface of the preform shape. Decreases in areal coverage that occur with increases in the local shear angle will lead to a resulting increase in local thickness. During the consolidation phase, multiple preform layers are compressed in a set of matched tools, and the compounding of the thickness variations can adversely affect the uniformity of pressure distribution between matched die tooling. Pressure variations over the surface of the part can lead to incomplete consolidation of the ply stack, as well as weakened, resin-rich areas. Because wrinkling of the composite reinforcement, incomplete consolidation and resin-rich areas can result in a compromised structural performance, it is important that the manufacturing process be well understood so it can be designed to mitigate formation of such defects. In the current work, the material properties derived from shear, bending and tensile tests are implemented in a finite element model of the cross-ply lamina. The finite element model uses a hybrid discrete mesoscopic approach, and deep-draw forming of the material is simulated to investigate its formability to a hemispherical geometry. Thickening of the lamina resulting from shear deformation is investigated and incorporated into models single-layer preform simulations. The simulation results are used to inform the design of multiple-layer preforms to mitigate the development of thin regions and out-of-plane waves to ensure complete, uniform consolidation.

Detection of lack of fusion using opaque additives

NASA Technical Reports Server (NTRS)

Cook, J. L.

1973-01-01

Reliable nondestructive inspection for incomplete weldment penetration and rapid oxidation of aluminum surfaces when exposed to the atmosphere are currently two major problems in welded aluminum spacecraft structure. Incomplete-penetration defects are extremely difficult to detect and can lead to catastrophic failure of the structure. The moisture absorbed by aluminum oxide on the surface can cause weldment porosity if the surface is not cleaned before welding. The approach employed in this program to solve both problems was to employ copper as a coating to prevent oxidation of the aluminum. Also, copper was used as an opaque additive in the weldment to enhance X-ray detection in the event of incomplete penetration.

Functional role of A-type potassium currents in rat presympathetic PVN neurones

PubMed Central

Sonner, Patrick M; Stern, Javier E

2007-01-01

Despite the fact that paraventricular nucleus (PVN) neurones innervating the rostral ventrolateral medulla (RVLM) play important roles in the control of sympathetic function both in physiological and pathological conditions, the precise mechanisms controlling their activity are still incompletely understood. In the present study, we evaluated whether the transient outward potassium current IA is expressed in PVN-RVLM neurones, characterized its biophysical and pharmacological properties, and determined its role in shaping action potentials and firing discharge in these neurones. Patch-clamp recordings obtained from retrogradely labelled, PVN-RVLM neurones indicate that a 4-AP sensitive, TEA insensitive current, with biophysical properties consistent with IA, is present in these neurones. Pharmacological blockade of IA depolarized resting Vm and prolonged Na+ action potential duration, by increasing its width and by slowing down its decay time course. Interestingly, blockade of IA either increased or decreased the firing activity of PVN-RVLM neurones, supporting the presence of subsets of PVN-RVLM neurones differentially modulated by IA. In all cases, the effects of IA on firing activity were prevented by a broad spectrum Ca2+ channel blocker. Immunohistochemical studies suggest that IA in PVN-RVLM neurons is mediated by Kv1.4 and/or Kv4.3 channel subunits. Overall, our results demonstrate the presence of IA in PVN-RVLM neurones, which actively modulates their action potential waveform and firing activity. These studies support IA as an important intrinsic mechanism controlling neuronal excitability in this central presympathetic neuronal population. PMID:17525115

Latent Class Analysis of Incomplete Data via an Entropy-Based Criterion

PubMed Central

Larose, Chantal; Harel, Ofer; Kordas, Katarzyna; Dey, Dipak K.

2016-01-01

Latent class analysis is used to group categorical data into classes via a probability model. Model selection criteria then judge how well the model fits the data. When addressing incomplete data, the current methodology restricts the imputation to a single, pre-specified number of classes. We seek to develop an entropy-based model selection criterion that does not restrict the imputation to one number of clusters. Simulations show the new criterion performing well against the current standards of AIC and BIC, while a family studies application demonstrates how the criterion provides more detailed and useful results than AIC and BIC. PMID:27695391

Vast underestimation of Madagascar's biodiversity evidenced by an integrative amphibian inventory

PubMed Central

Vieites, David R.; Wollenberg, Katharina C.; Andreone, Franco; Köhler, Jörn; Glaw, Frank; Vences, Miguel

2009-01-01

Amphibians are in decline worldwide. However, their patterns of diversity, especially in the tropics, are not well understood, mainly because of incomplete information on taxonomy and distribution. We assess morphological, bioacoustic, and genetic variation of Madagascar's amphibians, one of the first near-complete taxon samplings from a biodiversity hotspot. Based on DNA sequences of 2,850 specimens sampled from over 170 localities, our analyses reveal an extreme proportion of amphibian diversity, projecting an almost 2-fold increase in species numbers from the currently described 244 species to a minimum of 373 and up to 465. This diversity is widespread geographically and across most major phylogenetic lineages except in a few previously well-studied genera, and is not restricted to morphologically cryptic clades. We classify the genealogical lineages in confirmed and unconfirmed candidate species or deeply divergent conspecific lineages based on concordance of genetic divergences with other characters. This integrative approach may be widely applicable to improve estimates of organismal diversity. Our results suggest that in Madagascar the spatial pattern of amphibian richness and endemism must be revisited, and current habitat destruction may be affecting more species than previously thought, in amphibians as well as in other animal groups. This case study suggests that worldwide tropical amphibian diversity is probably underestimated at an unprecedented level and stresses the need for integrated taxonomic surveys as a basis for prioritizing conservation efforts within biodiversity hotspots. PMID:19416818

Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells.

PubMed

Dai, Haiming; Ding, Husheng; Meng, X Wei; Peterson, Kevin L; Schneider, Paula A; Karp, Judith E; Kaufmann, Scott H

2015-10-15

Mitochondrial outer membrane permeabilization (MOMP), a key step in the intrinsic apoptotic pathway, is incompletely understood. Current models emphasize the role of BH3-only BCL2 family members in BAX and BAK activation. Here we demonstrate concentration-dependent BAK autoactivation under cell-free conditions and provide evidence that this autoactivation plays a key role in regulating the intrinsic apoptotic pathway in intact cells. In particular, we show that up to 80% of BAK (but not BAX) in lymphohematopoietic cell lines is oligomerized and bound to anti-apoptotic BCL2 family members in the absence of exogenous death stimuli. The extent of this constitutive BAK oligomerization is diminished by BAK knockdown and unaffected by BIM or PUMA down-regulation. Further analysis indicates that sensitivity of cells to BH3 mimetics reflects the identity of the anti-apoptotic proteins to which BAK is constitutively bound, with extensive BCLXL•BAK complexes predicting navitoclax sensitivity, and extensive MCL1•BAK complexes predicting A1210477 sensitivity. Moreover, high BAK expression correlates with sensitivity of clinical acute myelogenous leukemia to chemotherapy, whereas low BAK levels correlate with resistance and relapse. Collectively, these results inform current understanding of MOMP and provide new insight into the ability of BH3 mimetics to induce apoptosis without directly activating BAX or BAK. © 2015 Dai et al.; Published by Cold Spring Harbor Laboratory Press.

Targeted Coagulation Management in Severe Trauma: The Controversies and the Evidence.

PubMed

Winearls, James; Reade, Michael; Miles, Helen; Bulmer, Andrew; Campbell, Don; Görlinger, Klaus; Fraser, John F

2016-10-01

Hemorrhage in the setting of severe trauma is a leading cause of death worldwide. The pathophysiology of hemorrhage and coagulopathy in severe trauma is complex and remains poorly understood. Most clinicians currently treating trauma patients acknowledge the presence of a coagulopathy unique to trauma patients-trauma-induced coagulopathy (TIC)-independently associated with increased mortality. The complexity and incomplete understanding of TIC has resulted in significant controversy regarding optimum management. Although the majority of trauma centers utilize fixed-ratio massive transfusion protocols in severe traumatic hemorrhage, a widely accepted "ideal" transfusion ratio of blood to blood products remains elusive. The recent use of viscoelastic hemostatic assays (VHAs) to guide blood product replacement has further provoked debate as to the optimum transfusion strategy. The use of VHA to quantify the functional contributions of individual components of the coagulation system may permit targeted treatment of TIC but remains controversial and is unlikely to demonstrate a mortality benefit in light of the heterogeneity of the trauma population. Thus, VHA-guided algorithms as an alternative to fixed product ratios in trauma are not universally accepted, and a hybrid strategy starting with fixed-ratio transfusion and incorporating VHA data as they become available is favored by some institutions. We review the current evidence for the management of coagulopathy in trauma, the rationale behind the use of targeted and fixed-ratio approaches and explore future directions.

Vast underestimation of Madagascar's biodiversity evidenced by an integrative amphibian inventory.

PubMed

Vieites, David R; Wollenberg, Katharina C; Andreone, Franco; Köhler, Jörn; Glaw, Frank; Vences, Miguel

2009-05-19

Amphibians are in decline worldwide. However, their patterns of diversity, especially in the tropics, are not well understood, mainly because of incomplete information on taxonomy and distribution. We assess morphological, bioacoustic, and genetic variation of Madagascar's amphibians, one of the first near-complete taxon samplings from a biodiversity hotspot. Based on DNA sequences of 2,850 specimens sampled from over 170 localities, our analyses reveal an extreme proportion of amphibian diversity, projecting an almost 2-fold increase in species numbers from the currently described 244 species to a minimum of 373 and up to 465. This diversity is widespread geographically and across most major phylogenetic lineages except in a few previously well-studied genera, and is not restricted to morphologically cryptic clades. We classify the genealogical lineages in confirmed and unconfirmed candidate species or deeply divergent conspecific lineages based on concordance of genetic divergences with other characters. This integrative approach may be widely applicable to improve estimates of organismal diversity. Our results suggest that in Madagascar the spatial pattern of amphibian richness and endemism must be revisited, and current habitat destruction may be affecting more species than previously thought, in amphibians as well as in other animal groups. This case study suggests that worldwide tropical amphibian diversity is probably underestimated at an unprecedented level and stresses the need for integrated taxonomic surveys as a basis for prioritizing conservation efforts within biodiversity hotspots.

Myocardial Hypertrophy and Its Role in Heart Failure with Preserved Ejection Fraction

PubMed Central

Heinzel, Frank R.; Hohendanner, Felix; Jin, Ge; Sedej, Simon; Edelmann, Frank

2015-01-01

Left ventricular hypertrophy (LVH) is the most common myocardial structural abnormality associated with heart failure with preserved ejection fraction (HFpEF). LVH is driven by neurohumoral activation, increased mechanical load and cytokines associated with arterial hypertension, chronic kidney disease, diabetes and other co-morbidities. Here we discuss the experimental and clinical evidence that links LVH to diastolic dysfunction and qualifies LVH as one diagnostic marker for HFpEF. Mechanisms leading to diastolic dysfunction in LVH are incompletely understood but may include extracellular matrix changes, vascular dysfunction as well as altered cardiomyocyte mechano-elastical properties. Beating cardiomyocytes from HFpEF patients have not yet been studied, but we and others have shown increased Ca2+ turnover and impaired relaxation in cardiomyocytes from hypertrophied hearts. Structural myocardial remodeling can lead to heterogeneity in regional myocardial contractile function, which contributes to diastolic dysfunction in HFpEF. In the clinical setting of patients with compound co-morbidities, diastolic dysfunction may occur independently of LVH. This may be one explanation why current approaches to reduce LVH have not been effective to improve symptoms and prognosis in HFpEF. Exercise training on the other hand, in clinical trials improved exercise tolerance and diastolic function but did not reduce LVH. Thus, current clinical evidence does not support regression of LVH as a surrogate marker for (short-term) improvement of HFpEF. PMID:26183480

Psychosocial Factors and Central Sensitivity Syndromes

PubMed Central

Adams, Leah M.; Turk, Dennis C.

2016-01-01

Central sensitivity syndromes (CSSs) represent a heterogeneous group of disorders (e.g., fibromyalgia [FM], irritable bowel syndrome [IBS], chronic headache, temporomandibular disorders [TMDs], pelvic pain syndromes) that share common symptoms, with persistent pain being the most prominent feature. Although the etiology and pathophysiology of CSSs are currently incompletely understood, central sensitization has emerged as one of the significant mechanisms. Given that there are currently no known cures for CSSs, people living with these disorders must learn to cope with and manage their symptoms throughout their lives. Medical interventions alone have not proven to be sufficient for helping people with CSSs manage their symptoms. A biopsychosocial perspective that considers the ways that biological, psychological, and social factors work independently and jointly to affect a person's experience is the most effective conceptualization and guide for effective treatment. In this article, we discuss several psychological and social features that may influence the experience of a person with CSS and their symptom management, regardless of their specific diagnosis. We highlight the longitudinal aspect of adjustment to illness, the distinction between psychosocial factors as causes of symptoms versus modifiers and perpetuators of symptoms, dispel the notion that all patients with the same diagnosis are a homogeneous group (the “patient-uniformity myth”), and acknowledge the importance of environmental and situational context on symptom management for individuals with any CSS. PMID:26088211

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility.

PubMed

Devenyi, Ryan A; Ortega, Francis A; Groenendaal, Willemijn; Krogh-Madsen, Trine; Christini, David J; Sobie, Eric A

2017-04-01

Arrhythmias result from disruptions to cardiac electrical activity, although the factors that control cellular action potentials are incompletely understood. We combined mathematical modelling with experiments in heart cells from guinea pigs to determine how cellular electrical activity is regulated. A mismatch between modelling predictions and the experimental results allowed us to construct an improved, more predictive mathematical model. The balance between two particular potassium currents dictates how heart cells respond to perturbations and their susceptibility to arrhythmias. Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. In the present study, we combined mathematical modelling with information-rich dynamic clamp experiments to determine the regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell. Surprisingly, we found that a leading mathematical model, developed with traditional approaches, systematically underestimated experimental responses to dynamic clamp perturbations. We then re-parameterized the model using a genetic algorithm, which allowed us to estimate ionic current levels in each of the cells studied. This unbiased model adjustment consistently predicted an increase in the rapid delayed rectifier K + current and a drastic decrease in the slow delayed rectifier K + current, and this prediction was validated experimentally. Subsequent simulations with the adjusted model generated the clinically relevant prediction that the slow delayed rectifier is better able to stabilize the action potential and suppress pro-arrhythmic events than the rapid delayed rectifier. In summary, iterative coupling of simulations and experiments enabled novel insight into how the balance between cardiac K + currents influences ventricular arrhythmia susceptibility. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Switch-Hitting Immune Cells: From Tumor Protection to Metastasis Promotion | Center for Cancer Research

Cancer.gov

The leading cause of death from cancer is not a primary tumor but is the metastases, or invasion of tumor cells into other locations in the body, that result from it. A complex and incompletely understood process, metastatic tumor formation is thought to require several steps in which tumor cells invade the tissue surrounding the primary tumor, enter local blood vessels, navigate the circulation, exit the vasculature, and colonize a new site. Tumor cells do not, however, operate independently, and the role that the immune system plays in this metastatic process is beginning to be appreciated.

Identification of point mutations in clinical Staphylococcus aureus strains that produce small-colony variants auxotrophic for menadione.

PubMed

Dean, Melissa A; Olsen, Randall J; Long, S Wesley; Rosato, Adriana E; Musser, James M

2014-04-01

Staphylococcus aureus small-colony variants (SCVs) are implicated in chronic and relapsing infections that are difficult to diagnose and treat. Despite many years of study, the underlying molecular mechanisms and virulence effect of the small-colony phenotype remain incompletely understood. We sequenced the genomes of five S. aureus SCV strains recovered from human patients and discovered previously unidentified nonsynonymous point mutations in three genes encoding proteins in the menadione biosynthesis pathway. Analysis of genetic revertants and complementation with wild-type alleles confirmed that these mutations caused the SCV phenotype and decreased virulence for mice.

Alternative, Complementary, and Forgotten Remedies for Atopic Dermatitis

PubMed Central

Goddard, Allison L.; Lio, Peter A.

2015-01-01

Atopic dermatitis, perhaps more than other dermatologic diseases, has garnered much attention in the realm of alternative medicine. This may be because its etiopathogenesis is incompletely understood, it is increasingly common, and it waxes and wanes often without clear precipitants, opening up many opportunities for misinterpretation. Herein we explore the evidence for a number of different alternative and complementary therapies, from textiles to vitamin supplements. By definition, none have enough data to be deemed “effective” in a conventional sense, but it is hopeful that some show promising evidence that may one day lead to mainstream acceptance with further research. PMID:26257817

Levels and trends of child and adult mortality rates in the Islamic Republic of Iran, 1990-2013; protocol of the NASBOD study.

PubMed

Mohammadi, Younes; Parsaeian, Mahboubeh; Farzadfar, Farshad; Kasaeian, Amir; Mehdipour, Parinaz; Sheidaei, Ali; Mansouri, Anita; Saeedi Moghaddam, Sahar; Djalalinia, Shirin; Mahmoudi, Mahmood; Khosravi, Ardeshir; Yazdani, Kamran

2014-03-01

Calculation of burden of diseases and risk factors is crucial to set priorities in the health care systems. Nevertheless, the reliable measurement of mortality rates is the main barrier to reach this goal. Unfortunately, in many developing countries the vital registration system (VRS) is either defective or does not exist at all. Consequently, alternative methods have been developed to measure mortality. This study is a subcomponent of NASBOD project, which is currently conducting in Iran. In this study, we aim to calculate incompleteness of the Death Registration System (DRS) and then to estimate levels and trends of child and adult mortality using reliable methods. In order to estimate mortality rates, first, we identify all possible data sources. Then, we calculate incompleteness of child and adult morality separately. For incompleteness of child mortality, we analyze summary birth history data using maternal age cohort and maternal age period methods. Then, we combine these two methods using LOESS regression. However, these estimates are not plausible for some provinces. We use additional information of covariates such as wealth index and years of schooling to make predictions for these provinces using spatio-temporal model. We generate yearly estimates of mortality using Gaussian process regression that covers both sampling and non-sampling errors within uncertainty intervals. By comparing the resulted estimates with mortality rates from DRS, we calculate child mortality incompleteness. For incompleteness of adult mortality, Generalized Growth Balance, Synthetic Extinct Generation and a hybrid of two mentioned methods are used. Afterwards, we combine incompleteness of three methods using GPR, and apply it to correct and adjust the number of deaths. In this study, we develop a conceptual framework to overcome the existing challenges for accurate measuring of mortality rates. The resulting estimates can be used to inform policy-makers about past, current and future mortality rates as a major indicator of health status of a population.

NF-κB activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer

PubMed Central

Blakely, Collin M.; Pazarentzos, Evangelos; Olivas, Victor; Asthana, Saurabh; Yan, Jenny Jiacheng; Tan, Irena; Hrustanovic, Gorjan; Chan, Elton; Lin, Luping; Neel, Dana S.; Newton, William; Bobb, Kathryn; Fouts, Timothy; Meshulam, Jeffrey; Gubens, Matthew A.; Jablons, David M.; Johnson, Jeffrey R.; Bandyopadhyay, Sourav; Krogan, Nevan J.; Bivona, Trever G.

2015-01-01

Summary Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR-mutant lung adenocarcinoma we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses. PMID:25843712

Plant Development, Auxin, and the Subsystem Incompleteness Theorem

PubMed Central

Niklas, Karl J.; Kutschera, Ulrich

2012-01-01

Plant morphogenesis (the process whereby form develops) requires signal cross-talking among all levels of organization to coordinate the operation of metabolic and genomic subsystems operating in a larger network of subsystems. Each subsystem can be rendered as a logic circuit supervising the operation of one or more signal-activated system. This approach simplifies complex morphogenetic phenomena and allows for their aggregation into diagrams of progressively larger networks. This technique is illustrated here by rendering two logic circuits and signal-activated subsystems, one for auxin (IAA) polar/lateral intercellular transport and another for IAA-mediated cell wall loosening. For each of these phenomena, a circuit/subsystem diagram highlights missing components (either in the logic circuit or in the subsystem it supervises) that must be identified experimentally if each of these basic plant phenomena is to be fully understood. We also illustrate the “subsystem incompleteness theorem,” which states that no subsystem is operationally self-sufficient. Indeed, a whole-organism perspective is required to understand even the most simple morphogenetic process, because, when isolated, every biological signal-activated subsystem is morphogenetically ineffective. PMID:22645582

CURRENT METHODS AND RESEARCH STRATEGIES FOR MODELING ATMOSPHERIC MERCURY

EPA Science Inventory

The atmospheric pathway of the global mercury cycle is known to be the primary source of mercury contamination to most threatened aquatic ecosystems. Current efforts toward numerical modeling of atmospheric mercury are hindered by an incomplete understanding of emissions, atmosp...

The Analysis of a Core Course for Community College Nursing Students.

ERIC Educational Resources Information Center

Grippando, Gloria M.

An extensive review of the literature and a survey of nursing faculties revealed the incompleteness and obsolescence of current texts to meet the needs of the Associate Degree Nursing (ADN) course in current trends. It became evident while researching course content materials for the current trends course that the personal and vocational…

Anxiety-like behavior and proinflammatory cytokine levels in the brain of C57BL/6 mice infected with Plasmodium berghei (strain ANKA).

PubMed

de Miranda, Aline Silva; Lacerda-Queiroz, Norinne; de Carvalho Vilela, Márcia; Rodrigues, David Henrique; Rachid, Milene Alvarenga; Quevedo, João; Teixeira, Antônio Lúcio

2011-03-24

Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection. The underlying mechanisms of CM pathogenesis remain incompletely understood. The imbalance between the release of proinflammatory and anti-inflammatory cytokines has been associated with central nervous system dysfunction found in human and experimental CM. The current study investigated anxiety-like behavior, histopathological changes and release of brain cytokines in C57BL/6 mice infected with Plasmodium berghei strain ANKA (PbA). Anxiety-like behavior was assessed in control and PbA-infected mice using the elevated plus maze test. Histopathological changes in brain tissue were assessed by haematoxylin and eosin staining. Brain concentration of the cytokines IL-1β, IL-4, IL-10, TNF-α and IFN-γ was determined by ELISA. We found that PbA-infected mice on day 5 post-infection presented anxiety symptoms, histopathological alterations in the brainstem, cerebrum and hippocampus and increased cerebral levels of proinflammatory cytokines IL-1β and TNF-α. These findings suggest an involvement of central nervous system inflammatory mediators in anxiety symptoms found in CM. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

From Discovery to Function: The Expanding Roles of Long NonCoding RNAs in Physiology and Disease

PubMed Central

Sun, Miao

2015-01-01

Long noncoding RNAs (lncRNAs) are a relatively poorly understood class of RNAs with little or no coding capacity transcribed from a set of incompletely annotated genes. They have received considerable attention in the past few years and are emerging as potentially important players in biological regulation. Here we discuss the evolving understanding of this new class of molecular regulators that has emerged from ongoing research, which continues to expand our databases of annotated lncRNAs and provide new insights into their physical properties, molecular mechanisms of action, and biological functions. We outline the current strategies and approaches that have been employed to identify and characterize lncRNAs, which have been instrumental in revealing their multifaceted roles ranging from cis- to trans-regulation of gene expression and from epigenetic modulation in the nucleus to posttranscriptional control in the cytoplasm. In addition, we highlight the molecular and biological functions of some of the best characterized lncRNAs in physiology and disease, especially those relevant to endocrinology, reproduction, metabolism, immunology, neurobiology, muscle biology, and cancer. Finally, we discuss the tremendous diagnostic and therapeutic potential of lncRNAs in cancer and other diseases. PMID:25426780

Trypanosoma cruzi: adaptation to its vectors and its hosts

PubMed Central

Noireau, François; Diosque, Patricio; Jansen, Ana Maria

2009-01-01

American trypanosomiasis is a parasitic zoonosis that occurs throughout Latin America. The etiological agent, Trypanosoma cruzi, is able to infect almost all tissues of its mammalian hosts and spreads in the environment in multifarious transmission cycles that may or not be connected. This biological plasticity, which is probably the result of the considerable heterogeneity of the taxon, exemplifies a successful adaptation of a parasite resulting in distinct outcomes of infection and a complex epidemiological pattern. In the 1990s, most endemic countries strengthened national control programs to interrupt the transmission of this parasite to humans. However, many obstacles remain to the effective control of the disease. Current knowledge of the different components involved in elaborate system that is American trypanosomiasis (the protozoan parasite T. cruzi, vectors Triatominae and the many reservoirs of infection), as well as the interactions existing within the system, is still incomplete. The Triatominae probably evolve from predatory reduvids in response to the availability of vertebrate food source. However, the basic mechanisms of adaptation of some of them to artificial ecotopes remain poorly understood. Nevertheless, these adaptations seem to be associated with a behavioral plasticity, a reduction in the genetic repertoire and increasing developmental instability. PMID:19250627

Viral causes of feline lymphoma: retroviruses and beyond.

PubMed

Beatty, Julia

2014-08-01

The most widely recognised cause of feline lymphoma is the gammaretrovirus feline leukaemia virus (FeLV). Research into the mechanisms of cellular transformation employed by FeLV and other oncogenic retroviruses has provided as much information on the regulation of eukaryotic cell growth and differentiation as it has about cancer. The recognition that a cancer has a viral cause opens up the possibility of novel treatments that spare the host from cytotoxic side-effects by specifically targeting the virus, or the host's immune response to it. The ultimate prize for viral-associated cancers is their prevention. Vaccination and changes in management practices have seen the global prevalence of FeLV infection fall and, with it, the incidence of FeLV-related cancers. Remarkably, in the face of this success, the prevalence of feline lymphoma remains high. At least one other virus, the lentivirus feline immunodeficiency virus (FIV), accounts for some of these cases. Transformation by FIV involves incompletely understood mechanisms that are distinct from those employed by FeLV. This review will focus on the current understanding of FeLV-associated and FIV-associated lymphoma and consider whether yet more viral aetiologies could be waiting to be discovered. Copyright © 2014 Elsevier Ltd. All rights reserved.

Predictors of Drought Recovery across Forest Ecosystems

NASA Astrophysics Data System (ADS)

Anderegg, W.

2016-12-01

The impacts of climate extremes on terrestrial ecosystems are poorly understood but central for predicting carbon cycle feedbacks to climate change. Coupled climate-carbon cycle models typically assume that vegetation recovery from extreme drought is immediate and complete, which conflicts with basic plant physiological understanding. Here, we discuss what we have learned about forest ecosystem recovery from extreme drought across spatial and temporal scales, drawing on inference from tree rings, eddy covariance data, large scale gross primary productivity products, and ecosystem models. In tree rings, we find pervasive and substantial "legacy effects" of reduced growth and incomplete recovery for 1-4 years after severe drought, and that legacy effects are most prevalent in dry ecosystems, Pinaceae, and species with low hydraulic safety margins. At larger scales, we see relatively rapid recovery of ecosystem fluxes, with strong influences of ecosystem productivity and diversity and longer recovery periods in high latidue forests. In contrast, no or limited legacy effects are simulated in current climate-vegetation models after drought, and we highlight some of the key missing mechanisms in dynamic vegetation models. Our results reveal hysteresis in forest ecosystem carbon cycling and delayed recovery from climate extremes and help advance a predictive understanding of ecosystem recovery.

The Vital Infrared to X-ray Link in the Sgr A* Accretion Flow

NASA Astrophysics Data System (ADS)

Fazio, Giovanni; Ashby, Matthew; Baganoff, Frederick; Becklin, Eric; Boyce, Hope; Carey, Sean; Gammie, Charles; Ghez, Andrea; Glaccum, William; Gurwell, Mark; Haggard, Daryl; Herrero-Illana, Ruben; Hora, Joseph; Ingalls, James; Lowrance, Patrick; Markoff, Sera; Marrone, Daniel; Morris, Mark; Narayan, Ramesh; Neilsen, Joseph; Ponti, Gabriele; Smith, Howard; Willner, Steven; Witzel, Gunther

2018-05-01

Black hole accretion drives extreme astrophysical phenomena in the universe. Sgr A*, the radiating counterpart of the nearest supermassive black hole, is highly variable, but sparse data and short observations have left its emission physics in question. Despite enormous advances in accretion models, physical description of the interacting radiation mechanisms is incomplete. The X-ray emission mechanism in particular remains unknown. Because the necessary information is contained in the time-dependent relation between X-ray and infrared emission, we have begun monitoring Sgr A* simultaneously with Chandra in X-rays and with Spitzer in the infrared. Defining the X-ray to infrared flux density ratio will allow the entire energy distribution to be understood. We therefore request two new 24-hour epochs of Spitzer monitoring at 4.5 microns simultaneous with Chandra time already approved. This will increase the exposure time for X-ray flares where the NIR state is known, moving us out of the realm of small-number statistics and enabling diagnostics of the true X-ray/IR ratio. Under current NASA plans, this will be the last chance for these valuable Spitzer+Chandra observations.

Gut Microbiome and Obesity: A Plausible Explanation for Obesity.

PubMed

Sanmiguel, Claudia; Gupta, Arpana; Mayer, Emeran A

2015-06-01

Obesity is a multifactorial disorder that results in excessive accumulation of adipose tissue. Although obesity is caused by alterations in the energy consumption/expenditure balance, the factors promoting this disequilibrium are incompletely understood. The rapid development of new technologies and analysis strategies to decode the gut microbiota composition and metabolic pathways has opened a door into the complexity of the guest-host interactions between the gut microbiota and its human host in health and in disease. Pivotal studies have demonstrated that manipulation of the gut microbiota and its metabolic pathways can affect host's adiposity and metabolism. These observations have paved the way for further assessment of the mechanisms underlying these changes. In this review we summarize the current evidence for possible mechanisms underlying gut microbiota induced obesity. The review addresses some well-known effects of the gut microbiota on energy harvesting and changes in metabolic machinery, on metabolic and immune interactions and on possible changes in brain function and behavior. Although there is limited understanding on the symbiotic relationship between us and our gut microbiome, and how disturbances of this relationship affects our health, there is compelling evidence for an important role of the gut microbiota in the development and perpetuation of obesity.

Inside-out neuropharmacology of nicotinic drugs.

PubMed

Henderson, Brandon J; Lester, Henry A

2015-09-01

Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as "inside-out pharmacology". This term contrasts with the better-known, acute, "outside-in" effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Emerging facets of prokaryotic glycosylation

PubMed Central

Schäffer, Christina; Messner, Paul

2017-01-01

Glycosylation of proteins is one of the most prevalent post-translational modifications occurring in nature, with a wide repertoire of biological implications. Pathways for the main types of this modification, the N- and O-glycosylation, can be found in all three domains of life—the Eukarya, Bacteria and Archaea—thereby following common principles, which are valid also for lipopolysaccharides, lipooligosaccharides and glycopolymers. Thus, studies on any glycoconjugate can unravel novel facets of the still incompletely understood fundamentals of protein N- and O-glycosylation. While it is estimated that more than two-thirds of all eukaryotic proteins would be glycosylated, no such estimate is available for prokaryotic glycoproteins, whose understanding is lagging behind, mainly due to the enormous variability of their glycan structures and variations in the underlying glycosylation processes. Combining glycan structural information with bioinformatic, genetic, biochemical and enzymatic data has opened up an avenue for in-depth analyses of glycosylation processes as a basis for glycoengineering endeavours. Here, the common themes of glycosylation are conceptualised for the major classes of prokaryotic (i.e. bacterial and archaeal) glycoconjugates, with a special focus on glycosylated cell-surface proteins. We describe the current knowledge of biosynthesis and importance of these glycoconjugates in selected pathogenic and beneficial microbes. PMID:27566466

What causes racial disparities in very preterm birth? A biosocial perspective.

PubMed

Kramer, Michael R; Hogue, Carol R

2009-01-01

Very preterm birth (<32 weeks' gestation) occurs in approximately 2% of livebirths but is a leading cause of infant mortality and morbidity in the United States. African-American women have a 2-fold to 3-fold elevated risk compared with non-Hispanic white women for reasons that are incompletely understood. This paper reviews the evidence for the biologic and social patterning of very preterm birth, with attention to leading hypotheses regarding the etiology of the racial disparity. A systematic review of the literature in the MEDLINE, CINAHL, PsycInfo, and EMBASE indices was conducted. The literature to date suggests a complex, multifactorial causal framework for understanding racial disparities in very preterm birth, with maternal inflammatory, vascular, or neuroendocrine dysfunction as proximal pathways and maternal exposure to stress, racial differences in preconceptional health, and genetic, epigenetic, and gene-environment interactions as more distal mediators. Interpersonal and institutionalized racism are mechanisms that may drive racially patterned differences. Current literature is limited in that research on social determinants and biologic processes of prematurity has been generally disconnected. Improved etiologic understanding and the potential for effective intervention may come with better integration of these research approaches.

From discovery to function: the expanding roles of long noncoding RNAs in physiology and disease.

PubMed

Sun, Miao; Kraus, W Lee

2015-02-01

Long noncoding RNAs (lncRNAs) are a relatively poorly understood class of RNAs with little or no coding capacity transcribed from a set of incompletely annotated genes. They have received considerable attention in the past few years and are emerging as potentially important players in biological regulation. Here we discuss the evolving understanding of this new class of molecular regulators that has emerged from ongoing research, which continues to expand our databases of annotated lncRNAs and provide new insights into their physical properties, molecular mechanisms of action, and biological functions. We outline the current strategies and approaches that have been employed to identify and characterize lncRNAs, which have been instrumental in revealing their multifaceted roles ranging from cis- to trans-regulation of gene expression and from epigenetic modulation in the nucleus to posttranscriptional control in the cytoplasm. In addition, we highlight the molecular and biological functions of some of the best characterized lncRNAs in physiology and disease, especially those relevant to endocrinology, reproduction, metabolism, immunology, neurobiology, muscle biology, and cancer. Finally, we discuss the tremendous diagnostic and therapeutic potential of lncRNAs in cancer and other diseases.

Valbenazine for the treatment of tardive dyskinesia.

PubMed

Seeberger, Lauren C; Hauser, Robert A

2017-08-01

Tardive dyskinesia (TD) is a hyperkinetic movement disorder that may result from treatment with antipsychotics or other dopamine receptor blocking agents. Underlying pathophysiology is incompletely understood but since the 1970s dopamine depleting agents have been used to reduce involuntary movements. The search for safe, effective treatments for TD is ongoing. Valbenazine, a novel VMAT2 inhibitor, has recently been FDA approved for treatment of TD. Areas covered: An overview of TD, unmet medical needs and current treatment guidelines are presented. The background, chemistry and clinical development of valbenazine to treat TD is detailed. A competitive market is developing as the treatment gap is identified and potential therapies are discussed in context of a broader market overview. Expert opinion: Antipsychotic use is growing among adults and children in the U.S. Consequently, prevalence of TD is expected to rise. Cessation of antipsychotics is often not possible as the psychiatric condition may deteriorate. Increasing doses of an antipsychotic to suppress involuntary movements is not sustainable long term as underlying TD worsens and movements typically recur. There were no FDA approved treatments for TD. The approval of valbenazine to treat TD is a critical step in addressing this gap in neurologic care.

Zebrafish Models of Prader-Willi Syndrome: Fast Track to Pharmacotherapeutics

PubMed Central

Spikol, Emma D.; Laverriere, Caroline E.; Robnett, Maya; Carter, Gabriela; Wolfe, Erin; Glasgow, Eric

2016-01-01

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder characterized by an insatiable appetite, leading to chronic overeating and obesity. Additional features include short stature, intellectual disability, behavioral problems and incomplete sexual development. Although significant progress has been made in understanding the genetic basis of PWS, the mechanisms underlying the pathogenesis of the disorder remain poorly understood. Treatment for PWS consists mainly of palliative therapies; curative therapies are sorely needed. Zebrafish, Danio rerio, represent a promising way forward for elucidating physiological problems such as obesity and identifying new pharmacotherapeutic options for PWS. Over the last decade, an increased appreciation for the highly conserved biology among vertebrates and the ability to perform high-throughput drug screening has seen an explosion in the use of zebrafish for disease modeling and drug discovery. Here, we review recent advances in developing zebrafish models of human disease. Aspects of zebrafish genetics and physiology that are relevant to PWS will be discussed, and the advantages and disadvantages of zebrafish models will be contrasted with current animal models for this syndrome. Finally, we will present a paradigm for drug screening in zebrafish that is potentially the fastest route for identifying and delivering curative pharmacotherapies to PWS patients. PMID:27857842

Gut Microbiome and Obesity: A Plausible Explanation for Obesity

PubMed Central

Sanmiguel, Claudia; Gupta, Arpana; Mayer, Emeran A.

2015-01-01

Obesity is a multifactorial disorder that results in excessive accumulation of adipose tissue. Although obesity is caused by alterations in the energy consumption/expenditure balance, the factors promoting this disequilibrium are incompletely understood. The rapid development of new technologies and analysis strategies to decode the gut microbiota composition and metabolic pathways has opened a door into the complexity of the guest-host interactions between the gut microbiota and its human host in health and in disease. Pivotal studies have demonstrated that manipulation of the gut microbiota and its metabolic pathways can affect host’s adiposity and metabolism. These observations have paved the way for further assessment of the mechanisms underlying these changes. In this review we summarize the current evidence for possible mechanisms underlying gut microbiota induced obesity. The review addresses some well-known effects of the gut microbiota on energy harvesting and changes in metabolic machinery, on metabolic and immune interactions and on possible changes in brain function and behavior. Although there is limited understanding on the symbiotic relationship between us and our gut microbiome, and how disturbances of this relationship affects our health, there is compelling evidence for an important role of the gut microbiota in the development and perpetuation of obesity. PMID:26029487

[Innovative therapeutics for idiopathic pulmonary fibrosis].

PubMed

Uzunhan, Yurdagül; Nunes, Hilario; Gille, Thomas; Bron, Camille; Planès, Carole; Valeyre, Dominique

2011-12-01

Idiopathic pulmonary fibrosis (IPF), the most common and severe interstitial lung disease, remains a great challenge for clinicians. The natural history of the disease is incompletely understood and its prognosis is as devastating as that of many cancers. The most recent international consensus conference on IPF does not recommend any specific medical treatment and underlines the role of symptomatic care and management of co-morbidities, as well as lung transplantation, which should be openly discussed with the patient, if applicable, without delay. The lack of efficacy observed with steroids and immunosuppressive agents argues the current pathogenic hypothesis consistent with an abnormal alveolar epithelium wound healing after repeated injury. Thus, a need for anti-fibrosing and epithelial protective drugs emerged. Considerable progress has been made regarding the validation of relevant endpoints for clinical trials on IPF and pathogenesis, these two aspects of research being a framework for the exploration of new therapeutic approaches. Pirfenidone is the first drug that has been approved by health-care system for IPF treatment in Japan and in Europe. Many novel and promising drugs based on recent targets are under investigation. Combined therapies targeting different pathogenic pathways may represent the future for the treatment of IPF. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Current Perspectives on Systemic Hypertension in Heart Failure with Preserved Ejection Fraction.

PubMed

Tam, Marty C; Lee, Ran; Cascino, Thomas M; Konerman, Matthew C; Hummel, Scott L

2017-02-01

Heart failure with preserved ejection fraction (HFpEF) is a prevalent but incompletely understood syndrome. Traditional models of HFpEF pathophysiology revolve around systemic HTN and other causes of increased left ventricular afterload leading to left ventricular hypertrophy (LVH) and diastolic dysfunction. However, emerging models attribute the development of HFpEF to systemic proinflammatory changes secondary to common comorbidities which include HTN. Alterations in passive ventricular stiffness, ventricular-arterial coupling, peripheral microvascular function, systolic reserve, and chronotropic response occur. As a result, HFpEF is heterogeneous in nature, making it difficult to prescribe uniform therapies to all patients. Nonetheless, treating systemic HTN remains a cornerstone of HFpEF management. Antihypertensive therapies have been linked to LVH regression and improvement in diastolic dysfunction. However, to date, no therapies have definitive mortality benefit in HFpEF. Non-pharmacologic management for HTN, including dietary modification, exercise, and treating sleep disordered breathing, may provide some morbidity benefit in the HFpEF population. Future research is need to identify effective treatments, perhaps in more specific subgroups, and focus may need to shift from reducing mortality to improving exercise capacity and symptoms. Tailoring antihypertensive therapies to specific phenotypes of HFpEF may be an important component of this strategy.

Bcıı--RFLP profiles for serum amiloid A1 and mutated MEFV gene prevalence in chronic renal failure patients requiring long-term hemodialysis.

PubMed

Ozdemir, Ozturk; Kayatas, Mansur; Cetinkaya, Selma; Yildirim, Malik Ejder; Silan, Fatma; Kurtulgan, Hande Kucuk; Koksal, Binnur; Urfali, Mine; Candan, Ferhan

2015-03-01

There is an increased mortality risk in long-term hemodialysis patients of renal failure due to the chronic inflammation. The relationship between the chronic renal failure (CRF) and the role of familial genetic markers remains incompletely understood. In the current study, it was aimed to find out the prevalence of common MEFV gene mutations and BcII polymorphism in serum amyloid A1 (SAA1) gene in chronic renal patients (CRF) who require long-term hemodialysis. Current cohort includes 242 CRF patients and 245 healthy individuals from the same population. Total genomic DNA was isolated from peripheral blood-EDTA samples and genotyping of target MEFV gene was carried out by reverse hybridization Strip Assay and real-time techniques. The SAA1 gene was genotyped by the BclI-RFLP method. Increased mutated MEFV genotypes were found in current CRF patients when compared with the control group from the same ethnicity and the difference was statistically significant (Table 2) (OR: 4.9401, 95% CI: 3.0694-7.9509), p<0.0001. The most frequent point mutations were M694V and E148Q. The mutated T allel frequency in the SAA1 gene was also different when compared with the healthy controls and the difference was found to be statistically significant (χ2: 13.18; p=0.000). The current results indicate the germ-line mutations in both genetic biomarkers (MEFV and SAA1 genes) that are related to inflammation and amyloidosis processes may play a crucial role in CRF pathogenesis due to the long-term chronic inflammation.

Activation of Corticostriatal Circuitry Relieves Chronic Neuropathic Pain

PubMed Central

Lee, Michelle; Manders, Toby R.; Eberle, Sarah E.; Su, Chen; D'amour, James; Yang, Runtao; Lin, Hau Yueh; Deisseroth, Karl; Froemke, Robert C.

2015-01-01

Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation. PMID:25834050

Microcavitation as a Neuronal Damage Mechanism in Blast Traumatic Brain Injury

NASA Astrophysics Data System (ADS)

Franck, Christian; Estrada, Jonathan

2015-11-01

Blast traumatic brain injury (bTBI) is a leading cause of injury in the armed forces. Diffuse axonal injury, the hallmark feature of blunt TBI, has been investigated in direct mechanical loading conditions. However, recent evidence suggests inertial cavitation as a possible bTBI mechanism, particularly in the case of exposure to blasts. Cavitation damage to free surfaces has been well-studied, but bubble interactions within confined 3D environments, in particular their stress and strain signatures are not well understood. The structural damage due to cavitation in living tissues - particularly at the cellular level - are incompletely understood, in part due to the rapid bubble formation and deformation strain rates of up to ~ 105-106 s-1. This project aims to characterize material damage in 2D and 3D cell culture environments by utilizing a novel high-speed red-blue diffraction assisted image correlation method at speeds of up to 106 frames per second. We gratefully acknowledge funding from the Office of Naval Research (POC: Dr. Tim Bentley).

Inhibiting platelet-derived growth factor beta reduces Ewing's sarcoma growth and metastasis in a novel orthotopic human xenograft model.

PubMed

Wang, Yong Xin; Mandal, Deendayal; Wang, Suizhau; Hughes, Dennis; Pollock, Raphael E; Lev, Dina; Kleinerman, Eugenie; Hayes-Jordan, Andrea

2009-01-01

Despite aggressive therapy, Ewing's sarcoma (ES) patients have a poor five-year overall survival of only 20-40%. Pulmonary metastasis is the most common form of demise in these patients. The pathogenesis of pulmonary metastasis is poorly understood and few orthotopic models exist that allow study of spontaneous pulmonary metastasis in ES. We have developed a novel orthotopic xenograft model in which spontaneous pulmonary metastases develop. While the underlying biology of ES is incompletely understood, in addition to the EWS-FLI-1 mutation, it is known that platelet-derived growth factor receptor beta (PDGFR-beta) is highly expressed in ES. Hypothesizing that PDGFR-beta expression is indicative of a specific role for this receptor protein in ES progression, the effect of PDGFR-beta inhibition on ES growth and metastasis was assessed in this novel orthotopic ES model. Silencing PDGFR-beta reduced spontaneous growth and metastasis in ES. Preclinical therapeutically relevant findings such as these may ultimately lead to new treatment initiatives in ES.

Rapid DNA Synthesis During Early Drosophila Embryogenesis Is Sensitive to Maternal Humpty Dumpty Protein Function.

PubMed

Lesly, Shera; Bandura, Jennifer L; Calvi, Brian R

2017-11-01

Problems with DNA replication cause cancer and developmental malformations. It is not fully understood how DNA replication is coordinated with development and perturbed in disease. We had previously identified the Drosophila gene humpty dumpty ( hd ), and showed that null alleles cause incomplete DNA replication, tissue undergrowth, and lethality. Animals homozygous for the missense allele, hd 272-9 , were viable, but adult females had impaired amplification of eggshell protein genes in the ovary, resulting in the maternal effects of thin eggshells and embryonic lethality. Here, we show that expression of an hd transgene in somatic cells of the ovary rescues amplification and eggshell synthesis but not embryo viability. The germline of these mothers remain mutant for the hd 272-9 allele, resulting in reduced maternal Hd protein and embryonic arrest during mitosis of the first few S/M nuclear cleavage cycles with chromosome instability and chromosome bridges. Epistasis analysis of hd with the rereplication mutation plutonium indicates that the chromosome bridges of hd embryos are the result of a failed attempt to segregate incompletely replicated sister chromatids. This study reveals that maternally encoded Humpty dumpty protein is essential for DNA replication and genome integrity during the little-understood embryonic S/M cycles. Moreover, the two hd 272-9 maternal-effect phenotypes suggest that ovarian gene amplification and embryonic cleavage are two time periods in development that are particularly sensitive to mild deficits in DNA replication function. This last observation has broader relevance for interpreting why mild mutations in the human ortholog of humpty dumpty and other DNA replication genes cause tissue-specific malformations of microcephalic dwarfisms. Copyright © 2017 by the Genetics Society of America.

The therapeutic impact of new migraine discoveries.

PubMed

Vécsei, Laszlo; Lukács, Melinda; Tajti, Janos; Fülöp, Ferenc; Toldi, Jozsef; Edvinsson, Lars

2018-05-29

Migraine is one the most disabling neurological conditions and associates with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. The present study is a review of the current literature regarding new therapeutic lines in migraine research. A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in migraine published until July 2017. Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Chemical kinetics and modeling of planetary atmospheres

NASA Technical Reports Server (NTRS)

Yung, Yuk L.

1990-01-01

A unified overview is presented for chemical kinetics and chemical modeling in planetary atmospheres. The recent major advances in the understanding of the chemistry of the terrestrial atmosphere make the study of planets more interesting and relevant. A deeper understanding suggests that the important chemical cycles have a universal character that connects the different planets and ultimately link together the origin and evolution of the solar system. The completeness (or incompleteness) of the data base for chemical kinetics in planetary atmospheres will always be judged by comparison with that for the terrestrial atmosphere. In the latter case, the chemistry of H, O, N, and Cl species is well understood. S chemistry is poorly understood. In the atmospheres of Jovian planets and Titan, the C-H chemistry of simple species (containing 2 or less C atoms) is fairly well understood. The chemistry of higher hydrocarbons and the C-N, P-N chemistry is much less understood. In the atmosphere of Venus, the dominant chemistry is that of chlorine and sulfur, and very little is known about C1-S coupled chemistry. A new frontier for chemical kinetics both in the Earth and planetary atmospheres is the study of heterogeneous reactions. The formation of the ozone hole on Earth, the ubiquitous photochemical haze on Venus and in the Jovian planets and Titan all testify to the importance of heterogeneous reactions. It remains a challenge to connect the gas phase chemistry to the production of aerosols.

Identification of Point Mutations in Clinical Staphylococcus aureus Strains That Produce Small-Colony Variants Auxotrophic for Menadione

PubMed Central

Dean, Melissa A.; Olsen, Randall J.; Long, S. Wesley; Rosato, Adriana E.

2014-01-01

Staphylococcus aureus small-colony variants (SCVs) are implicated in chronic and relapsing infections that are difficult to diagnose and treat. Despite many years of study, the underlying molecular mechanisms and virulence effect of the small-colony phenotype remain incompletely understood. We sequenced the genomes of five S. aureus SCV strains recovered from human patients and discovered previously unidentified nonsynonymous point mutations in three genes encoding proteins in the menadione biosynthesis pathway. Analysis of genetic revertants and complementation with wild-type alleles confirmed that these mutations caused the SCV phenotype and decreased virulence for mice. PMID:24452687

Simvastatin Potently Induces Calcium-dependent Apoptosis of Human Leiomyoma Cells*

PubMed Central

Borahay, Mostafa A.; Kilic, Gokhan S.; Yallampalli, Chandrasekha; Snyder, Russell R.; Hankins, Gary D. V.; Al-Hendy, Ayman; Boehning, Darren

2014-01-01

Statins are drugs commonly used for the treatment of high plasma cholesterol levels. Beyond these well known lipid-lowering properties, they possess broad-reaching effects in vivo, including antitumor effects. Statins inhibit the growth of multiple tumors. However, the mechanisms remain incompletely understood. Here we show that simvastatin inhibits the proliferation of human leiomyoma cells. This was associated with decreased mitogen-activated protein kinase signaling and multiple changes in cell cycle progression. Simvastatin potently stimulated leiomyoma cell apoptosis in a manner mechanistically dependent upon apoptotic calcium release from voltage-gated calcium channels. Therefore, simvastatin possesses antitumor effects that are dependent upon the apoptotic calcium release machinery. PMID:25359773

Enrichment of cardiac differentiation of mouse embryonic stem cells by optimizing the hanging drop method.

PubMed

Chen, Ming; Lin, Yong-Qing; Xie, Shuang-Lun; Wu, Hong-Fu; Wang, Jing-Feng

2011-04-01

Hanging drop (HD) culture is used to induce differentiation of embryonic stem cells (ESCs) into other cell types including cardiomyocytes. However, the factors affecting cardiac differentiation of ESCs with this method remain incompletely understood. We have investigated the effects of the starting number of ESCs in embryoid bodies (EBs) and the time of EB adherence to gelatin-coated plates on cardiac differentiation: cardiac differentiation was increased in the EBs by a larger number of ESCs and was decreased by plating EBs at day 4 or earlier. These two factors can thus be optimized to enrich the cardiac differentiation in ESCs using the HD method.

Physiology and pathogenesis of gastroesophageal reflux disease.

PubMed

Mikami, Dean J; Murayama, Kenric M

2015-06-01

Gastroesophageal reflux disease (GERD) is one of the most common problems treated by primary care physicians. Almost 20% of the population in the United States experiences occasional regurgitation, heartburn, or retrosternal pain because of GERD. Reflux disease is complex, and the physiology and pathogenesis are still incompletely understood. However, abnormalities of any one or a combination of the three physiologic processes, namely, esophageal motility, lower esophageal sphincter function, and gastric motility or emptying, can lead to GERD. There are many diagnostic and therapeutic approaches to GERD today, but more studies are needed to better understand this complex disease process. Copyright © 2015 Elsevier Inc. All rights reserved.

Urbanization and kidney function decline in low and middle income countries.

PubMed

Jagannathan, Ram; Patzer, Rachel E

2017-08-29

Urbanization is expected to increase in low and middle-income countries (LMICs), and might contribute to the increased disease burden. The association between urbanization and CKD is incompletely understood among LMICs. Recently, Inoue et al., explored the association of urbanization on renal function from the China Health and Nutrition Survey. The study found that individuals living in an urban environment had a higher odds of reduced renal function independent of behavioral and cardiometabolic measures, and this effect increased in a dose dependent manner. In this commentary, we discuss the results of these findings and explain the need for more surveillance studies among LMICs.

Brain iron homeostasis, the choroid plexus, and localization of iron transport proteins.

PubMed

Rouault, Tracey A; Zhang, De-Liang; Jeong, Suh Young

2009-12-01

Maintenance of appropriate iron homeostasis in the brain is important, but the mechanisms involved in brain iron uptake are incompletely understood. Here, we have analyzed where messenger RNAs that encode iron transport proteins are expressed in the brain, using the Allen Brain atlas, and we conclude that several important iron transporters are highly expressed in the choroid plexus. Based on recent estimates of the surface area of the choroid plexus and on MRI imaging studies of manganese uptake in the brain, we propose that the choroid plexus may have a much greater role than has been previously appreciated in brain iron transport.

Initiation of follicular atresia: gene networks during early atresia in pig ovaries.

PubMed

Zhang, Jinbi; Liu, Yang; Yao, Wang; Li, Qifa; Liu, Hong-Lin; Pan, Zengxiang

2018-05-09

In mammals, more than 99% of ovarian follicles undergo a degenerative process known as atresia. The molecular events involve in atresia initiation remain incompletely understood. The objective of this study was to analyze differential gene expression profiles of medium antral ovarian follicles during early atresia in pig. The transcriptome evaluation was performed on cDNA microarrays using healthy and early atretic follicle samples and was validated by quantitative PCR. Annotation analysis applying current database (sus scrofa 11.1) revealed 450 significantly differential expressed genes between healthy and early atretic follicles. Among them, 142 were significantly up-regulated in early atretic with respect to healthy group and 308 were down-regulated. Similar expression trends were observed between microarray data and qRT-PCR confirmation, which indicated the reliability of the microarray analysis. Further analysis of the differential expressed genes revealed the most significantly affected biological functions during early atresia including blood vessel development, regulation of DNA-templated transcription in response to stress and negative regulation of cell adhesion. The pathway and interaction analysis suggested that atresia initiation associates with 1) a crosstalk of cell apoptosis, autophagy, and ferroptosis rather than change of typical apoptosis markers, 2) dramatic shift of steroidogenic enzymes, 3) deficient glutathione metabolism, and 4) vascular degeneration. The novel gene candidates and pathways identified in the current study will lead to a comprehensive view of the molecular regulation of ovarian follicular atresia and a new understanding of atresia initiation.

Functional studies of Drosophila zinc transporters reveal the mechanism for dietary zinc absorption and regulation

PubMed Central

2013-01-01

Background Zinc is key to the function of many proteins, but the process of dietary zinc absorption is not well clarified. Current knowledge about dietary zinc absorption is fragmented, and mostly derives from incomplete mammalian studies. To gain a comprehensive picture of this process, we systematically characterized all zinc transporters (that is, the Zip and ZnT family members) for their possible roles in dietary zinc absorption in a genetically amenable model organism, Drosophila melanogaster. Results A set of plasma membrane-resident zinc transporters was identified to be responsible for absorbing zinc from the lumen into the enterocyte and the subsequent exit of zinc to the circulation. dZip1 and dZip2, two functionally overlapping zinc importers, are responsible for absorbing zinc from the lumen into the enterocyte. Exit of zinc to the circulation is mediated through another two functionally overlapping zinc exporters, dZnT1, and its homolog CG5130 (dZnT77C). Somewhat surprisingly, it appears that the array of intracellular ZnT proteins, including the Golgi-resident dZnT7, is not directly involved in dietary zinc absorption. By modulating zinc status in different parts of the body, we found that regulation of dietary zinc absorption, in contrast to that of iron, is unresponsive to bodily needs or zinc status outside the gut. The zinc transporters that are involved in dietary zinc absorption, including the importers dZip1 and dZip2, and the exporter dZnT1, are respectively regulated at the RNA and protein levels by zinc in the enterocyte. Conclusions Our study using the model organism Drosophila thus starts to reveal a comprehensive sketch of dietary zinc absorption and its regulatory control, a process that is still incompletely understood in mammalian organisms. The knowledge gained will act as a reference for future mammalian studies, and also enable an appreciation of this important process from an evolutionary perspective. PMID:24063361

Bears in a Forest of Gene Trees: Phylogenetic Inference Is Complicated by Incomplete Lineage Sorting and Gene Flow

PubMed Central

Kutschera, Verena E.; Bidon, Tobias; Hailer, Frank; Rodi, Julia L.; Fain, Steven R.; Janke, Axel

2014-01-01

Ursine bears are a mammalian subfamily that comprises six morphologically and ecologically distinct extant species. Previous phylogenetic analyses of concatenated nuclear genes could not resolve all relationships among bears, and appeared to conflict with the mitochondrial phylogeny. Evolutionary processes such as incomplete lineage sorting and introgression can cause gene tree discordance and complicate phylogenetic inferences, but are not accounted for in phylogenetic analyses of concatenated data. We generated a high-resolution data set of autosomal introns from several individuals per species and of Y-chromosomal markers. Incorporating intraspecific variability in coalescence-based phylogenetic and gene flow estimation approaches, we traced the genealogical history of individual alleles. Considerable heterogeneity among nuclear loci and discordance between nuclear and mitochondrial phylogenies were found. A species tree with divergence time estimates indicated that ursine bears diversified within less than 2 My. Consistent with a complex branching order within a clade of Asian bear species, we identified unidirectional gene flow from Asian black into sloth bears. Moreover, gene flow detected from brown into American black bears can explain the conflicting placement of the American black bear in mitochondrial and nuclear phylogenies. These results highlight that both incomplete lineage sorting and introgression are prominent evolutionary forces even on time scales up to several million years. Complex evolutionary patterns are not adequately captured by strictly bifurcating models, and can only be fully understood when analyzing multiple independently inherited loci in a coalescence framework. Phylogenetic incongruence among gene trees hence needs to be recognized as a biologically meaningful signal. PMID:24903145

Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations

PubMed Central

Segars, James H.; Parrott, Estella C.; Nagel, Joan D.; Guo, Xiaoxiao Catherine; Gao, Xiaohua; Birnbaum, Linda S.; Pinn, Vivian W.; Dixon, Darlene

2014-01-01

BACKGROUND Uterine fibroids are the most common gynecologic tumors in women of reproductive age yet the etiology and pathogenesis of these lesions remain poorly understood. Age, African ancestry, nulliparity and obesity have been identified as predisposing factors for uterine fibroids. Symptomatic tumors can cause excessive uterine bleeding, bladder dysfunction and pelvic pain, as well as associated reproductive disorders such as infertility, miscarriage and other adverse pregnancy outcomes. Currently, there are limited noninvasive therapies for fibroids and no early intervention or prevention strategies are readily available. This review summarizes the advances in basic, applied and translational uterine fibroid research, in addition to current and proposed approaches to clinical management as presented at the ‘Advances in Uterine Leiomyoma Research: 3rd NIH International Congress’. Congress recommendations and a review of the fibroid literature are also reported. METHODS This review is a report of meeting proceedings, the resulting recommendations and a literature review of the subject. RESULTS The research data presented highlights the complexity of uterine fibroids and the convergence of ethnicity, race, genetics, epigenetics and environmental factors, including lifestyle and possible socioeconomic parameters on disease manifestation. The data presented suggest it is likely that the majority of women with uterine fibroids will have normal pregnancy outcomes; however, additional research is warranted. As an alternative to surgery, an effective long-term medical treatment for uterine fibroids should reduce heavy uterine bleeding and fibroid/uterine volume without excessive side effects. This goal has not been achieved and current treatments reduce symptoms only temporarily; however, a multi-disciplined approach to understanding the molecular origins and pathogenesis of uterine fibroids, as presented in this report, makes our quest for identifying novel targets for noninvasive, possibly nonsystemic and effective long-term treatment very promising. CONCLUSIONS The Congress facilitated the exchange of scientific information among members of the uterine leiomyoma research and health-care communities. While advances in research have deepened our knowledge of the pathobiology of fibroids, their etiology still remains incompletely understood. Further needs exist for determination of risk factors and initiation of preventive measures for fibroids, in addition to continued development of new medical and minimally invasive options for treatment. PMID:24401287

Culture as a variable in health research: perspectives and caveats.

PubMed

Al-Bannay, Hana; Jarus, Tal; Jongbloed, Lyn; Yazigi, Maya; Dean, Elizabeth

2014-09-01

To augment the rigor of health promotion research, this perspective article describes how cultural factors impact the outcomes of health promotion studies either intentionally or unintentionally. It proposes ways in which these factors can be addressed or controlled in designing studies and interpreting their results. We describe how variation within and across cultures can be considered within a study, e.g. the conceptualization of research questions or hypotheses, and the methodology including sampling, surveys and interviews. We provide multiple examples of how culture influences the interpretation of study findings. Inadequately accounting or controlling for cultural variations in health promotion studies, whether they are planned or unplanned, can lead to incomplete research questions, incomplete data gathering, spurious results and limited generalizability of the findings. In health promotion research, factors related to culture and cultural variations need to be considered, acknowledged or controlled irrespective of the purpose of the study, to maximize the reliability, validity and generalizability of study findings. These issues are particularly relevant in contemporary health promotion research focusing on global lifestyle-related conditions where cultural factors have a pivotal role and warrant being understood. © The Author (2013). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice

PubMed Central

Hasan, S. Naimul; Mark, Brian; Harlalka, Gaurav V.; Patton, Michael A.; Ishida, Miho; Sharma, Sanjay; Faqeih, Eissa; Blakley, Brian; Jackson, Mike; Lees, Melissa; Dolinsky, Vernon; Cross, Leroy; Stanier, Philip; Salter, Claire; Baple, Emma L.; Crosby, Andrew H.

2017-01-01

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development. PMID:28081210

Deep reticulation and incomplete lineage sorting obscure the diploid phylogeny of rain-lilies and allies (Amaryllidaceae tribe Hippeastreae)

USDA-ARS?s Scientific Manuscript database

Hybridization is currently considered to be a frequent and important force in plant evolution; NGS methods offer new possibilities for clade resolution and ambitious sampling of gene genealogies, yet difficulty remains in detecting deep reticulation events using currently available methods. We exami...

Chronic EtOH effects on putative measures of compulsive behavior in mice

PubMed Central

Radke, Anna K.; Jury, Nicholas J.; Kocharian, Adrina; Marcinkiewcz, Catherine A.; Lowery-Gionta, Emily G.; Pleil, Kristen E.; McElligott, Zoe A.; McKlveen, Jessica M.; Kash, Thomas L.; Holmes, Andrew

2015-01-01

Addictions, including alcohol use disorders (AUDs), are characterized by the loss of control over drug seeking and consumption, but the neural circuits and signaling mechanisms responsible for the transition from controlled use to uncontrolled abuse remain incompletely understood. Prior studies have shown that ‘compulsive-like’ behaviors in rodents, e.g., persistent responding for ethanol (EtOH) despite punishment, are increased after chronic exposure to EtOH. The main goal of the current study was to assess the effects of chronic intermittent EtOH (CIE) exposure on multiple, putative measures of compulsive-like EtOH seeking in C57BL/6J mice. Mice were exposed to two or four weekly cycles of CIE and then, post-withdrawal, tested for progressive ratio responding for EtOH, sustained responding during signaled EtOH-unavailability and (footshock) punished-suppression of responding for EtOH. Results showed that mice exposed to CIE exhibited attenuated suppression of EtOH-seeking during punishment, as compared to air-exposed controls. By contrast, CIE exposure affected neither punished food reward-seeking behavior, nor other putative measures of compulsive-like EtOH-seeking. Ex vivo RT-PCR analysis of brain tissue found reduced sensitivity to punished EtOH-seeking after CIE exposure was accompanied by a significant increase in gene expression of the GluN1 and GluN2A subunits of the N-methyl-D-aspartate receptor (NMDAR), specifically in the medial orbitofrontal cortex (mOFC). Moreover, slice electrophysiological analysis revealed increased NMDAR-mediated currents in the mOFC after CIE exposure in test-naïve mice. Collectively, the current findings add to growing body of evidence demonstrating that chronic exposure to EtOH fosters resistance to punished EtOH-seeking in association with adaptations in cortical glutamatergic transmission. PMID:26687341

National Cancer Institute-National Heart, Lung and Blood Institute/pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: long-term organ damage and dysfunction.

PubMed

Nieder, Michael L; McDonald, George B; Kida, Aiko; Hingorani, Sangeeta; Armenian, Saro H; Cooke, Kenneth R; Pulsipher, Michael A; Baker, K Scott

2011-11-01

Long-term complications after hematopoietic cell transplantation (HCT) have been studied in detail. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects remain incompletely understood. This article describes our current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, and pulmonary systems, and discusses post-HCT metabolic syndrome studies. Underlying diseases, pretransplantation exposures, transplantation conditioning regimens, graft-versus-host disease, and other treatments contribute to these problems. Because organ systems are interdependent, long-term complications with similar pathophysiologic mechanisms often involve multiple organ systems. Current data suggest that post-HCT organ complications result from cellular damage that leads to a cascade of complex events. The interplay between inflammatory processes and dysregulated cellular repair likely contributes to end-organ fibrosis and dysfunction. Although many long-term problems cannot be prevented, appropriate monitoring can enable detection and organ-preserving medical management at earlier stages. Current management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in our knowledge of the pathophysiology of therapy-related organ toxicities disease after HCT. These gaps can be addressed by closely examining disease biology and identifying those patients at greatest risk for adverse outcomes. In addition, strategies are needed for targeted disease prevention and health promotion efforts for individuals deemed at high risk because of their genetic makeup or specific exposure profile. Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Development of intraoperative electrochemical detection: wireless instantaneous neurochemical concentration sensor for deep brain stimulation feedback

PubMed Central

Van Gompel, Jamie J.; Chang, Su-Youne; Goerss, Stephan J.; Kim, In Yong; Kimble, Christopher; Bennet, Kevin E.; Lee, Kendall H.

2010-01-01

Deep brain stimulation (DBS) is effective when there appears to be a distortion in the complex neurochemical circuitry of the brain. Currently, the mechanism of DBS is incompletely understood; however, it has been hypothesized that DBS evokes release of neurochemicals. Well-established chemical detection systems such as microdialysis and mass spectrometry are impractical if one is assessing changes that are happening on a second-to-second time scale or for chronically used implanted recordings, as would be required for DBS feedback. Electrochemical detection techniques such as fast-scan cyclic voltammetry (FSCV) and amperometry have until recently remained in the realm of basic science; however, it is enticing to apply these powerful recording technologies to clinical and translational applications. The Wireless Instantaneous Neurochemical Concentration Sensor (WINCS) currently is a research device designed for human use capable of in vivo FSCV and amperometry, sampling at subsecond time resolution. In this paper, the authors review recent advances in this electrochemical application to DBS technologies. The WINCS can detect dopamine, adenosine, and serotonin by FSCV. For example, FSCV is capable of detecting dopamine in the caudate evoked by stimulation of the subthalamic nucleus/substantia nigra in pig and rat models of DBS. It is further capable of detecting dopamine by amperometry and, when used with enzyme linked sensors, both glutamate and adenosine. In conclusion, WINCS is a highly versatile instrument that allows near real-time (millisecond) detection of neurochemicals important to DBS research. In the future, the neurochemical changes detected using WINCS may be important as surrogate markers for proper DBS placement as well as the sensor component for a “smart” DBS system with electrochemical feedback that allows automatic modulation of stimulation parameters. Current work is under way to establish WINCS use in humans. PMID:20672923

Acute exposure to wood smoke from incomplete combustion--indications of cytotoxicity.

PubMed

Muala, Ala; Rankin, Gregory; Sehlstedt, Maria; Unosson, Jon; Bosson, Jenny A; Behndig, Annelie; Pourazar, Jamshid; Nyström, Robin; Pettersson, Esbjörn; Bergvall, Christoffer; Westerholm, Roger; Jalava, Pasi I; Happo, Mikko S; Uski, Oskari; Hirvonen, Maija-Riitta; Kelly, Frank J; Mudway, Ian S; Blomberg, Anders; Boman, Christoffer; Sandström, Thomas

2015-10-29

Smoke from combustion of biomass fuels is a major risk factor for respiratory disease, but the underlying mechanisms are poorly understood. The aim of this study was to determine whether exposure to wood smoke from incomplete combustion would elicit airway inflammation in humans. Fourteen healthy subjects underwent controlled exposures on two separate occasions to filtered air and wood smoke from incomplete combustion with PM1 concentration at 314 μg/m(3) for 3 h in a chamber. Bronchoscopy with bronchial wash (BW), bronchoalveolar lavage (BAL) and endobronchial mucosal biopsies was performed after 24 h. Differential cell counts and soluble components were analyzed, with biopsies stained for inflammatory markers using immunohistochemistry. In parallel experiments, the toxicity of the particulate matter (PM) generated during the chamber exposures was investigated in vitro using the RAW264.7 macrophage cell line. Significant reductions in macrophage, neutrophil and lymphocyte numbers were observed in BW (p < 0.01, <0.05, <0.05, respectively) following the wood smoke exposure, with a reduction in lymphocytes numbers in BAL fluid (<0.01. This unexpected cellular response was accompanied by decreased levels of sICAM-1, MPO and MMP-9 (p < 0.05, <0.05 and <0.01). In contrast, significant increases in submucosal and epithelial CD3+ cells, epithelial CD8+ cells and submucosal mast cells (p < 0.01, <0.05, <0.05 and <0.05, respectively), were observed after wood smoke exposure. The in vitro data demonstrated that wood smoke particles generated under these incomplete combustion conditions induced cell death and DNA damage, with only minor inflammatory responses. Short-term exposure to sooty PAH rich wood smoke did not induce an acute neutrophilic inflammation, a classic hallmark of air pollution exposure in humans. While minor proinflammatory lymphocytic and mast cells effects were observed in the bronchial biopsies, significant reductions in BW and BAL cells and soluble components were noted. This unexpected observation, combined with the in vitro data, suggests that wood smoke particles from incomplete combustion could be potentially cytotoxic. Additional research is required to establish the mechanism of this dramatic reduction in airway leukocytes and to clarify how this acute response contributes to the adverse health effects attributed to wood smoke exposure. NCT01488500.

Invariant protection of high-voltage electric motors of technological complexes at industrial enterprises at partial single-phase ground faults

NASA Astrophysics Data System (ADS)

Abramovich, B. N.; Sychev, Yu A.; Pelenev, D. N.

2018-03-01

Development results of invariant protection of high-voltage motors at incomplete single-phase ground faults are observed in the article. It is established that current protections have low action selectivity because of an inadmissible decrease in entrance signals during the shirt circuit occurrence in the place of transient resistance. The structural functional scheme and an algorithm of protective actions where correction of automatic zero sequence currents signals of the protected accessions implemented according to the level of incompleteness of ground faults are developed. It is revealed that automatic correction of zero sequence currents allows one to provide the invariance of sensitivity factor for protection under the variation conditions of a transient resistance in the place of damage. Application of invariant protection allows one to minimize damages in 6-10 kV electrical installations of industrial enterprises for a cause of infringement of consumers’ power supply and their system breakdown due to timely localization of emergency of ground faults modes.

Darwin and Genetics

PubMed Central

Charlesworth, Brian; Charlesworth, Deborah

2009-01-01

Darwin's theory of natural selection lacked an adequate account of inheritance, making it logically incomplete. We review the interaction between evolution and genetics, showing how, unlike Mendel, Darwin's lack of a model of the mechanism of inheritance left him unable to interpret his own data that showed Mendelian ratios, even though he shared with Mendel a more mathematical and probabilistic outlook than most biologists of his time. Darwin's own “pangenesis” model provided a mechanism for generating ample variability on which selection could act. It involved, however, the inheritance of characters acquired during an organism's life, which Darwin himself knew could not explain some evolutionary situations. Once the particulate basis of genetics was understood, it was seen to allow variation to be passed intact to new generations, and evolution could then be understood as a process of changes in the frequencies of stable variants. Evolutionary genetics subsequently developed as a central part of biology. Darwinian principles now play a greater role in biology than ever before, which we illustrate with some examples of studies of natural selection that use DNA sequence data and with some recent advances in answering questions first asked by Darwin. PMID:19933231

Targeting obesity-related adipose tissue dysfunction to prevent cancer development and progression

PubMed Central

Gucalp, Ayca; Iyengar, Neil M.; Hudis, Clifford A.; Dannenberg, Andrew J.

2016-01-01

The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies. PMID:26970134

Cerebral vasculopathy in children with sickle cell anemia.

PubMed

Fasano, Ross M; Meier, Emily R; Hulbert, Monica L

2015-01-01

Sickle cell anemia (SCA)-associated cerebral vasculopathy and moyamoya is a unique entity reflecting the abnormal interactions between sickled red blood cells (RBCs) and the cerebral arterial endothelium. Endothelial injury, coagulation activation, and the inflammatory response generated by sickled RBCs are implicated in the development of cerebral vasculopathy, but the pathophysiology remains incompletely understood. SCA-specific screening and treatment guidelines have successfully reduced the incidence of overt strokes in this high-risk population. However, despite aggressive hematological management, many children with cerebral vasculopathy due to SCA have progressive vasculopathy and recurrent strokes; therefore, more effective therapies, such as revascularization surgery and curative hematopoietic stem cell transplant, are urgently needed. Copyright © 2014 Elsevier Inc. All rights reserved.

Sulfate burial constraints on the Phanerozoic sulfur cycle.

PubMed

Halevy, Itay; Peters, Shanan E; Fischer, Woodward W

2012-07-20

The sulfur cycle influences the respiration of sedimentary organic matter, the oxidation state of the atmosphere and oceans, and the composition of seawater. However, the factors governing the major sulfur fluxes between seawater and sedimentary reservoirs remain incompletely understood. Using macrostratigraphic data, we quantified sulfate evaporite burial fluxes through Phanerozoic time. Approximately half of the modern riverine sulfate flux comes from weathering of recently deposited evaporites. Rates of sulfate burial are unsteady and linked to changes in the area of marine environments suitable for evaporite formation and preservation. By contrast, rates of pyrite burial and weathering are higher, less variable, and largely balanced, highlighting a greater role of the sulfur cycle in regulating atmospheric oxygen.

[Brain oedema and acute liver failure].

PubMed

Spahr, L

2003-04-01

Brain oedema leading to intracranial hypertension occurs in a significant proportion of patients with acute liver failure in whom it is a leading cause of death. Although precise pathogenic mechanisms associated to this severe complication remain incompletely understood, increasing evidence points to gut-derived neurotoxins including ammonia as key mediators in cerebral osmotic and perfusion disturbances. The management of brain oedema and intracranial hypertension requires a multidisciplinar approach in a center where liver transplantation is available, as this option is the only treatment modality that provides improvement in outcome. This article reviews the most common causes of acute liver failure and the standard of supportive care management, and describes future potential therapeutic aspects of brain oedema and intracranial hypertension.

Reconciling controversies about the ‘global warming hiatus’

NASA Astrophysics Data System (ADS)

Medhaug, Iselin; Stolpe, Martin B.; Fischer, Erich M.; Knutti, Reto

2017-05-01

Between about 1998 and 2012, a time that coincided with political negotiations for preventing climate change, the surface of Earth seemed hardly to warm. This phenomenon, often termed the ‘global warming hiatus’, caused doubt in the public mind about how well anthropogenic climate change and natural variability are understood. Here we show that apparently contradictory conclusions stem from different definitions of ‘hiatus’ and from different datasets. A combination of changes in forcing, uptake of heat by the oceans, natural variability and incomplete observational coverage reconciles models and data. Combined with stronger recent warming trends in newer datasets, we are now more confident than ever that human influence is dominant in long-term warming.

Reconciling controversies about the 'global warming hiatus'.

PubMed

Medhaug, Iselin; Stolpe, Martin B; Fischer, Erich M; Knutti, Reto

2017-05-03

Between about 1998 and 2012, a time that coincided with political negotiations for preventing climate change, the surface of Earth seemed hardly to warm. This phenomenon, often termed the 'global warming hiatus', caused doubt in the public mind about how well anthropogenic climate change and natural variability are understood. Here we show that apparently contradictory conclusions stem from different definitions of 'hiatus' and from different datasets. A combination of changes in forcing, uptake of heat by the oceans, natural variability and incomplete observational coverage reconciles models and data. Combined with stronger recent warming trends in newer datasets, we are now more confident than ever that human influence is dominant in long-term warming.

Advances in color science: from retina to behavior

PubMed Central

Chatterjee, Soumya; Field, Greg D.; Horwitz, Gregory D.; Johnson, Elizabeth N.; Koida, Kowa; Mancuso, Katherine

2010-01-01

Color has become a premier model system for understanding how information is processed by neural circuits, and for investigating the relationships among genes, neural circuits and perception. Both the physical stimulus for color and the perceptual output experienced as color are quite well characterized, but the neural mechanisms that underlie the transformation from stimulus to perception are incompletely understood. The past several years have seen important scientific and technical advances that are changing our understanding of these mechanisms. Here, and in the accompanying minisymposium, we review the latest findings and hypotheses regarding color computations in the retina, primary visual cortex and higher-order visual areas, focusing on non-human primates, a model of human color vision. PMID:21068298

Single molecule data under scrutiny. Comment on "Extracting physics of life at the molecular level: A review of single-molecule data analyses" by W. Colomb & S.K. Sarkar

NASA Astrophysics Data System (ADS)

Wohland, Thorsten

2015-06-01

Single Molecule Detection and Spectroscopy have grown from their first beginnings into mainstream, mature research areas that are widely applied in the biological sciences. However, despite the advances in technology and the application of many single molecule techniques even in in vivo settings, the data analysis of single molecule experiments is complicated by noise, systematic errors, and complex underlying processes that are only incompletely understood. Colomb and Sarkar provide in this issue an overview of single molecule experiments and the accompanying problems in data analysis, which have to be overcome for a proper interpretation of the experiments [1].

Mouse models to study the effect of cardiovascular risk factors on brain structure and cognition

PubMed Central

Bink, Diewertje I; Ritz, Katja; Aronica, Eleonora; van der Weerd, Louise; Daemen, Mat JAP

2013-01-01

Recent clinical data indicates that hemodynamic changes caused by cardiovascular diseases such as atherosclerosis, heart failure, and hypertension affect cognition. Yet, the underlying mechanisms of the resulting vascular cognitive impairment (VCI) are poorly understood. One reason for the lack of mechanistic insights in VCI is that research in dementia primarily focused on Alzheimer's disease models. To fill in this gap, we critically reviewed the published data and various models of VCI. Typical findings in VCI include reduced cerebral perfusion, blood–brain barrier alterations, white matter lesions, and cognitive deficits, which have also been reported in different cardiovascular mouse models. However, the tests performed are incomplete and differ between models, hampering a direct comparison between models and studies. Nevertheless, from the currently available data we conclude that a few existing surgical animal models show the key features of vascular cognitive decline, with the bilateral common carotid artery stenosis hypoperfusion mouse model as the most promising model. The transverse aortic constriction and myocardial infarction models may be good alternatives, but these models are as yet less characterized regarding the possible cerebral changes. Mixed models could be used to study the combined effects of different cardiovascular diseases on the deterioration of cognition during aging. PMID:23963364

Preoperative Plasma Aldosterone Levels and Postoperative Atrial Fibrillation Occurrence Following Cardiac Surgery: A Review of Literature and Design of the ALDO-POAF Study (ALDOsterone for Prediction of Post-Operative Atrial Fibrillation).

PubMed

Chequel, Mathieu; Ollitrault, Pierre; Saloux, Eric; Parienti, Jean-Jacques; Fischer, Marc-Olivier; Desgué, Julien; Allouche, Stéphane; Milliez, Paul; Alexandre, Joachim

2016-01-01

Post-operative atrial fibrillation (POAF) is a major and frequent complication occurring after cardiac surgery, contributing to prolonged intensive care and hospital stays and is associated with several cardiovascular complications. The exact mechanisms and signaling pathways involved in the development of POAF seem to be multifactorial and remain to date incompletely understood. β-blockers and amiodarone are the first line preventive drugs but are partially effective and near 30% of POAF resist to these strategies. In this work, we review the current knowledge about pathophysiological POAF mechanisms and preventive pharmacological strategies. We also discuss the rational for the use of pre-operative plasma aldosterone and galectin-3 (Gal-3) levels as predictive biomarkers of POAF and the potential role of aldosterone antagonists in the POAF preventive strategy. POAF is a major complication occurring after cardiac surgery. In this context, there is some evidence indicating that renin-angiotensin-aldosterone system and Gal-3 could be very useful predictive biomarkers of POAF and potentially interesting therapeutic target to prevent POAF occurrence. We present the rationale and the design of the ALDO-POAF trial (ALDOsterone for prediction of Post- Operative Atrial Fibrillation, NCT 02814903).

Sensitivity of secondary production and export flux to choice of trophic transfer formulation in marine ecosystem models

NASA Astrophysics Data System (ADS)

Anderson, Thomas R.; Hessen, Dag O.; Mitra, Aditee; Mayor, Daniel J.; Yool, Andrew

2013-09-01

The performance of four contemporary formulations describing trophic transfer, which have strongly contrasting assumptions as regards the way that consumer growth is calculated as a function of food C:N ratio and in the fate of non-limiting substrates, was compared in two settings: a simple steady-state ecosystem model and a 3D biogeochemical general circulation model. Considerable variation was seen in predictions for primary production, transfer to higher trophic levels and export to the ocean interior. The physiological basis of the various assumptions underpinning the chosen formulations is open to question. Assumptions include Liebig-style limitation of growth, strict homeostasis in zooplankton biomass, and whether excess C and N are released by voiding in faecal pellets or via respiration/excretion post-absorption by the gut. Deciding upon the most appropriate means of formulating trophic transfer is not straightforward because, despite advances in ecological stoichiometry, the physiological mechanisms underlying these phenomena remain incompletely understood. Nevertheless, worrying inconsistencies are evident in the way in which fundamental transfer processes are justified and parameterised in the current generation of marine ecosystem models, manifested in the resulting simulations of ocean biogeochemistry. Our work highlights the need for modellers to revisit and appraise the equations and parameter values used to describe trophic transfer in marine ecosystem models.

Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

PubMed Central

O'Donoghue, Robert J J; Knight, Darryl A; Richards, Carl D; Prêle, Cecilia M; Lau, Hui Ling; Jarnicki, Andrew G; Jones, Jessica; Bozinovski, Steven; Vlahos, Ross; Thiem, Stefan; McKenzie, Brent S; Wang, Bo; Stumbles, Philip; Laurent, Geoffrey J; McAnulty, Robin J; Rose-John, Stefan; Zhu, Hong Jian; Anderson, Gary P; Ernst, Matthias R; Mutsaers, Steven E

2012-01-01

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)-β signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;µMT−/− compound mutant mice, but fibrosis still occurred in their Smad3−/− counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1α1 gene transcription independently of canonical TGF-β/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin-induced lung fibrosis. PMID:22684844

The diastolic function to cyclic variation of myocardial ultrasonic backscatter relation: the influence of parameterized diastolic filling (PDF) formalism determined chamber properties.

PubMed

Lloyd, Christopher W; Shmuylovich, Leonid; Holland, Mark R; Miller, James G; Kovács, Sándor J

2011-08-01

Myocardial tissue characterization represents an extension of currently available echocardiographic imaging. The systematic variation of backscattered energy during the cardiac cycle (the "cyclic variation" of backscatter) has been employed to characterize cardiac function in a wide range of investigations. However, the mechanisms responsible for observed cyclic variation remain incompletely understood. As a step toward determining the features of cardiac structure and function that are responsible for the observed cyclic variation, the present study makes use of a kinematic approach of diastolic function quantitation to identify diastolic function determinants that influence the magnitude and timing of cyclic variation. Echocardiographic measurements of 32 subjects provided data for determination of the cyclic variation of backscatter to diastolic function relation characterized in terms of E-wave determined, kinematic model-based parameters of chamber stiffness, viscosity/relaxation and load. The normalized time delay of cyclic variation appears to be related to the relative viscoelasticity of the chamber and predictive of the kinematic filling dynamics as determined using the parameterized diastolic filling formalism (with r-values ranging from .44 to .59). The magnitude of cyclic variation does not appear to be strongly related to the kinematic parameters. Copyright © 2011 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

The neurobiology of social environmental risk for schizophrenia: an evolving research field.

PubMed

Akdeniz, Ceren; Tost, Heike; Meyer-Lindenberg, Andreas

2014-04-01

Schizophrenia is a severe and complex brain disorder that usually manifests in early adulthood and disturbs a wide range of human functions. More than 100 years after its initial description, the pathophysiology of the disorder is still incompletely understood. Many epidemiological studies strongly suggest a complex interaction between genetic and environmental risk factors for the development of the disorder. While there is considerable evidence for a social environmental component of this risk, the links between adverse social factors and altered brain function have just come into focus. In the present review, we first summarize epidemiological evidence for the significance of social environmental risk factors, outline the role of altered social stress processing in mental illness, and review the latest experimental evidence for the neural correlates of social environmental risk for schizophrenia. The studies we have discussed in this review provide a selection of the current work in the field. We suggest that many of the social environmental risk factors may impact on perceived social stress and engage neural circuits in the brain whose functional and structural architecture undergoes detrimental change in response to prolonged exposure. We conclude that multidisciplinary approaches involving various fields and thoroughly constructed longitudinal designs are necessary to capture complex structure of social environmental risks.

Delayed innocent bystander cell death following hypoxia in Caenorhabditis elegans

PubMed Central

Sun, C-L; Kim, E; Crowder, C M

2014-01-01

After hypoxia, cells may die immediately or have a protracted course, living or dying depending on an incompletely understood set of cell autonomous and nonautonomous factors. In stroke, for example, some neurons are thought to die from direct hypoxic injury by cell autonomous primary mechanisms, whereas other so called innocent bystander neurons die from factors released from the primarily injured cells. A major limitation in identifying these factors is the inability of current in vivo models to selectively target a set of cells for hypoxic injury so that the primarily injured cells and the innocent bystanders are clearly delineated. In order to develop such a model, we generated transgenic Caenorhabditis elegans strains where 2–3% of somatic cells were made selectively sensitive to hypoxia. This was accomplished by cell type-specific wild-type rescue in either pharyngeal myocytes or GABAergic neurons of a hypoxia resistance-producing translation factor mutation. Surprisingly, hypoxic targeting of these relatively small subsets of non-essential cells produced widespread innocent bystander cell injury, behavioral dysfunction and eventual organismal death. The hypoxic injury phenotypes of the myocyte or neuron sensitized strains were virtually identical. Using this model, we show that the C. elegans insulin receptor/FOXO transcription factor pathway improves survival when activated only after hypoxic injury and blocks innocent bystander death. PMID:24317200

Delayed innocent bystander cell death following hypoxia in Caenorhabditis elegans.

PubMed

Sun, C-L; Kim, E; Crowder, C M

2014-04-01

After hypoxia, cells may die immediately or have a protracted course, living or dying depending on an incompletely understood set of cell autonomous and nonautonomous factors. In stroke, for example, some neurons are thought to die from direct hypoxic injury by cell autonomous primary mechanisms, whereas other so called innocent bystander neurons die from factors released from the primarily injured cells. A major limitation in identifying these factors is the inability of current in vivo models to selectively target a set of cells for hypoxic injury so that the primarily injured cells and the innocent bystanders are clearly delineated. In order to develop such a model, we generated transgenic Caenorhabditis elegans strains where 2-3% of somatic cells were made selectively sensitive to hypoxia. This was accomplished by cell type-specific wild-type rescue in either pharyngeal myocytes or GABAergic neurons of a hypoxia resistance-producing translation factor mutation. Surprisingly, hypoxic targeting of these relatively small subsets of non-essential cells produced widespread innocent bystander cell injury, behavioral dysfunction and eventual organismal death. The hypoxic injury phenotypes of the myocyte or neuron sensitized strains were virtually identical. Using this model, we show that the C. elegans insulin receptor/FOXO transcription factor pathway improves survival when activated only after hypoxic injury and blocks innocent bystander death.

In vitro gastric survival of commercially available probiotic strains and oral dosage forms.

PubMed

Caillard, Romain; Lapointe, Nicolas

2017-03-15

Although the intestinal microbial community is still incompletely understood, there is strong evidence of the benefits of using probiotics to address some medical states or conditions. As a result, the probiotics oral supplements market has exploded during the last few years. However, while their sensitivity to gastric juices, acidic pH and bile is well known, most of these oral forms would not guarantee any survival of the strains in such conditions. In this work, we have studied the resistance to simulated gastric juices of several commercially available probiotics products. These included sixteen strains and ten oral forms such as enteric/non-enteric capsules/tablets and microencapsulated strains. Results demonstrated that all tested strains showed high sensitivity to acidic conditions and suggested that most of these microorganisms would not show any viability when immersed in the stomach at fasting. Most probiotics oral forms did not provide any protection to strains, unless these forms presented strong enteric protection. Consequently, the efficacy of non-enteric products to fully provide to the patient the benefits related to the consumption of probiotics supplement would be strongly questionable. This study underlines the chasm between the current opinion about probiotics protection needs and the products proposed by many companies in the dietary supplements area. Copyright © 2017 Elsevier B.V. All rights reserved.

Modeling the effect of exogenous melatonin on the sleep-wake switch.

PubMed

Johnson, Nicholas; Jain, Gauray; Sandberg, Lianne; Sheets, Kevin

2012-01-01

According to the Centers for Disease Control and Prevention and the Institute of Medicine of the National Academies, insufficient sleep has become a public health epidemic. Approximately 50-70 million adults (20 years or older) suffer from some disorder of sleep and wakefulness, hindering daily functioning and adversely affecting health and longevity. Melatonin, a naturally produced hormone which plays a role in sleep-wake regulation, is currently offered as an over-the-counter sleep aid. However, the effects of melatonin on the sleep-wake cycle are incompletely understood. The goal of this modeling study was to incorporate the effects of exogenous melatonin administration into a mathematical model of the human sleep-wake switch. The model developed herein adds a simple kinetic model of the MT1 melatonin receptor to an existing model which simulates the interactions of different neuronal groups thought to be involved in sleep-wake regulation. Preliminary results were obtained by simulating the effects of an exogenous melatonin dose typical of over-the-counter sleep aids. The model predicted an increase in homeostatic sleep drive and a resulting alteration in circadian rhythm consistent with experimental results. The time of melatonin administration was also observed to have a strong influence on the sleep-wake effects elicited, which is also consistent with prior experimental findings.

NOTE: Haemodynamic resistance model of monochorionic twin pregnancies complicated by acardiac twinning

NASA Astrophysics Data System (ADS)

Umur, Asli; van Gemert, Martin J. C.; van den Wijngaard, Jeroen P. H. M.; Ross, Michael G.; Nikkels, Peter G. J.

2004-07-01

An acardiac twin is a severely malformed monochorionic twin fetus that lacks most organs, particularly a heart. It grows during pregnancy, because it is perfused by its developmentally normal co-twin (called the pump twin) via a set of placental arterioarterial and venovenous anastomoses. The pump twin dies intrauterine or neonatally in about 50% of the cases due to congestive heart failure, polyhydramnios and prematurity. Because the pathophysiology of this pregnancy is currently incompletely understood, we modified our previous haemodynamic model of monochorionic twins connected by placental vascular anastomoses to include the analysis of acardiac twin pregnancies. We incorporated the fetoplacental circulation as a resistance circuit and used the fetal umbilical flow that perfuses the body to define fetal growth, rather than the placental flow as done previously. Using this modified model, we predicted that the pump twin has excess blood volume and increased mean arterial blood pressure compared to those in the acardiac twin. Placental perfusion of the acardiac twin is significantly reduced compared to normal, as a consequence of an increased venous pressure, possibly implying reduced acardiac placental growth. In conclusion, the haemodynamic analysis may contribute to an increased knowledge of the pathophysiologic consequences of an acardiac body mass for the pump twin.

A case-control study of pathogen and lifestyle risk factors for diarrhoea in dogs.

PubMed

Stavisky, Jenny; Radford, Alan David; Gaskell, Rosalind; Dawson, Susan; German, Alex; Parsons, Bryony; Clegg, Simon; Newman, Jenny; Pinchbeck, Gina

2011-05-01

Diarrhoea is a common and multi-factorial condition in dogs, the aetiology of which is often incompletely understood. A case-control study was carried out to compare the carriage of some common canine enteric pathogens (enteric coronavirus, parvovirus, distemper, endoparasites, Campylobacter and Salmonella spp.), as well as lifestyle factors such as vaccination history, diet and contact with other species, in dogs presenting at first opinion veterinary practices with and without diarrhoea. Multivariable conditional logistic regression showed that dogs in the study which scavenged or had had a recent change of diet (OR 3.5, p=0.002), had recently stayed in kennels (OR 9.5, p=0.01), or were fed a home-cooked diet (OR 4, p=0.002) were at a significantly greater risk of diarrhoea, whilst being female (OR 0.4, p=0.01), currently up to date with routine vaccinations (OR 0.4, p=0.05) and having contact with horse faeces (OR 0.4, p=0.06) were associated with a reduced risk. None of the pathogens tested for was a significant factor in the final multivariable model suggesting that in this predominantly vaccinated population, diarrhoea may be more associated with lifestyle risk factors than specific pathogens. Copyright © 2011 Elsevier B.V. All rights reserved.

Marijuana.

PubMed

Ammerman, Seth

2014-04-01

Marijuana use in pediatric populations remains an ongoing concern, and marijuana use by adolescents had known medical, psychological, and cognitive side effects. Marijuana alters brain development and has detrimental effects on brain structure and function in ways that are incompletely understood at this point in time. Furthermore, marijuana smoke contains tar and other harmful chemicals, so marijuana cannot be recommended by physicians. At this time, no studies suggest a benefit of marijuana use by children and adolescents. In the context of limited but clear evidence showing harm or potential harm from marijuana use by adolescents, any recommendations for medical marijuana use by adolescents are based on research studies with adults and on anecdotal evidence. Criminal prosecution for marijuana possession adversely affects hundreds of thousands of youth yearly in the United States, particularly minority youth. Current evidence does not support a focus on punishment for youth who use marijuana. Rather, drug education and treatment programs should be encouraged to better help youth who are experimenting with or are dependent on marijuana. Decriminalization of recreational use of marijuana by adults has not led to an increase in youth use rates of recreational marijuana. Thus, decriminalization may be a reasonable alternative to outright criminalization, as long as it is coupled with drug education and treatment programs. The effect of outright legalization of adult recreational use of marijuana on youth use is unknown.

Muscles and their role in episodic tension-type headache: implications for treatment.

PubMed

Bendtsen, L; Ashina, S; Moore, A; Steiner, T J

2016-02-01

Tension-type headache (TTH) imposes a heavy burden on the global population but remains incompletely understood and poorly managed. Here, we review current knowledge of peripheral factors involved in the mechanism of TTH and make recommendations for the treatment of episodic TTH based on these. Peripheral activation or sensitization of myofascial nociceptors is most probably involved in the development of muscle pain and the acute episode of TTH. Repetitive episodes of muscle pain may sensitize the central nervous system resulting in progression of TTH to the chronic form. Thus, muscular factors may be responsible not only for the acute headache episode but also for chronification of the disorder. Simple analgesics and non-steroidal anti-inflammatory drugs are the mainstays of management of individual headache episodes. Ibuprofen 400 mg and aspirin 1000 mg are recommended as drugs of first choice based on treatment effect, safety profile and costs. Non-pharmacological therapies include electromyographic biofeedback, physiotherapy and muscle relaxation therapy. Future studies should aim to identify the triggers of peripheral nociception and how to avoid peripheral and central sensitization. There is a need for more effective, faster acting drugs for acute TTH. Muscular factors play an important role in episodic TTH. Ibuprofen 400 mg and aspirin 1000 mg are recommended as drugs of first choice. © 2015 European Pain Federation - EFIC®

The SAM, not the electrodes, dominates charge transport in metal-monolayer//Ga2O3/gallium-indium eutectic junctions.

PubMed

Reus, William F; Thuo, Martin M; Shapiro, Nathan D; Nijhuis, Christian A; Whitesides, George M

2012-06-26

The liquid-metal eutectic of gallium and indium (EGaIn) is a useful electrode for making soft electrical contacts to self-assembled monolayers (SAMs). This electrode has, however, one feature whose effect on charge transport has been incompletely understood: a thin (approximately 0.7 nm) film-consisting primarily of Ga(2)O(3)-that covers its surface when in contact with air. SAMs that rectify current have been measured using this electrode in Ag(TS)-SAM//Ga(2)O(3)/EGaIn (where Ag(TS) = template-stripped Ag surface) junctions. This paper organizes evidence, both published and unpublished, showing that the molecular structure of the SAM (specifically, the presence of an accessible molecular orbital asymmetrically located within the SAM), not the difference between the electrodes or the characteristics of the Ga(2)O(3) film, causes the observed rectification. By examining and ruling out potential mechanisms of rectification that rely either on the Ga(2)O(3) film or on the asymmetry of the electrodes, this paper demonstrates that the structure of the SAM dominates charge transport through Ag(TS)-SAM//Ga(2)O(3)/EGaIn junctions, and that the electrical characteristics of the Ga(2)O(3) film have a negligible effect on these measurements.

The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity

PubMed Central

2016-01-01

The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning. PMID:27403348

Big Data and Genome Editing Technology: A New Paradigm of Cardiovascular Genomics.

PubMed

Krittanawong, Chayakrit; Sun, Tao; Herzog, Eyal

2017-01-01

Opinion Statements: Cardiovascular diseases (CVDs) encompass a range of conditions extending from congenital heart disease to acute coronary syndrome most of which are heterogenous in nature and some of them are multiple genetic loci. However, the pathogenesis of most CVDs remains incompletely understood. The advance in genome-editing technologies, an engineering process of DNA sequences at precise genomic locations, has enabled a new paradigm that human genome can be precisely modified to achieve a therapeutic effect. Genome-editing includes the correction of genetic variants that cause disease, the addition of therapeutic genes to specific sites in the genomic locations, and the removal of deleterious genes or genome sequences. Site-specific genome engineering can be used as nucleases (known as molecular scissors) including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) systems to provide remarkable opportunities for developing novel therapies in cardiovascular clinical care. Here we discuss genetic polymorphisms and mechanistic insights in CVDs with an emphasis on the impact of genome-editing technologies. The current challenges and future prospects for genomeediting technologies in cardiovascular medicine are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy

PubMed Central

Ghorayeb, Nada El; Rondeau, Geneviève; Latour, Mathieu; Cohade, Christian; Olney, Harold; Lacroix, André; Perrotte, Paul; Sabourin, Alexis; Mazzuco, Tania L; Bourdeau, Isabelle

2016-01-01

Abstract Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients. PMID:27043680

A New Basal Sauropod Dinosaur from the Middle Jurassic of Niger and the Early Evolution of Sauropoda

PubMed Central

Remes, Kristian; Ortega, Francisco; Fierro, Ignacio; Joger, Ulrich; Kosma, Ralf; Marín Ferrer, José Manuel; Ide, Oumarou Amadou; Maga, Abdoulaye

2009-01-01

Background The early evolution of sauropod dinosaurs is poorly understood because of a highly incomplete fossil record. New discoveries of Early and Middle Jurassic sauropods have a great potential to lead to a better understanding of early sauropod evolution and to reevaluate the patterns of sauropod diversification. Principal Findings A new sauropod from the Middle Jurassic of Niger, Spinophorosaurus nigerensis n. gen. et sp., is the most complete basal sauropod currently known. The taxon shares many anatomical characters with Middle Jurassic East Asian sauropods, while it is strongly dissimilar to Lower and Middle Jurassic South American and Indian forms. A possible explanation for this pattern is a separation of Laurasian and South Gondwanan Middle Jurassic sauropod faunas by geographic barriers. Integration of phylogenetic analyses and paleogeographic data reveals congruence between early sauropod evolution and hypotheses about Jurassic paleoclimate and phytogeography. Conclusions Spinophorosaurus demonstrates that many putatively derived characters of Middle Jurassic East Asian sauropods are plesiomorphic for eusauropods, while South Gondwanan eusauropods may represent a specialized line. The anatomy of Spinophorosaurus indicates that key innovations in Jurassic sauropod evolution might have taken place in North Africa, an area close to the equator with summer-wet climate at that time. Jurassic climatic zones and phytogeography possibly controlled early sauropod diversification. PMID:19756139

Solving the muon g -2 anomaly in deflected anomaly mediated SUSY breaking with messenger-matter interactions

NASA Astrophysics Data System (ADS)

Wang, Fei; Wang, Wenyu; Yang, Jin Min

2017-10-01

We propose to introduce general messenger-matter interactions in the deflected anomaly mediated supersymmetry (SUSY) breaking (AMSB) scenario to explain the gμ-2 anomaly. Scenarios with complete or incomplete grand unified theory (GUT) multiplet messengers are discussed, respectively. The introduction of incomplete GUT mulitiplets can be advantageous in various aspects. We found that the gμ-2 anomaly can be solved in both scenarios under current constraints including the gluino mass bounds, while the scenarios with incomplete GUT representation messengers are more favored by the gμ-2 data. We also found that the gluino is upper bounded by about 2.5 TeV (2.0 TeV) in scenario A and 3.0 TeV (2.7 TeV) in scenario B if the generalized deflected AMSB scenarios are used to fully account for the gμ-2 anomaly at 3 σ (2 σ ) level. Such a gluino should be accessible in the future LHC searches. Dark matter (DM) constraints, including DM relic density and direct detection bounds, favor scenario B with incomplete GUT multiplets. Much of the allowed parameter space for scenario B could be covered by the future DM direct detection experiments.

Operative hysteroscopy versus vacuum aspiration for incomplete spontaneous abortion (HY-PER): study protocol for a randomized controlled trial.

PubMed

Huchon, Cyrille; Koskas, Martin; Agostini, Aubert; Akladios, Cherif; Alouini, Souhail; Bauville, Estelle; Bourdel, Nicolas; Fernandez, Hervé; Fritel, Xavier; Graesslin, Olivier; Legendre, Guillaume; Lucot, Jean-Philippe; Matheron, Isabelle; Panel, Pierre; Raiffort, Cyril; Fauconnier, Arnaud

2015-08-19

Incomplete spontaneous abortions are defined by the intrauterine retention of the products of conception after their incomplete or partial expulsion. This condition may be managed by expectant care, medical treatment or surgery. Vacuum aspiration is currently the standard surgical treatment in most centers. However, operative hysteroscopy has the advantage over vacuum aspiration of allowing the direct visualization of the retained conception product, facilitating its elective removal while limiting surgical complications. Inadequately powered retrospective studies reported subsequent fertility to be higher in patients treated by operative hysteroscopy than in those treated by vacuum aspiration. These data require confirmation in a randomized controlled trial comparing fertility rates between women undergoing hysteroscopy and those undergoing vacuum aspiration for incomplete spontaneous abortion. After providing written informed consent, 572 women with incomplete spontaneous abortion recruited from 15 centers across France will undergo randomization by a centralized computer system for treatment by either vacuum aspiration or operative hysteroscopy. Patients will not be informed of the type of treatment that they receive and will be cared for during their hospital stay in accordance with standard practices at each center. The patients will be monitored for pregnancy or adverse effects by a telephone conversation or questionnaire sent by e-mail or post over a period of two years. In cases of complications, failure of the intervention or diagnosis of uterine cavity disease, patient care will be left to the discretion of the medical center team. If our hypothesis is confirmed, this study will provide evidence that the use of operative hysteroscopy can increase the number of pregnancies continuing beyond 22 weeks of gestation in the two-year period following incomplete spontaneous abortion without increasing the incidence of morbidity and peri- and postoperative complications. The standard surgical treatment of this condition would thus be modified. This study would therefore have a large effect on the surgical management of incomplete spontaneous abortion. ClinicalTrials.gov Identifier: NCT02201732 ; registered on 17 July 2014.

Incomplete fusion analysis of the 7Li-induced reaction on 93Nb within 3-6.5 MeV/nucleon

NASA Astrophysics Data System (ADS)

Kumar, Deepak; Maiti, Moumita

2017-10-01

Background: It is understood from the recent experimental studies that prompt/resonant breakup, and transfer followed by breakup in the weakly bound Li,76-induced reactions play a significant role in the complete-incomplete fusion (CF-ICF), suppression/enhancement in the fusion cross section around the Coulomb barrier. Purpose: Investigation of ICF over CF by measuring cross sections of the populated residues, produced via different channels in the 7Li-induced reaction on a natNb target within the 3-6.5 MeV/nucleon energy region. Method: The 7Li beam was allowed to hit the self-supporting 93Nb targets, backed by the aluminium (Al) foil alternately, within 3-6.5 MeV/nucleon energy. Populated residues were identified by offline γ -ray spectrometry. Measured excitation functions of different channels were compared with different equilibrium and pre-equilibrium models. Result: The enhancement in cross sections in the proton (˜20 -30 MeV) and α -emitting channels, which may be ascribed to ICF, was observed in the measured energy range when compared to the Hauser-Feshbach and exciton model calculations using empire, which satisfactorily reproduces the neutron channels, compared to the Weisskopf-Ewing model and hybrid Monte Carlo calculations. The increment of the incomplete fusion fraction was observed with rising projectile energy. Conclusion: Contrary to the alice14, experimental results are well reproduced by the empire throughout the measured energy range. The signature of ICF over CF indicates that the breakup/transfer processes are involved in the weakly bound 7Li-induced reaction on 93Nb slightly above the Coulomb barrier.

Bears in a forest of gene trees: phylogenetic inference is complicated by incomplete lineage sorting and gene flow.

PubMed

Kutschera, Verena E; Bidon, Tobias; Hailer, Frank; Rodi, Julia L; Fain, Steven R; Janke, Axel

2014-08-01

Ursine bears are a mammalian subfamily that comprises six morphologically and ecologically distinct extant species. Previous phylogenetic analyses of concatenated nuclear genes could not resolve all relationships among bears, and appeared to conflict with the mitochondrial phylogeny. Evolutionary processes such as incomplete lineage sorting and introgression can cause gene tree discordance and complicate phylogenetic inferences, but are not accounted for in phylogenetic analyses of concatenated data. We generated a high-resolution data set of autosomal introns from several individuals per species and of Y-chromosomal markers. Incorporating intraspecific variability in coalescence-based phylogenetic and gene flow estimation approaches, we traced the genealogical history of individual alleles. Considerable heterogeneity among nuclear loci and discordance between nuclear and mitochondrial phylogenies were found. A species tree with divergence time estimates indicated that ursine bears diversified within less than 2 My. Consistent with a complex branching order within a clade of Asian bear species, we identified unidirectional gene flow from Asian black into sloth bears. Moreover, gene flow detected from brown into American black bears can explain the conflicting placement of the American black bear in mitochondrial and nuclear phylogenies. These results highlight that both incomplete lineage sorting and introgression are prominent evolutionary forces even on time scales up to several million years. Complex evolutionary patterns are not adequately captured by strictly bifurcating models, and can only be fully understood when analyzing multiple independently inherited loci in a coalescence framework. Phylogenetic incongruence among gene trees hence needs to be recognized as a biologically meaningful signal. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Toxicology of Biodiesel Combustion products

EPA Science Inventory

1. Introduction The toxicology of combusted biodiesel is an emerging field. Much of the current knowledge about biological responses and health effects stems from studies of exposures to other fuel sources (typically petroleum diesel, gasoline, and wood) incompletely combusted. ...

Caffeine Modulates Vesicle Release and Recovery at Cerebellar Parallel Fibre Terminals, Independently of Calcium and Cyclic AMP Signalling

PubMed Central

Dobson, Katharine L.; Jackson, Claire; Balakrishnan, Saju; Bellamy, Tomas C.

2015-01-01

Background Cerebellar parallel fibres release glutamate at both the synaptic active zone and at extrasynaptic sites—a process known as ectopic release. These sites exhibit different short-term and long-term plasticity, the basis of which is incompletely understood but depends on the efficiency of vesicle release and recycling. To investigate whether release of calcium from internal stores contributes to these differences in plasticity, we tested the effects of the ryanodine receptor agonist caffeine on both synaptic and ectopic transmission. Methods Whole cell patch clamp recordings from Purkinje neurons and Bergmann glia were carried out in transverse cerebellar slices from juvenile (P16-20) Wistar rats. Key Results Caffeine caused complex changes in transmission at both synaptic and ectopic sites. The amplitude of postsynaptic currents in Purkinje neurons and extrasynaptic currents in Bergmann glia were increased 2-fold and 4-fold respectively, but paired pulse ratio was substantially reduced, reversing the short-term facilitation observed under control conditions. Caffeine treatment also caused synaptic sites to depress during 1 Hz stimulation, consistent with inhibition of the usual mechanisms for replenishing vesicles at the active zone. Unexpectedly, pharmacological intervention at known targets for caffeine—intracellular calcium release, and cAMP signalling—had no impact on these effects. Conclusions We conclude that caffeine increases release probability and inhibits vesicle recovery at parallel fibre synapses, independently of known pharmacological targets. This complex effect would lead to potentiation of transmission at fibres firing at low frequencies, but depression of transmission at high frequency connections. PMID:25933382

Overview of the determinants of overweight and obesity: current evidence and research issues.

PubMed

Hill, J O; Melanson, E L

1999-11-01

The prevalence of obesity has reached epidemic proportions in many countries around the world. However, the genetic and environmental factors contributing to obesity are incompletely understood. We reviewed studies relating to the regulation of energy balance and how these factors may contribute to the development of obesity. Although it is widely believed that genetics contribute significantly to the variability in body fatness, the available data do not support a role for defects in resting metabolic rate, substrate metabolism, dietary induced thermogenesis, or the energy cost of physical activity as significant causes of obesity. Furthermore, it is safe to say that the human genotype has not changed substantially over the past two to three decades. Data from several national surveys indicate that over the past few decades, there has been either a slight increase or a very modest decline in total energy and fat intake. This suggests that decreases in physical activity are a major contributing factor. Participation in leisure time physical activity is low but has remained relatively constant. However, an increased reliance on technology has substantially reduced work-related physical activity and the energy expenditure required for daily living. The most likely environmental factor contributing to the current obesity epidemic is a continued decline in daily energy expenditure that has not been matched by an equivalent reduction in energy intake. Because daily energy expenditure is decreasing, it is difficult for most people to restrict intake to meet energy requirements, and more and more people are becoming obese. Thus, increasing physical activity may be the strategy of choice for public health efforts to prevent obesity.

EEG functional connectivity is partially predicted by underlying white matter connectivity

PubMed Central

Chu, CJ; Tanaka, N; Diaz, J; Edlow, BL; Wu, O; Hämäläinen, M; Stufflebeam, S; Cash, SS; Kramer, MA.

2015-01-01

Over the past decade, networks have become a leading model to illustrate both the anatomical relationships (structural networks) and the coupling of dynamic physiology (functional networks) linking separate brain regions. The relationship between these two levels of description remains incompletely understood and an area of intense research interest. In particular, it is unclear how cortical currents relate to underlying brain structural architecture. In addition, although theory suggests that brain communication is highly frequency dependent, how structural connections influence overlying functional connectivity in different frequency bands has not been previously explored. Here we relate functional networks inferred from statistical associations between source imaging of EEG activity and underlying cortico-cortical structural brain connectivity determined by probabilistic white matter tractography. We evaluate spontaneous fluctuating cortical brain activity over a long time scale (minutes) and relate inferred functional networks to underlying structural connectivity for broadband signals, as well as in seven distinct frequency bands. We find that cortical networks derived from source EEG estimates partially reflect both direct and indirect underlying white matter connectivity in all frequency bands evaluated. In addition, we find that when structural support is absent, functional connectivity is significantly reduced for high frequency bands compared to low frequency bands. The association between cortical currents and underlying white matter connectivity highlights the obligatory interdependence of functional and structural networks in the human brain. The increased dependence on structural support for the coupling of higher frequency brain rhythms provides new evidence for how underlying anatomy directly shapes emergent brain dynamics at fast time scales. PMID:25534110

Incompletely characterized incidental renal masses: emerging data support conservative management.

PubMed

Silverman, Stuart G; Israel, Gary M; Trinh, Quoc-Dien

2015-04-01

With imaging, most incidental renal masses can be diagnosed promptly and with confidence as being either benign or malignant. For those that cannot, management recommendations can be devised on the basis of a thorough evaluation of imaging features. However, most renal masses are either too small to characterize completely or are detected initially in imaging examinations that are not designed for full evaluation of them. These masses constitute a group of masses that are considered incompletely characterized. On the basis of current published guidelines, many masses warrant additional imaging. However, while the diagnosis of renal cancer at a curable stage remains the first priority, there is the additional need to reduce unnecessary healthcare costs and radiation exposure. As such, emerging data now support foregoing additional imaging for many incompletely characterized renal masses. These data include the low risk of progression to metastases or death for small renal masses that have undergone active surveillance (including biopsy-proven cancers) and a better understanding of how specific imaging features can be used to diagnose their origins. These developments support (a) avoidance of imaging entirely for those incompletely characterized renal masses that are highly likely to be benign cysts and (b) delay of further imaging of small solid masses in selected patients. Although more evidence-based data are needed and comprehensive management algorithms have yet to be defined, these recommendations are medically appropriate and practical, while limiting the imaging of many incompletely characterized incidental renal masses.

Classifying with confidence from incomplete information.

DOE PAGES

Parrish, Nathan; Anderson, Hyrum S.; Gupta, Maya R.; ...

2013-12-01

For this paper, we consider the problem of classifying a test sample given incomplete information. This problem arises naturally when data about a test sample is collected over time, or when costs must be incurred to compute the classification features. For example, in a distributed sensor network only a fraction of the sensors may have reported measurements at a certain time, and additional time, power, and bandwidth is needed to collect the complete data to classify. A practical goal is to assign a class label as soon as enough data is available to make a good decision. We formalize thismore » goal through the notion of reliability—the probability that a label assigned given incomplete data would be the same as the label assigned given the complete data, and we propose a method to classify incomplete data only if some reliability threshold is met. Our approach models the complete data as a random variable whose distribution is dependent on the current incomplete data and the (complete) training data. The method differs from standard imputation strategies in that our focus is on determining the reliability of the classification decision, rather than just the class label. We show that the method provides useful reliability estimates of the correctness of the imputed class labels on a set of experiments on time-series data sets, where the goal is to classify the time-series as early as possible while still guaranteeing that the reliability threshold is met.« less

The effect of incomplete fuel-air mixing on the lean blowout limit, lean stability limit and NO(x) emissions in lean premixed gas turbine combustors

NASA Technical Reports Server (NTRS)

Shih, W.-P.; Lee, J. G.; Santavicca, D. A.

1994-01-01

Gas turbine engines for both land-based and aircraft propulsion applications are facing regulations on NOx emissions which cannot be met with current combustor technology. A number of alternative combustor strategies are being investigated which have the potential capability of achieving ultra-low NOx emissions, including lean premixed combustors, direct injection combustors, rich burn-quick quench-lean burn combustors and catalytic combustors. The research reported in this paper addresses the effect of incomplete fuel-air mixing on the lean limit performance and the NOx emissions characteristics of lean premixed combustors.

Recruitment of human aquaporin 3 to internal membranes in the Plasmodium falciparum infected erythrocyte.

PubMed

Bietz, Sven; Montilla, Irine; Külzer, Simone; Przyborski, Jude M; Lingelbach, Klaus

2009-09-01

The molecular mechanisms underlying the formation of the parasitophorous vacuolar membrane in Plasmodium falciparum infected erythrocytes are incompletely understood, and the protein composition of this membrane is still enigmatic. Although the differentiated mammalian erythrocyte lacks the machinery required for endocytosis, some reports have described a localisation of host cell membrane proteins at the parasitophorous vacuolar membrane. Aquaporin 3 is an abundant plasma membrane protein of various cells, including mammalian erythrocytes where it is found in distinct oligomeric states. Here we show that human aquaporin 3 is internalized into infected erythrocytes, presumably during or soon after invasion. It is integrated into the PVM where it is organized in novel oligomeric states which are not found in non-infected cells.

Gut failure in critical care: old school versus new school

PubMed Central

Sertaridou, Eleni; Papaioannou, Vasilios; Kolios, George; Pneumatikos, Ioannis

2015-01-01

The concept of bacterial translocation and gut-origin sepsis as causes of systemic infectious complications and multiple organ deficiency syndrome in surgical and critically ill patients has been a recurring issue over the last decades attracting the scientific interest. Although gastrointestinal dysfunction seemingly arises frequently in intensive care unit patients, it is usually underdiagnosed or underestimated, because the pathophysiology involved is incompletely understood and its exact clinical relevance still remains controversial with an unknown yet probably adverse impact on the patients’ outcome. The purpose of this review is to define gut-origin sepsis and related terms, to describe the mechanisms leading to gut-derived complications, and to illustrate the therapeutic options to prevent or limit these untoward processes. PMID:26130136

Mei-P26 Cooperates with Bam, Bgcn and Sxl to Promote Early Germline Development in the Drosophila Ovary

PubMed Central

Li, Yun; Zhang, Qiao; Carreira-Rosario, Arnaldo; Maines, Jean Z.; McKearin, Dennis M.; Buszczak, Michael

2013-01-01

In the Drosophila female germline, spatially and temporally specific translation of mRNAs governs both stem cell maintenance and the differentiation of their progeny. However, the mechanisms that control and coordinate different modes of translational repression within this lineage remain incompletely understood. Here we present data showing that Mei-P26 associates with Bam, Bgcn and Sxl and nanos mRNA during early cyst development, suggesting that this protein helps to repress the translation of nanos mRNA. Together with recently published studies, these data suggest that Mei-P26 mediates both GSC self-renewal and germline differentiation through distinct modes of translational repression depending on the presence of Bam. PMID:23526974

The importance of pro-inflammatory signaling in neonatal NEC

PubMed Central

Frost, Brandy L.; Jilling, Tamas; Caplan, Michael S.

2008-01-01

Despite modern medical advances, necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in neonatal intensive care units, affecting 10 percent of premature neonates born weighing less than 1500 grams. Although many advances have been made in the understanding of this disease, the etiology and pathophysiology remain incompletely understood, and treatment is limited to supportive care. In recent years, studies have focused on the role of the inflammatory cascade and its’ impact on the disease process, and investigators are evaluating strategies to attenuate inflammatory signaling that might prevent and/or ameliorate neonatal NEC. In this review, we examine the key points in the signaling pathways involved in NEC, and potential strategies for prevention and treatment of this dreaded disease. PMID:18346533

Anemia and heart failure: a cause of progression or only a consequence?

PubMed Central

METRA, MARCO; NODARI, SAVINA; BORDONALI, TANIA; BUGATTI, SILVIA; FONTANELLA, BENEDETTA; LOMBARDI, CARLO; SAPORETTI, ALBERTO; VERZURA, GIULIA; DANESI, ROSSELLA; DEI CAS, LIVIO

2007-01-01

Anemia is one of the most frequent co-morbidities in the patients with heart failure. Its prevalence increases from 4–7% in the subjects with asymptomatic left ventricular dysfunction to >30% in the patients with severe heart failure. Renal insufficiency, activation of inflammatory mediators, and treatment with renin-angiotensin antagonists seem to be its main determinants. The results of many studies agree in showing that anemia is a powerful independent determinant of survival in patients with heart failure. However, the mechanisms of this relation are still incompletely understood. Moreover a favourable effect on prognosis of the correction of anemia has not been shown, yet, and also controlled studies assessing its effects on exercise tolerance have yielded controversial results. PMID:21977269

Chromatin Constrains the Initiation and Elongation of DNA Replication.

PubMed

Devbhandari, Sujan; Jiang, Jieqing; Kumar, Charanya; Whitehouse, Iestyn; Remus, Dirk

2017-01-05

Eukaryotic chromosomal DNA is faithfully replicated in a complex series of cell-cycle-regulated events that are incompletely understood. Here we report the reconstitution of DNA replication free in solution with purified proteins from the budding yeast Saccharomyces cerevisiae. The system recapitulates regulated bidirectional origin activation; synthesis of leading and lagging strands by the three replicative DNA polymerases Pol α, Pol δ, and Pol ε; and canonical maturation of Okazaki fragments into continuous daughter strands. We uncover a dual regulatory role for chromatin during DNA replication: promoting origin dependence and determining Okazaki fragment length by restricting Pol δ progression. This system thus provides a functional platform for the detailed mechanistic analysis of eukaryotic chromosome replication. Copyright © 2017 Elsevier Inc. All rights reserved.

Diabetic cardiomyopathy: Where are we 40 years later?

PubMed Central

Sharma, Vijay; McNeill, John H

2006-01-01

Diabetic cardiomyopathy is a cardiac disease that arises as a result of the diabetic state, independent of vascular or valvular pathology. It manifests initially as asymptomatic diastolic dysfunction, which progresses to symptomatic heart failure. The compliance of the heart wall is decreased and contractile function is impaired. The pathophysiology is incompletely understood, but appears to be initiated both by hyperglycemia and changes in cardiac metabolism. These changes induce oxidative stress and activate a number of secondary messenger pathways, leading to cardiac hypertrophy, fibrosis and cell death. Alterations in contractile proteins and intracellular ions impair excitation-contraction coupling, while decreased autonomic responsiveness and autonomic neuropathy impair its regulation. Extensive structural abnormalities also occur, which have deleterious mechanical and functional consequences. PMID:16568154

A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis.

PubMed

Edens, Brittany M; Yan, Jianhua; Miller, Nimrod; Deng, Han-Xiang; Siddique, Teepu; Ma, Yongchao C

2017-05-02

The etiological underpinnings of amyotrophic lateral sclerosis (ALS) are complex and incompletely understood, although contributions to pathogenesis by regulators of proteolytic pathways have become increasingly apparent. Here, we present a novel variant in UBQLN4 that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. We further demonstrate that the ALS-associated UBQLN4 variant impairs proteasomal function, and identify the Wnt signaling pathway effector beta-catenin as a UBQLN4 substrate. Inhibition of beta-catenin function rescues the UBQLN4 variant-induced motor axon phenotypes. These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways.

“The Mind Is Its Own Place”: Amelioration of Claustrophobia in Semantic Dementia

PubMed Central

Clark, Camilla N.; Downey, Laura E.; Golden, Hannah L.; Fletcher, Phillip D.; Cifelli, Alberto; Warren, Jason D.

2014-01-01

Phobias are among the few intensely fearful experiences we regularly have in our everyday lives, yet the brain basis of phobic responses remains incompletely understood. Here we describe the case of a 71-year-old patient with a typical clinicoanatomical syndrome of semantic dementia led by selective (predominantly right-sided) temporal lobe atrophy, who showed striking amelioration of previously disabling claustrophobia following onset of her cognitive syndrome. We interpret our patient's newfound fearlessness as an interaction of damaged limbic and autonomic responsivity with loss of the cognitive meaning of previously threatening situations. This case has implications for our understanding of brain network disintegration in semantic dementia and the neurocognitive basis of phobias more generally. PMID:24825962

Assessing Impact Direction in 3-point Bending of Human Femora: Incomplete Butterfly Fractures and Fracture Surfaces,.

PubMed

Isa, Mariyam I; Fenton, Todd W; Deland, Trevor; Haut, Roger C

2018-01-01

Current literature associates bending failure with butterfly fracture, in which fracture initiates transversely at the tensile surface of a bent bone and branches as it propagates toward the impact surface. The orientation of the resulting wedge fragment is often considered diagnostic of impact direction. However, experimental studies indicate bending does not always produce complete butterfly fractures or produces wedge fragments variably in tension or compression, precluding their use in interpreting directionality. This study reports results of experimental 3-point bending tests on thirteen unembalmed human femora. Complete fracture patterns varied following bending failure, but incomplete fractures and fracture surface characteristics were observed in all impacted specimens. A flat, billowy fracture surface was observed in tension, while jagged, angular peaks were observed in compression. Impact direction was accurately reconstructed using incomplete tension wedge butterfly fractures and tension and compression fracture surface criteria in all thirteen specimens. © 2017 American Academy of Forensic Sciences.

Recommendations for shoulder restraint installation in general aviation aircraft.

DOT National Transportation Integrated Search

1966-09-01

The use of inadequate or incomplete body restraint systems is a major factor in the current trend of increasing serious and fatal type injuries reported from general aviation accidents. An analysis of these accident injuries and conditions clearly in...

Pak2 is required for actin cytoskeleton remodeling, TCR signaling, and normal thymocyte development and maturation

PubMed Central

Phee, Hyewon; Au-Yeung, Byron B; Pryshchep, Olga; O'Hagan, Kyle Leonard; Fairbairn, Stephanie Grace; Radu, Maria; Kosoff, Rachelle; Mollenauer, Marianne; Cheng, Debra; Chernoff, Jonathan; Weiss, Arthur

2014-01-01

The molecular mechanisms that govern thymocyte development and maturation are incompletely understood. The P21-activated kinase 2 (Pak2) is an effector for the Rho family GTPases Rac and Cdc42 that regulate actin cytoskeletal remodeling, but its role in the immune system remains poorly understood. In this study, we show that T-cell specific deletion of Pak2 gene in mice resulted in severe T cell lymphopenia accompanied by marked defects in development, maturation, and egress of thymocytes. Pak2 was required for pre-TCR β-selection and positive selection. Surprisingly, Pak2 deficiency in CD4 single positive thymocytes prevented functional maturation and reduced expression of S1P1 and KLF2. Mechanistically, Pak2 is required for actin cytoskeletal remodeling triggered by TCR. Failure to induce proper actin cytoskeletal remodeling impaired PLCγ1 and Erk1/2 signaling in the absence of Pak2, uncovering the critical function of Pak2 as an essential regulator that governs the actin cytoskeleton-dependent signaling to ensure normal thymocyte development and maturation. DOI: http://dx.doi.org/10.7554/eLife.02270.001 PMID:24843022

Masseteric-facial nerve transposition for reanimation of the smile in incomplete facial paralysis.

PubMed

Hontanilla, Bernardo; Marre, Diego

2015-12-01

Incomplete facial paralysis occurs in about a third of patients with Bell's palsy. Although their faces are symmetrical at rest, when they smile they have varying degrees of disfigurement. Currently, cross-face nerve grafting is one of the most useful techniques for reanimation. Transfer of the masseteric nerve, although widely used for complete paralysis, has not to our knowledge been reported for incomplete palsy. Between December 2008 and November 2013, we reanimated the faces of 9 patients (2 men and 7 women) with incomplete unilateral facial paralysis with transposition of the masseteric nerve. Sex, age at operation, cause of paralysis, duration of denervation, recipient nerves used, and duration of follow-up were recorded. Commissural excursion, velocity, and patients' satisfaction were evaluated with the FACIAL CLIMA and a questionnaire, respectively. The mean (SD) age at operation was 39 (±6) years and the duration of denervation was 29 (±19) months. There were no complications that required further intervention. Duration of follow-up ranged from 6-26 months. FACIAL CLIMA showed improvement in both commissural excursion and velocity of more than two thirds in 6 patients, more than one half in 2 patients and less than one half in one. Qualitative evaluation showed a slight or pronounced improvement in 7/9 patients. The masseteric nerve is a reliable alternative for reanimation of the smile in patients with incomplete facial paralysis. Its main advantages include its consistent anatomy, a one-stage operation, and low morbidity at the donor site. Copyright © 2015 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Nonthermal Inhalation Injury.

DTIC Science & Technology

1992-01-01

toxic gases and particles that are coated with toxic materials ( Vanacker , Boeckx, Van Aken & Gruwez, 1989). Some of the toxic byproducts of incomplete...Canadian experience. Annals of Surgery. 212(6), 720-727. Vanacker , B., Boeckx, W., Van Aken, H. & Gruwez, J.A. (1989). Current concepts in inhalation

A comprehensive porcine blood transcriptome

USDA-ARS?s Scientific Manuscript database

Blood sample analyses are extensively used in high throughput assays in biomedicine, as well as animal genetics and physiology research. However, the draft quality of the current pig genome (Sscrofa 10.2) is insufficient for accurate interpretation of many of these assays because of incomplete gene ...

Kisspeptin modulates sexual and emotional brain processing in humans.

PubMed

Comninos, Alexander N; Wall, Matthew B; Demetriou, Lysia; Shah, Amar J; Clarke, Sophie A; Narayanaswamy, Shakunthala; Nesbitt, Alexander; Izzi-Engbeaya, Chioma; Prague, Julia K; Abbara, Ali; Ratnasabapathy, Risheka; Salem, Victoria; Nijher, Gurjinder M; Jayasena, Channa N; Tanner, Mark; Bassett, Paul; Mehta, Amrish; Rabiner, Eugenii A; Hönigsperger, Christoph; Silva, Meire Ribeiro; Brandtzaeg, Ole Kristian; Lundanes, Elsa; Wilson, Steven Ray; Brown, Rachel C; Thomas, Sarah A; Bloom, Stephen R; Dhillo, Waljit S

2017-02-01

Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behavior. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviors, and is a likely candidate system for the integration of behavior with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behavior. Using a combination of functional neuroimaging and hormonal and psychometric analyses, we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men. We demonstrated that kisspeptin administration enhanced limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin's enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, kisspeptin administration attenuated negative mood. Collectively, our data provide evidence of an undescribed role for kisspeptin in integrating sexual and emotional brain processing with reproduction in humans. These results have important implications for our understanding of reproductive biology and are highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function. National Institute for Health Research (NIHR), Wellcome Trust (Ref 080268), and the Medical Research Council (MRC).

13C-labelled microdialysis studies of cerebral metabolism in TBI patients☆

PubMed Central

Carpenter, Keri L.H.; Jalloh, Ibrahim; Gallagher, Clare N.; Grice, Peter; Howe, Duncan J.; Mason, Andrew; Timofeev, Ivan; Helmy, Adel; Murphy, Michael P.; Menon, David K.; Kirkpatrick, Peter J.; Carpenter, T. Adrian; Sutherland, Garnette R.; Pickard, John D.; Hutchinson, Peter J.

2014-01-01

Human brain chemistry is incompletely understood and better methodologies are needed. Traumatic brain injury (TBI) causes metabolic perturbations, one result of which includes increased brain lactate levels. Attention has largely focussed on glycolysis, whereby glucose is converted to pyruvate and lactate, and is proposed to act as an energy source by feeding into neurons’ tricarboxylic acid (TCA) cycle, generating ATP. Also reportedly upregulated by TBI is the pentose phosphate pathway (PPP) that does not generate ATP but produces various molecules that are putatively neuroprotective, antioxidant and reparative, in addition to lactate among the end products. We have developed a novel combination of 13C-labelled cerebral microdialysis both to deliver 13C-labelled substrates into brains of TBI patients and recover the 13C-labelled metabolites, with high-resolution 13C NMR analysis of the microdialysates. This methodology has enabled us to achieve the first direct demonstration in humans that the brain can utilise lactate via the TCA cycle. We are currently using this methodology to make the first direct comparison of glycolysis and the PPP in human brain. In this article, we consider the application of 13C-labelled cerebral microdialysis for studying brain energy metabolism in patients. We set this methodology within the context of metabolic pathways in the brain, and 13C research modalities addressing them. PMID:24361470

Connecting the coronaries: How the coronary plexus develops and is functionalized

PubMed Central

Dyer, Laura; Pi, Xinchun; Patterson, Cam

2015-01-01

The establishment of the coronary circulation is one of the final critical steps during heart development. Despite decades of research, our understanding of how the coronary vasculature develops and connects to the aorta remains limited. This review serves two specific purposes: it addresses recent advances in understanding the origin of the coronary endothelium, and it then focuses on the last crucial step of coronary vasculature development, the connection of the coronary plexus to the aorta. The chick and quail animal models have yielded most of the information for how these connections form, starting with a fine network of vessels that penetrate the aorta and coalesce to form two distinct ostia. Studies in mouse and rat confirm that at least some of these steps are conserved in mammals, but gaps still exist in our understanding of mammalian coronary ostia formation. The signaling cues necessary to guide the coronary plexus to the aorta are also incompletely understood. Hypoxia-inducible transcription factor-1 and its downstream targets are among the few identified genes that promote the formation of the coronary stems. Together, this review summarizes our current knowledge of coronary vascular formation and highlights the significant gaps that remain. In addition, it highlights some of the coronary artery anomalies known to affect human health, demonstrating that even seemingly subtle defects arising from incorrect coronary plexus formation can result in significant health crises. PMID:25173872

Implications for bidirectional signaling between afferent nerves and urothelial cells-ICI-RS 2014.

PubMed

Kanai, Anthony; Fry, Christopher; Ikeda, Youko; Kullmann, Florenta Aura; Parsons, Brian; Birder, Lori

2016-02-01

To present a synopsis of the presentations and discussions from Think Tank I, "Implications for afferent-urothelial bidirectional communication" of the 2014 International Consultation on Incontinence-Research Society (ICI-RS) meeting in Bristol, UK. The participants presented what is new, currently understood or still unknown on afferent-urothelial signaling mechanisms. New avenues of research and experimental methodologies that are or could be employed were presented and discussed. It is clear that afferent-urothelial interactions are integral to the regulation of normal bladder function and that its disruption can have detrimental consequences. The urothelium is capable of releasing numerous signaling factors that can affect sensory neurons innervating the suburothelium. However, the understanding of how factors released from urothelial cells and afferent nerve terminals regulate one another is incomplete. Utilization of techniques such as viruses that genetically encode Ca(2+) sensors, based on calmodulin and green fluorescent protein, has helped to address the cellular mechanisms involved. Additionally, the epithelial-neuronal interactions in the urethra may also play a significant role in lower urinary tract regulation and merit further investigation. The signaling capabilities of the urothelium and afferent nerves are well documented, yet how these signals are integrated to regulate bladder function is unclear. There is unquestionably a need for expanded methodologies to further our understanding of lower urinary tract sensory mechanisms and their contribution to various pathologies. © 2016 Wiley Periodicals, Inc.

Brain-machine interfaces in neurorehabilitation of stroke.

PubMed

Soekadar, Surjo R; Birbaumer, Niels; Slutzky, Marc W; Cohen, Leonardo G

2015-11-01

Stroke is among the leading causes of long-term disabilities leaving an increasing number of people with cognitive, affective and motor impairments depending on assistance in their daily life. While function after stroke can significantly improve in the first weeks and months, further recovery is often slow or non-existent in the more severe cases encompassing 30-50% of all stroke victims. The neurobiological mechanisms underlying recovery in those patients are incompletely understood. However, recent studies demonstrated the brain's remarkable capacity for functional and structural plasticity and recovery even in severe chronic stroke. As all established rehabilitation strategies require some remaining motor function, there is currently no standardized and accepted treatment for patients with complete chronic muscle paralysis. The development of brain-machine interfaces (BMIs) that translate brain activity into control signals of computers or external devices provides two new strategies to overcome stroke-related motor paralysis. First, BMIs can establish continuous high-dimensional brain-control of robotic devices or functional electric stimulation (FES) to assist in daily life activities (assistive BMI). Second, BMIs could facilitate neuroplasticity, thus enhancing motor learning and motor recovery (rehabilitative BMI). Advances in sensor technology, development of non-invasive and implantable wireless BMI-systems and their combination with brain stimulation, along with evidence for BMI systems' clinical efficacy suggest that BMI-related strategies will play an increasing role in neurorehabilitation of stroke. Copyright © 2014. Published by Elsevier Inc.

Multi-locus phylogenetic analysis reveals the pattern and tempo of bony fish evolution

PubMed Central

Broughton, Richard E.; Betancur-R., Ricardo; Li, Chenhong; Arratia, Gloria; Ortí, Guillermo

2013-01-01

Over half of all vertebrates are “fishes”, which exhibit enormous diversity in morphology, physiology, behavior, reproductive biology, and ecology. Investigation of fundamental areas of vertebrate biology depend critically on a robust phylogeny of fishes, yet evolutionary relationships among the major actinopterygian and sarcopterygian lineages have not been conclusively resolved. Although a consensus phylogeny of teleosts has been emerging recently, it has been based on analyses of various subsets of actinopterygian taxa, but not on a full sample of all bony fishes. Here we conducted a comprehensive phylogenetic study on a broad taxonomic sample of 61 actinopterygian and sarcopterygian lineages (with a chondrichthyan outgroup) using a molecular data set of 21 independent loci. These data yielded a resolved phylogenetic hypothesis for extant Osteichthyes, including 1) reciprocally monophyletic Sarcopterygii and Actinopterygii, as currently understood, with polypteriforms as the first diverging lineage within Actinopterygii; 2) a monophyletic group containing gars and bowfin (= Holostei) as sister group to teleosts; and 3) the earliest diverging lineage among teleosts being Elopomorpha, rather than Osteoglossomorpha. Relaxed-clock dating analysis employing a set of 24 newly applied fossil calibrations reveals divergence times that are more consistent with paleontological estimates than previous studies. Establishing a new phylogenetic pattern with accurate divergence dates for bony fishes illustrates several areas where the fossil record is incomplete and provides critical new insights on diversification of this important vertebrate group. PMID:23788273

Signaling pathways underpinning the manifestations of ionizing radiation-induced bystander effects.

PubMed

Hamada, Nobuyuki; Maeda, Munetoshi; Otsuka, Kensuke; Tomita, Masanori

2011-06-01

For nearly a century, ionizing radiation has been indispensable to medical diagnosis. Furthermore, various types of electromagnetic and particulate radiation have also been used in cancer therapy. However, the biological mechanism of radiation action remains incompletely understood. In this regard, a rapidly growing body of experimental evidence indicates that radiation exposure induces biological effects in cells whose nucleus has not been irradiated. This phenomenon termed the 'non-targeted effects' challenges the long-held tenet that radiation traversal through the cell nucleus is a prerequisite to elicit genetic damage and biological responses. The non-targeted effects include biological effects in cytoplasm-irradiated cells, bystander effects that arise in non-irradiated cells having received signals from irradiated cells, and genomic instability occurring in the progeny of irradiated cells. Such non-targeted responses are interrelated, and the bystander effect is further related with an adaptive response that manifests itself as the attenuated stressful biological effects of acute high-dose irradiation in cells that have been pre-exposed to low-dose or low-dose-rate radiation. This paper reviews the current body of knowledge about the bystander effect with emphasis on experimental approaches, in vitro and in vivo manifestations, radiation quality dependence, temporal and spatial dependence, proposed mechanisms, and clinical implications. Relations of bystander responses with the effects in cytoplasm-irradiated cells, genomic instability and adaptive response will also be briefly discussed.

Biomarkers for prostate cancer detection and progression: Beyond prostate-specific antigen.

PubMed

Berney, Daniel M

2010-04-01

Prostate cancer is a major health problem with an incompletely understood pathogenesis and etiology. The advent of the prostate-specific antigen (PSA) test in the 1980s caused a revolution in how the disease was detected, but the evidence for PSA as a screening test is deficient. Biomarkers have been investigated, both for detection and discrimination of indolent from aggressive cancers. Refinements to the PSA test have been proposed but for practical and evidence-based reasons none have translated through to widespread clinical use. Of the novel biomarkers, the most promising is the prostate cancer antigen 3 (PCA3) test. New biomarkers to predict aggressive disease are even more contentious. The pathological grade of tumor remains the most powerful biomarker of prognosis. Other proven variables include tumor extent on biopsy and serum PSA. Tissue biomarkers have proven unhelpful due to a variable and biased literature with multiple methodological flaws, but Ki-67 probably shows more promise than any other current tissue biomarker. The recent discovery of a family of fusion genes in the prostate has led to considerable discussion on their prognostic role. Dissection of the genetic basis of the disease may lead to discoveries that will enhance our understanding and aid the search for prognostically valuable biomarkers. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Current and future developments in the field of central sleep apnoea.

PubMed

Bekfani, Tarek; Abraham, William T

2016-08-01

Central sleep apnoea (CSA) occurs in ∼30-50% of patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF) and in as much as in 18-30% of patients with preserved LVEF. In HF patients, it is characterized by periodic breathing also known as the Cheyne-Stokes respiration followed by pauses of breathing. Central sleep apnoea remains often unrecognized due to its chronic and insidious incidences. Patients may report excessive daytime somnolence, poor sleep quality, nocturnal angina, recurrent arrhythmias, refractory HF symptoms, or demonstrate abnormal respiratory pattern or apnoeas. The pathogenesis of CSA remains incompletely understood, but changes in CO2 above and below the apnoea threshold play a major role in its pathogenesis. The presence of CSA in patients with HF is associated with some neurohumoral and haemodynamic responses that are detrimental to the failing heart including increased morbidity and mortality. The development of successful therapies targeting CSA and its harmful downstream effects is therefore important. Several different therapies from medications to implantable devices have been tested with varying effects and primarily in small non-randomized and/or single-centre studies. Large studies to date have been disappointing, but therapeutic options targeting the physiology of the disease may herald a new era in understanding and treating CSA. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Cost-Effectiveness of Blood Donation Screening for Trypanosoma cruzi in Mexico.

PubMed

Sánchez-González, Gilberto; Figueroa-Lara, Alejandro; Elizondo-Cano, Miguel; Wilson, Leslie; Novelo-Garza, Barbara; Valiente-Banuet, Leopoldo; Ramsey, Janine M

2016-03-01

An estimated 2 million inhabitants are infected with Chagas disease in Mexico, with highest prevalence coinciding with highest demographic density in the southern half of the country. After vector-borne transmission, Trypanosoma cruzi is principally transmitted to humans via blood transfusion. Despite initiation of serological screening of blood donations or donors for T. cruzi since 1990 in most Latin American countries, Mexico only finally included mandatory serological screening nationwide in official Norms in 2012. Most recent regulatory changes and segmented blood services in Mexico may affect compliance of mandatory screening guidelines. The objective of this study was to calculate the incremental cost-effectiveness ratio for total compliance of current guidelines from both Mexican primary healthcare and regular salaried worker health service institutions: the Secretary of Health and the Mexican Institute for Social Security. We developed a bi-modular model to analyze compliance using a decision tree for the most common screening algorithms for each health institution, and a Markov transition model for the natural history of illness and care. The incremental cost effectiveness ratio based on life-years gained is US$ 383 for the Secretary of Health, while the cost for an additional life-year gained is US$ 463 for the Social Security Institute. The results of the present study suggest that due to incomplete compliance of Mexico's national legislation during 2013 and 2014, the MoH has failed to confirm 15,162 T. cruzi infections, has not prevented 2,347 avoidable infections, and has lost 333,483 life-years. Although there is a vast difference in T. cruzi prevalence between Bolivia and Mexico, Bolivia established mandatory blood screening for T.cruzi in 1996 and until 2002 detected and discarded 11,489 T. cruzi -infected blood units and prevented 2,879 potential infections with their transfusion blood screening program. In the first two years of Mexico's mandated program, the two primary institutions failed to prevent due to incomplete compliance more potential infections than those gained from the first five years of Bolivia's program. Full regulatory compliance should be clearly understood as mandatory for the sake of blood security, and its monitoring and analysis in Mexico should be part of the health authority's responsibility.

Impact of incomplete metal coverage on the electrical properties of metal-CNT contacts: A large-scale ab initio study

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

Fediai, Artem, E-mail: artem.fediai@nano.tu-dresden.de; Ryndyk, Dmitry A.; Center for Advancing Electronics Dresden, TU Dresden, 01062 Dresden

2016-09-05

Using a dedicated combination of the non-equilibrium Green function formalism and large-scale density functional theory calculations, we investigated how incomplete metal coverage influences two of the most important electrical properties of carbon nanotube (CNT)-based transistors: contact resistance and its scaling with contact length, and maximum current. These quantities have been derived from parameter-free simulations of atomic systems that are as close as possible to experimental geometries. Physical mechanisms that govern these dependences have been identified for various metals, representing different CNT-metal interaction strengths from chemisorption to physisorption. Our results pave the way for an application-oriented design of CNT-metal contacts.

Micro-calibration of space and motion by photoreceptors synchronized in parallel with cortical oscillations: A unified theory of visual perception.

PubMed

Jerath, Ravinder; Cearley, Shannon M; Barnes, Vernon A; Jensen, Mike

2018-01-01

A fundamental function of the visual system is detecting motion, yet visual perception is poorly understood. Current research has determined that the retina and ganglion cells elicit responses for motion detection; however, the underlying mechanism for this is incompletely understood. Previously we proposed that retinogeniculo-cortical oscillations and photoreceptors work in parallel to process vision. Here we propose that motion could also be processed within the retina, and not in the brain as current theory suggests. In this paper, we discuss: 1) internal neural space formation; 2) primary, secondary, and tertiary roles of vision; 3) gamma as the secondary role; and 4) synchronization and coherence. Movement within the external field is instantly detected by primary processing within the space formed by the retina, providing a unified view of the world from an internal point of view. Our new theory begins to answer questions about: 1) perception of space, erect images, and motion, 2) purpose of lateral inhibition, 3) speed of visual perception, and 4) how peripheral color vision occurs without a large population of cones located peripherally in the retina. We explain that strong oscillatory activity influences on brain activity and is necessary for: 1) visual processing, and 2) formation of the internal visuospatial area necessary for visual consciousness, which could allow rods to receive precise visual and visuospatial information, while retinal waves could link the lateral geniculate body with the cortex to form a neural space formed by membrane potential-based oscillations and photoreceptors. We propose that vision is tripartite, with three components that allow a person to make sense of the world, terming them "primary, secondary, and tertiary roles" of vision. Finally, we propose that Gamma waves that are higher in strength and volume allow communication among the retina, thalamus, and various areas of the cortex, and synchronization brings cortical faculties to the retina, while the thalamus is the link that couples the retina to the rest of the brain through activity by gamma oscillations. This novel theory lays groundwork for further research by providing a theoretical understanding that expands upon the functions of the retina, photoreceptors, and retinal plexus to include parallel processing needed to form the internal visual space that we perceive as the external world. Copyright © 2017 Elsevier Ltd. All rights reserved.

Surgical excision of skin cancer: the importance of training.

PubMed

Salmon, P; Mortimer, N; Rademaker, M; Adams, L; Stanway, A; Hill, S

2010-01-01

Background Skin cancers are the most common malignancy in New Zealand and their treatment imparts a huge burden on the healthcare system both in terms of the cost of surgical intervention and in treatment delivery (estimates are in excess of NZ$33 million per annum for the year 2000). Currently in New Zealand, skin cancers are excised by dermatologists, general practitioners (GPs), GPs with a special interest in skin surgery (GPSIs) and specialist surgeons with diverse training backgrounds including ear, nose and throat, ophthalmic and general surgeons. To date there is scant literature evaluating complete excision rates following surgical treatment of skin cancer between these vocational groups. Objectives To review retrospectively pathology reports from all skin excisions sent to one private pathology laboratory over three consecutive months. The aim was to investigate the margins of excision and completeness of skin cancer surgery performed by each vocational group. Methods A retrospective analysis of skin pathology reports was undertaken for a 3-month period between April and June 2007. Raw data obtained from the pathology reports included diagnosis, completeness of excision, size of specimens, body site and vocational group of the medical practitioner performing the surgery. Results In total, 1532 lesions were excised: 432 benign and 1100 malignant. Six hundred and seven were from the head and neck. Dermatologists excised 276 lesions of which 93% were malignant, 55% were from the head and neck, and 0% were incompletely excised. GPs excised 633 lesions: 63% malignant, 30% head and neck, 23% incomplete excision of malignant lesions. GPSIs excised 368 lesions: 71% malignant, 35% head and neck, 21.5% incomplete malignant excision. Specialist surgeons excised 255 lesions: 72% malignant, 53% head and neck, 20% incomplete malignant excision. Conclusion GPs and GPSIs excised more benign lesions and had higher incomplete excision rates of skin cancer surgery than dermatologists. Incomplete excision rates for the vocational groups ranged from 0% to 45% depending on site and pathology.

EJE prize 2014: current and evolving treatment options in adrenocortical carcinoma: where do we stand and where do we want to go?

PubMed

Ronchi, Cristina L; Kroiss, Matthias; Sbiera, Silviu; Deutschbein, Timo; Fassnacht, Martin

2014-07-01

Adrenocortical carcinoma (ACC) is not only a rare and heterogeneous disease but also one of the most aggressive endocrine tumors. Despite significant advances in the last decade, its pathogenesis is still only incompletely understood and overall therapeutic means are unsatisfactory. Herein, we provide our personal view of the currently available treatment options and suggest the following research efforts that we consider timely and necessary to improve therapy: i) for better outcome in localized ACCs, surgery should be restricted to experienced centers, which should then collaborate closely to address the key surgical questions (e.g. best approach and extent of surgery) in a multicenter manner. ii) For the development of better systemic therapies, it is crucial to elucidate the exact molecular mechanisms of action of mitotane. iii) A prospective trial is needed to address the role of cytotoxic drugs in the adjuvant setting in aggressive ACCs (e.g. mitotane vs mitotane+cisplatin). iv) For metastatic ACCs, new regimens should be investigated as first-line therapy. v) Several other issues (e.g. the role of radiotherapy and salvage therapies) might be answered - at least in a first step - by large retrospective multicenter studies. In conclusion, although it is unrealistic to expect that the majority of ACCs can be cured within the next decade, international collaborative efforts (including multiple translational and clinical studies) should allow significant improvement of clinical outcome of this disease. To this end, it might be reasonable to expand the European Network for the Study of Adrenal Tumors (ENSAT) to a truly worldwide international network - INSAT. © 2014 European Society of Endocrinology.

Possible Weakening Processes Imposed on California's Earthen Levees under Protracted Drought

NASA Astrophysics Data System (ADS)

Robinson, J. D.; Vahedifard, F.; AghaKouchak, A.

2015-12-01

California is currently suffering from a multiyear extreme drought and the impacts of the drought are anticipated to worsen in a warming climate. The resilience of critical infrastructure under extreme drought conditions is a major concern which has not been well understood. Thus, there is a crucial need to improve our understanding about the potential threats of drought on infrastructure and take subsequent actions in a timely manner to mitigate these threats and adopt our infrastructure for forthcoming extreme events. The need is more pronounced for earthen levees, since their functionality to protect limited water resources and dryland is more critical during drought. A significant amount of California's levee systems are currently operating under a high risk condition. Protracted drought can further threaten the structural competency of these already at-risk levee systems through several thermo-hydro mechanical weakening processes that undermine their stability. Viable information on the implications of these weakening processes, particularly on California's earthen levees, is relatively incomplete. This article discusses, from a geotechnical engineering perspective, how California's protracted drought might threaten the integrity of levee systems through the imposition of several thermo-hydro mechanical weakening processes. Pertinent facts and statistics regarding the drought in California are presented and discussed. Catastrophic levee failures and major damages resulting from drought-induce weakening processes such as shear strength reduction, desiccation cracking, land subsidence and surface erosion, fissuring and soil softening, and soil carbon oxidation are discussed to illustrate the devastating impacts that the California drought might impose on existing earthen levees. This article calls for further research in light of these potential drought-inducing weakening mechanisms to support mitigation strategies for reducing future catastrophic levee failures.

Past history of skin infection and risk of surgical site infection after elective surgery.

PubMed

Faraday, Nauder; Rock, Peter; Lin, Elaina E; Perl, Trish M; Carroll, Karen; Stierer, Tracey; Robarts, Polly; McFillin, Angela; Ross, Tracy; Shah, Ashish S; Riley, Lee H; Tamargo, Rafael J; Black, James H; Blasco-Colmenares, Elena; Guallar, Eliseo

2013-01-01

To identify baseline patient characteristics associated with increased susceptibility to surgical site infection (SSI) after elective surgery. The Center for Medicare and Medicaid Services considers SSI to be preventable through adherence to current infection control practices; however, the etiology of wound infection is incompletely understood. Prospective cohort study involving patients undergoing cardiac, vascular, craniotomy, and spinal surgery at 2 academic medical centers in Baltimore, MD. A comprehensive medical history was obtained at baseline, and participants were followed for 6 months using active inpatient and outpatient surveillance for deep SSI and infectious death. Infection control best practices were monitored perioperatively. The relative risk of SSI/infectious death was determined comparing those with versus those without a past medical history of skin infection using Cox proportional hazards models. Of 613 patients (mean [SD] = 62.3 [11.5] years; 42.1% women), 22.0% reported a history of skin infection. The cumulative incidence of deep SSI/infectious death was 6.7% versus 3.1% for those with and without a history of skin infection, respectively (unadjusted hazard ratio (HR) = 2.25; 95% confidence interval (95% CI), 0.98-5.14; P = 0.055). Risk estimates increased after adjustments for demographic and socioeconomic variables (HR = 2.82; 95% CI, 1.18-6.74; P = 0.019) and after propensity score adjustment for all potential confounders (HR = 3.41; 95% CI, 1.36-8.59; P = 0.009). Adjustments for intraoperative infection risk factors and adherence to infection control best practice metrics had no impact on risk estimates. A history of skin infection identified a state of enhanced susceptibility to SSI at baseline that is independent of traditional SSI risk factors and adherence to current infection control practices.

Researching pharmacist managerial capability: philosophical perspectives and paradigms of inquiry.

PubMed

Woods, Phillip; Gapp, Rod; King, Michelle A

2015-01-01

In successful community pharmacy business enterprises suitably responsive actions to meet ever-increasing change require capable pharmacy managers who readily learn and adapt. Capability as a concept is generally understood to be the ability of a manager to identify and act to solve unfamiliar problems in unfamiliar situations. Capability is characterized by adaptability and flexibility. However, different understandings of the concept 'capability' and what it means to be 'capable' are indirect and incomplete. This paper aims to clarify current theories regarding the concept of 'capability' at the level of the individual, and through this to make more explicit what is known about the phenomenon, but more particularly, how we know what we know. The analysis includes the concept of 'competence' because explanations of capability include competence, and the two concepts are not clearly separated in the literature. By probing the epistemological origins of current theory concerning both concepts, the limiting taken for granted assumptions are revealed. Assumptions about context and time, and the psychological theory through which individuals are assumed to perceive, know and learn, are illuminated. The analysis, in connection with the literature, shows how the interpretive philosophic research approach may reveal a different and useful theoretical perspective for explaining capability as a dynamic performance. It is suggested that such a perspective may narrow the gap between the theory of capability and its practice. The interpretive perspective holds potential to reveal how capability, as performed by successful community pharmacy managers, might be further researched and strengthened. This paper supports the challenging suggestion that pharmacy social research needs to rebalance the dominance of purely empirical research by exploring interpretive methodologies to better understand human actions and relations in the context of pharmacy. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

SOCIAL AND NON-SOCIAL CUEING OF VISUOSPATIAL ATTENTION IN AUTISM AND TYPICAL DEVELOPMENT

PubMed Central

Pruett, John R.; LaMacchia, Angela; Hoertel, Sarah; Squire, Emma; McVey, Kelly; Todd, Richard D.; Constantino, John N.; Petersen, Steven E.

2013-01-01

Three experiments explored attention to eye gaze, which is incompletely understood in typical development and is hypothesized to be disrupted in autism. Experiment 1 (n=26 typical adults) involved covert orienting to box, arrow, and gaze cues at two probabilities and cue-target times to test whether reorienting for gaze is endogenous, exogenous, or unique; experiment 2 (total n=80: male and female children and adults) studied age and sex effects on gaze cueing. Gaze cueing appears endogenous and may strengthen in typical development. Experiment 3 tested exogenous, endogenous, and/or gaze-based orienting in 25 typical and 27 Autistic Spectrum Disorder (ASD) children. ASD children made more saccades, slowing their reaction times; however, exogenous and endogenous orienting, including gaze cueing, appear intact in ASD. PMID:20809377

Human Polyomavirus Reactivation: Disease Pathogenesis and Treatment Approaches

PubMed Central

De Gascun, Cillian F.; Carr, Michael J.

2013-01-01

JC and BK polyomaviruses were discovered over 40 years ago and have become increasingly prevalent causes of morbidity and mortality in a variety of distinct, immunocompromised patient cohorts. The recent discoveries of eight new members of the Polyomaviridae family that are capable of infecting humans suggest that there are more to be discovered and raise the possibility that they may play a more significant role in human disease than previously understood. In spite of this, there remains a dearth of specific therapeutic options for human polyomavirus infections and an incomplete understanding of the relationship between the virus and the host immune system. This review summarises the human polyomaviruses with particular emphasis on pathogenesis in those directly implicated in disease aetiology and the therapeutic options available for treatment in the immunocompromised host. PMID:23737811

Role of adapter function in oncoprotein-mediated activation of NF-kappaB. Human T-cell leukemia virus type I Tax interacts directly with IkappaB kinase gamma.

PubMed

Jin, D Y; Giordano, V; Kibler, K V; Nakano, H; Jeang, K T

1999-06-18

Mechanisms by which the human T-cell leukemia virus type I Tax oncoprotein activates NF-kappaB remain incompletely understood. Although others have described an interaction between Tax and a holo-IkappaB kinase (IKK) complex, the exact details of protein-protein contact are not fully defined. Here we show that Tax binds to neither IKK-alpha nor IKK-beta but instead complexes directly with IKK-gamma, a newly characterized component of the IKK complex. This direct interaction with IKK-gamma correlates with Tax-induced IkappaB-alpha phosphorylation and NF-kappaB activation. Thus, our findings establish IKK-gamma as a key molecule for adapting an oncoprotein-specific signaling to IKK-alpha and IKK-beta.

Red blood cell dynamics: from cell deformation to ATP release.

PubMed

Wan, Jiandi; Forsyth, Alison M; Stone, Howard A

2011-10-01

The mechanisms of red blood cell (RBC) deformation under both static and dynamic, i.e., flow, conditions have been studied extensively since the mid 1960s. Deformation-induced biochemical reactions and possible signaling in RBCs, however, were proposed only fifteen years ago. Therefore, the fundamental relationship between RBC deformation and cellular signaling dynamics i.e., mechanotransduction, remains incompletely understood. Quantitative understanding of the mechanotransductive pathways in RBCs requires integrative studies of physical models of RBC deformation and cellular biochemical reactions. In this article we review the physical models of RBC deformation, spanning from continuum membrane mechanics to cellular skeleton dynamics under both static and flow conditions, and elaborate the mechanistic links involved in deformation-induced ATP release. This journal is © The Royal Society of Chemistry 2011

Epigenetic control of CD8+ T cell differentiation.

PubMed

Henning, Amanda N; Roychoudhuri, Rahul; Restifo, Nicholas P

2018-05-01

Upon stimulation, small numbers of naive CD8 + T cells proliferate and differentiate into a variety of memory and effector cell types. CD8 + T cells can persist for years and kill tumour cells and virally infected cells. The functional and phenotypic changes that occur during CD8 + T cell differentiation are well characterized, but the epigenetic states that underlie these changes are incompletely understood. Here, we review the epigenetic processes that direct CD8 + T cell differentiation and function. We focus on epigenetic modification of DNA and associated histones at genes and their regulatory elements. We also describe structural changes in chromatin organization that affect gene expression. Finally, we examine the translational potential of epigenetic interventions to improve CD8 + T cell function in individuals with chronic infections and cancer.

Taste receptors in the gastrointestinal tract. I. Bitter taste receptors and alpha-gustducin in the mammalian gut.

PubMed

Rozengurt, Enrique

2006-08-01

Molecular sensing by gastrointestinal (GI) cells plays a critical role in the control of multiple fundamental functions in digestion and also initiates hormonal and/or neural pathways leading to the regulation of caloric intake, pancreatic insulin secretion, and metabolism. Molecular sensing in the GI tract is also responsible for the detection of ingested harmful drugs and toxins, thereby initiating responses critical for survival. The initial recognition events and mechanism(s) involved remain incompletely understood. The notion to be discussed in this article is that there are important similarities between the chemosensory machinery elucidated in specialized neuroepithelial taste receptor cells of the lingual epithelium and the molecular transducers localized recently in enteroendocrine open GI cells that sense the chemical composition of the luminal contents of the gut.

The application and use of chemical space mapping to interpret crystallization screening results

PubMed Central

Snell, Edward H.; Nagel, Ray M.; Wojtaszcyk, Ann; O’Neill, Hugh; Wolfley, Jennifer L.; Luft, Joseph R.

2008-01-01

Macromolecular crystallization screening is an empirical process. It often begins by setting up experiments with a number of chemically diverse cocktails designed to sample chemical space known to promote crystallization. Where a potential crystal is seen a refined screen is set up, optimizing around that condition. By using an incomplete factorial sampling of chemical space to formulate the cocktails and presenting the results graphically, it is possible to readily identify trends relevant to crystallization, coarsely sample the phase diagram and help guide the optimization process. In this paper, chemical space mapping is applied to both single macromolecules and to a diverse set of macromolecules in order to illustrate how visual information is more readily understood and assimilated than the same information presented textually. PMID:19018100

The application and use of chemical space mapping to interpret crystallization screening results.

PubMed

Snell, Edward H; Nagel, Ray M; Wojtaszcyk, Ann; O'Neill, Hugh; Wolfley, Jennifer L; Luft, Joseph R

2008-12-01

Macromolecular crystallization screening is an empirical process. It often begins by setting up experiments with a number of chemically diverse cocktails designed to sample chemical space known to promote crystallization. Where a potential crystal is seen a refined screen is set up, optimizing around that condition. By using an incomplete factorial sampling of chemical space to formulate the cocktails and presenting the results graphically, it is possible to readily identify trends relevant to crystallization, coarsely sample the phase diagram and help guide the optimization process. In this paper, chemical space mapping is applied to both single macromolecules and to a diverse set of macromolecules in order to illustrate how visual information is more readily understood and assimilated than the same information presented textually.

Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

PubMed Central

Ibrahim, Samar H; Hirsova, Petra; Gores, Gregory J

2018-01-01

A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed nonalcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation. PMID:29367207

Resolving Single Molecule Lysozyme Dynamics with a Carbon Nanotube Electronic Circuit

NASA Astrophysics Data System (ADS)

Choi, Yongki; Moody, Issa S.; Perez, Israel; Sheps, Tatyana; Weiss, Gregory A.; Collins, Philip G.

2011-03-01

High resolution, real-time monitoring of a single lysozyme molecule is demonstrated by fabricating nanoscale electronic devices based on single-walled carbon nanotubes (SWCNT). In this sensor platform, a biomolecule of interest is attached to a single SWCNT device. The electrical conductance transduces chemical events with single molecule sensitivity and 10 microsecond resolution. In this work, enzymatic turnover by lysozyme is investigated, because the mechanistic details for its processivity and dynamics remain incompletely understood. Stochastically distributed binding events between a lysozyme and its binding substrate, peptidoglycan, are monitored via the sensor conductance. Furthermore, the magnitude and repetition rate of these events varies with pH and the presence of inhibitors or denaturation agents. Changes in the conductance signal are analyzed in terms of lysozyme's internal hinge motion, binding events, and enzymatic processing.

Towards understanding the guessing game: a dynamical systems’ perspective

NASA Astrophysics Data System (ADS)

Reimann, Stefan

2004-08-01

The so-called “Guessing Game” or α-Beauty Contest serves as a paradigmatic conceptual framework for competitive price formation on financial markets beyond traditional equilibrium finance. It highlights features that are reasonable to consider when dealing with price formation on real markets. Nonetheless this game is still poorly understood. We propose a model which is essentially based on two assumptions: (1) players consider intervals rather than exact numbers to cope with incomplete knowledge and (2) players iteratively update their recent guesses. It provides an explanation for typical patterns observed in real data, such as the strict positivity of outcomes in the 1-shot setting, the skew background distribution of guessed numbers, as well as the polynomial convergence towards the game-theoretic Nash equilibrium in the iterative setting.

Evolving Concepts of Pulmonary Hypertension Secondary to Left Heart Disease.

PubMed

Ramu, Bhavadharini; Thenappan, Thenappan

2016-04-01

Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension. Although its pathophysiology remains incompletely understood, it is now well recognized that the presence of pulmonary hypertension is associated with a worse prognosis. Right ventricular failure has independent and additive prognostic value over pulmonary hypertension for adverse outcomes in left heart disease. Recently, several new terminologies have been introduced to better define and characterize the nature and severity of pulmonary hypertension. Several new treatment options including the use of pulmonary arterial hypertension specific therapies are being considered, but there is lack of evidence. Here, we review the recent advances in this field and summarize the diagnostic and therapeutic modalities of use in the management of pulmonary hypertension associated with left heart disease.

Intravascular Papillary Endothelial Hyperplasia (Masson’s Tumor) of the Radial Artery: A Case Report

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

Stark, Christopher, E-mail: Christopher.stark@uvmhealth.org; Olsen, Daniel; Morris, Christopher

Intravascular papillary endothelial hyperplasia (IPEH), often referred to as Masson’s tumor, is a benign non-neoplastic vascular lesion of the skin and subcutaneous tissues. Although it is rare, knowledge of the existence of IPEH is important as it can mimic other benign and malignant tumors, most notably angiosarcoma. IPEH remains an incompletely understood entity; however, most consider it to be the result of reactive endothelial proliferation following thrombus formation within a vessel, vascular malformation, or adjacent to a vessel. In this article, we report a case of IPEH arising within an arteriovenous malformation of the radial artery and present accompanying multimodalitymore » imaging and pathology figures. We will also describe the clinical presentation, pathophysiology, histology, imaging features, and management of IPEH.« less

Epigenetics of prostate cancer and the prospect of identification of novel drug targets by RNAi screening of epigenetic enzymes.

PubMed

Björkman, Mari; Rantala, Juha; Nees, Matthias; Kallioniemi, Olli

2010-10-01

Alterations in epigenetic processes probably underlie most human malignancies. Novel genome-wide techniques, such as chromatin immunoprecipitation and high-throughput sequencing, have become state-of-the-art methods to map the epigenomic landscape of development and disease, such as in cancers. Despite these advances, the functional significance of epigenetic enzymes in cancer progression, such as prostate cancer, remain incompletely understood. A comprehensive mapping and functional understanding of the cancer epigenome will hopefully help to facilitate development of novel cancer therapy targets and improve future diagnostics. The authors have developed a novel cell microarray-based high-content siRNA screening technique suitable to address the putative functional role and impact of all known putative and novel epigenetic enzymes in cancer, including prostate cancer.

The role of calcium and predation on plate morph evolution in the three-spined stickleback (Gasterosteus aculeatus).

PubMed

Smith, Carl; Spence, Rowena; Barber, Iain; Przybylski, Mirosław; Wootton, Robert J

2014-09-01

While the genetic basis to plate morph evolution of the three-spined stickleback (Gasterosteus aculeatus) is well described, the environmental variables that select for different plate and spine morphs are incompletely understood. Using replicate populations of three-spined sticklebacks on North Uist, Scotland, we previously investigated the role of predation pressure and calcium limitation on the adaptive evolution of stickleback morphology and behavior. While dissolved calcium proved a significant predictor of plate and spine morph, predator abundance did not. Ecol. Evol., xxx, 2014 and xxx performed a comparable analysis to our own to address the same question. They failed to detect a significant effect of dissolved calcium on morphological evolution, but did establish a significant effect of predation; albeit in the opposite direction to their prediction.

Species-specific identification from incomplete sampling: applying DNA barcodes to monitoring invasive solanum plants.

PubMed

Zhang, Wei; Fan, Xiaohong; Zhu, Shuifang; Zhao, Hong; Fu, Lianzhong

2013-01-01

Comprehensive sampling is crucial to DNA barcoding, but it is rarely performed because materials are usually unavailable. In practice, only a few rather than all species of a genus are required to be identified. Thus identification of a given species using a limited sample is of great importance in current application of DNA barcodes. Here, we selected 70 individuals representing 48 species from each major lineage of Solanum, one of the most species-rich genera of seed plants, to explore whether DNA barcodes can provide reliable specific-species discrimination in the context of incomplete sampling. Chloroplast genes ndhF and trnS-trnG and the nuclear gene waxy, the commonly used markers in Solanum phylogeny, were selected as the supplementary barcodes. The tree-building and modified barcode gap methods were employed to assess species resolution. The results showed that four Solanum species of quarantine concern could be successfully identified through the two-step barcoding sampling strategy. In addition, discrepancies between nuclear and cpDNA barcodes in some samples demonstrated the ability to discriminate hybrid species, and highlights the necessity of using barcode regions with different modes of inheritance. We conclude that efficient phylogenetic markers are good candidates as the supplementary barcodes in a given taxonomic group. Critically, we hypothesized that a specific-species could be identified from a phylogenetic framework using incomplete sampling-through this, DNA barcoding will greatly benefit the current fields of its application.

A systematic review of current osteoporotic metaphyseal fracture animal models.

PubMed

Wong, R M Y; Choy, M H V; Li, M C M; Leung, K-S; K-H Chow, S; Cheung, W-H; Cheng, J C Y

2018-01-01

The treatment of osteoporotic fractures is a major challenge, and the enhancement of healing is critical as a major goal in modern fracture management. Most osteoporotic fractures occur at the metaphyseal bone region but few models exist and the healing is still poorly understood. A systematic review was conducted to identify and analyse the appropriateness of current osteoporotic metaphyseal fracture animal models. A literature search was performed on the Pubmed, Embase, and Web of Science databases, and relevant articles were selected. A total of 19 studies were included. Information on the animal, induction of osteoporosis, fracture technique, site and fixation, healing results, and utility of the model were extracted. Fracture techniques included drill hole defects (3 of 19), bone defects (3 of 19), partial osteotomy (1 of 19), and complete osteotomies (12 of 19). Drill hole models and incomplete osteotomy models are easy to perform and allow the study of therapeutic agents but do not represent the usual clinical setting. Additionally, biomaterials can be filled into drill hole defects for analysis. Complete osteotomy models are most commonly used and are best suited for the investigation of therapeutic drugs or noninvasive interventions. The metaphyseal defect models allow the study of biomaterials, which are associated with complex and comminuted osteoporotic fractures. For a clinically relevant model, we propose that an animal model should satisfy the following criteria to study osteoporotic fracture healing: 1) induction of osteoporosis, 2) complete osteotomy or defect at the metaphysis unilaterally, and 3) internal fixation. Cite this article : R. M. Y. Wong, M. H. V. Choy, M. C. M. Li, K-S. Leung, S. K-H. Chow, W-H. Cheung, J. C. Y. Cheng. A systematic review of current osteoporotic metaphyseal fracture animal models. Bone Joint Res 2018;7:6-11. DOI: 10.1302/2046-3758.71.BJR-2016-0334.R2. © 2018 Wong et al.

Novel Approach to Classify Plants Based on Metabolite-Content Similarity.

PubMed

Liu, Kang; Abdullah, Azian Azamimi; Huang, Ming; Nishioka, Takaaki; Altaf-Ul-Amin, Md; Kanaya, Shigehiko

2017-01-01

Secondary metabolites are bioactive substances with diverse chemical structures. Depending on the ecological environment within which they are living, higher plants use different combinations of secondary metabolites for adaptation (e.g., defense against attacks by herbivores or pathogenic microbes). This suggests that the similarity in metabolite content is applicable to assess phylogenic similarity of higher plants. However, such a chemical taxonomic approach has limitations of incomplete metabolomics data. We propose an approach for successfully classifying 216 plants based on their known incomplete metabolite content. Structurally similar metabolites have been clustered using the network clustering algorithm DPClus. Plants have been represented as binary vectors, implying relations with structurally similar metabolite groups, and classified using Ward's method of hierarchical clustering. Despite incomplete data, the resulting plant clusters are consistent with the known evolutional relations of plants. This finding reveals the significance of metabolite content as a taxonomic marker. We also discuss the predictive power of metabolite content in exploring nutritional and medicinal properties in plants. As a byproduct of our analysis, we could predict some currently unknown species-metabolite relations.

Novel Approach to Classify Plants Based on Metabolite-Content Similarity

PubMed Central

Abdullah, Azian Azamimi; Huang, Ming; Nishioka, Takaaki

2017-01-01

Secondary metabolites are bioactive substances with diverse chemical structures. Depending on the ecological environment within which they are living, higher plants use different combinations of secondary metabolites for adaptation (e.g., defense against attacks by herbivores or pathogenic microbes). This suggests that the similarity in metabolite content is applicable to assess phylogenic similarity of higher plants. However, such a chemical taxonomic approach has limitations of incomplete metabolomics data. We propose an approach for successfully classifying 216 plants based on their known incomplete metabolite content. Structurally similar metabolites have been clustered using the network clustering algorithm DPClus. Plants have been represented as binary vectors, implying relations with structurally similar metabolite groups, and classified using Ward's method of hierarchical clustering. Despite incomplete data, the resulting plant clusters are consistent with the known evolutional relations of plants. This finding reveals the significance of metabolite content as a taxonomic marker. We also discuss the predictive power of metabolite content in exploring nutritional and medicinal properties in plants. As a byproduct of our analysis, we could predict some currently unknown species-metabolite relations. PMID:28164123

77 FR 43176 - Airworthiness Directives; Bombardier, Inc. Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-24

... alternating current (AC) generator failures in-service due to incomplete fusion in the weld joint of the rotor band assembly. This proposed AD would require inspecting the AC generator to determine the part number, and replacing the AC generator if necessary. We are proposing this AD to prevent rotor windings from...

Reactor antineutrino fluxes – Status and challenges

DOE PAGES

Huber, Patrick

2016-04-22

Here, we describe the current understanding of reactor antineutrino fluxes and point out some recent developments. This is not intended to be a complete review of this vast topic but merely a selection of observations and remarks, which despite their incompleteness, will highlight the status and the challenges of this field.

Role of Importance and Distinctiveness of Semantic Features in People with Aphasia: A Replication Study

ERIC Educational Resources Information Center

Mason-Baughman, Mary Beth; Wallace, Sarah E.

2014-01-01

Previous studies suggest that people with aphasia have incomplete lexical-semantic representations with decreased low-importance distinctive (LID) feature knowledge. In addition, decreased LID feature knowledge correlates with ability to discriminate among semantically related words. The current study seeks to replicate and extend previous…

The Sexual Assault Severity Scale: A Comprehensive Measure of Assault Severity

ERIC Educational Resources Information Center

Swinson, Karyn Crystal

2013-01-01

Many studies in the sexual assault literature have found a significant relationship between sexual assault severity and psychological distress, specifically PTSD and suicidality. However, in the current literature, there is an inconsistent and incomplete definition of the construct of assault severity. The present study aims to create a…

Seeing May Not Mean Believing: Examining Students' Understandings & Beliefs in Evolution

ERIC Educational Resources Information Center

Cavallo, Ann M. L.; McCall, David

2008-01-01

Science education currently has incomplete understandings of potential relationships between students' beliefs in Nature of Science (NOS) and evolution, and how these beliefs may be related to scientific understandings of evolution. Because of evolution's prominence in science education, curricula decisions, and the future of science teaching and…

High school incompletion and childhood maltreatment among street-involved young people in Vancouver, Canada.

PubMed

Barker, Brittany; Kerr, Thomas; Dong, Huiru; Wood, Evan; DeBeck, Kora

2017-03-01

While the link between educational attainment and future health and wellness is well understood, little investigation has considered the potential impacts of distinct forms of childhood maltreatment on high school completion. In the present study, the relationship between five categories of childhood maltreatment (physical, emotional, and sexual abuse, and physical and emotional neglect) and completion of high school education were examined using the Childhood Trauma Questionnaire (CTQ). From September 2005 to May 2013, data were collected for the At-Risk Youth Study (ARYS), a cohort of street-involved young people who use illicit drugs in Vancouver, Canada. We used logistic regression to examine the relationship between childhood maltreatment and high school completion, while controlling for a range of potential confounding variables. Specifically, five separate models for each category of maltreatment and two combined models were employed to examine the relative associations between, and cumulative impact of, different forms of childhood maltreatment and educational attainment. Among 974 young people, 737 (76%) reported not completing high school. In separate multivariable analyses physical abuse, emotional abuse, physical neglect, and emotional neglect remained positively and independently associated with an incomplete high school education. In a combined multivariable model with all forms of childhood maltreatment considered together, emotional abuse (adjusted odds ratio = 2.08; 95% confidence interval: 1.51-2.86) was the only form of maltreatment that remained significantly associated with an incomplete high school education. The cumulative impact assessment indicated a moderate dose-dependent trend where the greater the number of different forms of childhood maltreatment the greater the risk of not completing a high school education. These findings point to the need for trauma-informed interventions to improve educational attainment among vulnerable young people, as well as evidence-based prevention programmes, such as the Nurse-Family Partnership, aimed at supporting at-risk families before maltreatment occurs. © 2015 John Wiley & Sons Ltd.

Predictors of seizure freedom after incomplete resection in children.

PubMed

Perry, M S; Dunoyer, C; Dean, P; Bhatia, S; Bavariya, A; Ragheb, J; Miller, I; Resnick, T; Jayakar, P; Duchowny, M

2010-10-19

Incomplete resection of the epileptogenic zone (EZ) is the most important predictor of poor outcome after resective surgery for intractable epilepsy. We analyzed the contribution of preoperative and perioperative variables including MRI and EEG data as predictors of seizure-free (SF) outcome after incomplete resection. We retrospectively reviewed patients <18 years of age with incomplete resection for epilepsy with 2 years of follow-up. Fourteen preoperative and perioperative variables were compared in SF and non-SF (NSF) patients. We compared lesional patients, categorized by reason for incompleteness, to lesional patients with complete resection. We analyzed for effect of complete EEG resection on SF outcome in patients with incompletely resected MRI lesions and vice versa. Eighty-three patients with incomplete resection were included with 41% becoming SF. Forty-eight lesional patients with complete resection were included. Thirty-eight percent (57/151) of patients with incomplete resection and 34% (47/138) with complete resection were excluded secondary to lack of follow-up or incomplete records. Contiguous MRI lesions were predictive of seizure freedom after incomplete resection. Fifty-seven percent of patients incomplete by MRI alone, 52% incomplete by EEG alone, and 24% incomplete by both became SF compared to 77% of patients with complete resection (p = 0.0005). Complete resection of the MRI- and EEG-defined EZ is the best predictor of seizure freedom, though patients incomplete by EEG or MRI alone have better outcome compared to patients incomplete by both. More than one-third of patients with incomplete resection become SF, with contiguous MRI lesions a predictor of SF outcome.

A comparative study of prebiotic and present day translational models

NASA Technical Reports Server (NTRS)

Rein, R.; Raghunathan, G.; Mcdonald, J.; Shibata, M.; Srinivasan, S.

1986-01-01

It is generally recognized that the understanding of the molecular basis of primitive translation is a fundamental step in developing a theory of the origin of life. However, even in modern molecular biology, the mechanism for the decoding of messenger RNA triplet codons into an amino acid sequence of a protein on the ribosome is understood incompletely. Most of the proposed models for prebiotic translation lack, not only experimental support, but also a careful theoretical scrutiny of their compatibility with well understood stereochemical and energetic principles of nucleic acid structure, molecular recognition principles, and the chemistry of peptide bond formation. Present studies are concerned with comparative structural modelling and mechanistic simulation of the decoding apparatus ranging from those proposed for prebiotic conditions to the ones involved in modern biology. Any primitive decoding machinery based on nucleic acids and proteins, and most likely the modern day system, has to satisfy certain geometrical constraints. The charged amino acyl and the peptidyl termini of successive adaptors have to be adjacent in space in order to satisfy the stereochemical requirements for amide bond formation. Simultaneously, the same adaptors have to recognize successive codons on the messenger. This translational complex has to be realized by components that obey nucleic acid conformational principles, stabilities, and specificities. This generalized condition greatly restricts the number of acceptable adaptor structures.

Gut-kidney crosstalk in septic acute kidney injury.

PubMed

Zhang, Jingxiao; Ankawi, Ghada; Sun, Jian; Digvijay, Kumar; Yin, Yongjie; Rosner, Mitchell H; Ronco, Claudio

2018-05-03

Sepsis is the leading cause of acute kidney injury (AKI) in the intensive care unit (ICU). Septic AKI is a complex and multifactorial process that is incompletely understood. During sepsis, the disruption of the mucus membrane barrier, a shift in intestinal microbial flora, and microbial translocation may lead to systemic inflammation, which further alters host immune and metabolic homeostasis. This altered homeostasis may promote and potentiate the development of AKI. As part of this vicious cycle, when AKI develops, the clearance of inflammatory mediators and metabolic products is decreased. This will lead to further gut injury and breakdown in mucous membrane barriers. Thus, changes in the gut during sepsis can initiate and propagate septic AKI. This deleterious gut-kidney crosstalk may be a potential target for therapeutic maneuvers. This review analyses the underlying mechanisms in gut-kidney crosstalk in septic AKI.

Cooling Atomic Gases With Disorder

DOE PAGES

Paiva, Thereza; Khatami, Ehsan; Yang, Shuxiang; ...

2015-12-10

Cold atomic gases have proven capable of emulating a number of fundamental condensed matter phenomena including Bose-Einstein condensation, the Mott transition, Fulde-Ferrell-Larkin-Ovchinnikov pairing, and the quantum Hall effect. Cooling to a low enough temperature to explore magnetism and exotic superconductivity in lattices of fermionic atoms remains a challenge. Here in this paper, we propose a method to produce a low temperature gas by preparing it in a disordered potential and following a constant entropy trajectory to deliver the gas into a nondisordered state which exhibits these incompletely understood phases. We show, using quantum Monte Carlo simulations, that we can approachmore » the Néel temperature of the three-dimensional Hubbard model for experimentally achievable parameters. Recent experimental estimates suggest the randomness required lies in a regime where atom transport and equilibration are still robust.« less

The Role of Esophageal Hypersensitivity in Functional Esophageal Disorders.

PubMed

Farmer, Adam D; Ruffle, James K; Aziz, Qasim

2017-02-01

The Rome IV diagnostic criteria delineates 5 functional esophageal disorders which include functional chest pain, functional heartburn, reflux hypersensitivity, globus, and functional dysphagia. These are a heterogenous group of disorders which, despite having characteristic symptom profiles attributable to esophageal pathology, fail to demonstrate any structural, motility or inflammatory abnormalities on standard clinical testing. These disorders are associated with a marked reduction in patient quality of life, not least considerable healthcare resources. Furthermore, the pathophysiology of these disorders is incompletely understood. In this narrative review we provide the reader with an introductory primer to the structure and function of esophageal perception, including nociception that forms the basis of the putative mechanisms that may give rise to symptoms in functional esophageal disorders. We also discuss the provocative techniques and outcome measures by which esophageal hypersensitivity can be established.

Upper gastrointestinal sensory-motor dysfunction in diabetes mellitus

PubMed Central

Zhao, Jing-Bo; Frøkjær, Jens Brøndum; Drewes, Asbjørn Mohr; Ejskjaer, Niels

2006-01-01

Gastrointestinal (GI) sensory-motor abnormalities are common in patients with diabetes mellitus and may involve any part of the GI tract. Abnormalities are frequently sub-clinical, and fortunately only rarely do severe and life-threatening problems occur. The pathogenesis of abnormal upper GI sensory-motor function in diabetes is incompletely understood and is most likely multi-factorial of origin. Diabetic autonomic neuropathy as well as acute suboptimal control of diabetes has been shown to impair GI motor and sensory function. Morphological and biomechanical remodeling of the GI wall develops during the duration of diabetes, and may contribute to motor and sensory dysfunction. In this review sensory and motility disorders of the upper GI tract in diabetes is discussed; and the morphological changes and biomechanical remodeling related to the sensory-motor dysfunction is also addressed. PMID:16718808

The Origins of Scintillator Non-Proportionality

NASA Astrophysics Data System (ADS)

Moses, W. W.; Bizarri, G. A.; Williams, R. T.; Payne, S. A.; Vasil'ev, A. N.; Singh, J.; Li, Q.; Grim, J. Q.; Choong, W.-S.

2012-10-01

Recent years have seen significant advances in both theoretically understanding and mathematically modeling the underlying causes of scintillator non-proportionality. The core cause is that the interaction of radiation with matter invariably leads to a non-uniform ionization density in the scintillator, coupled with the fact that the light yield depends on the ionization density. The mechanisms that lead to the luminescence dependence on ionization density are incompletely understood, but several important features have been identified, notably Auger-like processes (where two carriers of excitation interact with each other, causing one to de-excite non-radiatively), the inability of excitation carriers to recombine (caused either by trapping or physical separation), and the carrier mobility. This paper reviews the present understanding of the fundamental origins of scintillator non-proportionality, specifically the various theories that have been used to explain non-proportionality.

Spectrum of MRI findings in clinical athletic pubalgia.

PubMed

Zajick, Donald C; Zoga, Adam C; Omar, Imran M; Meyers, William C

2008-03-01

Athletic pubalgia is a frequently encountered syndrome for clinicians who treat active patients participating in a wide variety of athletic endeavors worldwide. Pathologies associated with this clinical scenario span anatomically from the pubic symphysis to the hip and include a myriad of poorly understood and incompletely described musculoskeletal entities, many of which are centered about the pubic symphysis and its tendinous attachments. In this article, we discuss the relevant anatomy and pathophysiology for the most frequently encountered of these disorders, using magnetic resonance (MR) images as a guide. We describe an MR imaging protocol tailored to clinical athletic pubalgia. We then review reproducible MRI patterns of pathology about the pubic symphysis, the rectus abdominis/adductor aponeurosis and the inguinal ring, as well as a group of clinically confounding entities remote from the symphysis but visible by MRI.

Endothelial Response to Glucocorticoids in Inflammatory Diseases

PubMed Central

Zielińska, Karolina A.; Van Moortel, Laura; Opdenakker, Ghislain; De Bosscher, Karolien; Van den Steen, Philippe E.

2016-01-01

The endothelium plays a crucial role in inflammation. A balanced control of inflammation requires the action of glucocorticoids (GCs), steroidal hormones with potent cell-specific anti-inflammatory properties. Besides the classic anti-inflammatory effects of GCs on leukocytes, recent studies confirm that endothelial cells also represent an important target for GCs. GCs regulate different aspects of endothelial physiology including expression of adhesion molecules, production of pro-inflammatory cytokines and chemokines, and maintenance of endothelial barrier integrity. However, the regulation of endothelial GC sensitivity remains incompletely understood. In this review, we specifically examine the endothelial response to GCs in various inflammatory diseases ranging from multiple sclerosis, stroke, sepsis, and vasculitis to atherosclerosis. Shedding more light on the cross talk between GCs and endothelium will help to improve existing therapeutic strategies and develop new therapies better tailored to the needs of patients. PMID:28018358

Abdominal Sepsis.

PubMed

De Waele, Jan J

2016-08-01

Abdominal infections are an important challenge for the intensive care physician. In an era of increasing antimicrobial resistance, selecting the appropriate regimen is important and, with new drugs coming to the market, correct use is important more than ever before and abdominal infections are an excellent target for antimicrobial stewardship programs. Biomarkers may be helpful, but their exact role in managing abdominal infections remains incompletely understood. Source control also remains an ongoing conundrum, and evidence is increasing that its importance supersedes the impact of antibiotic therapy. New strategies such as open abdomen management may offer added benefit in severely ill patients, but more data are needed to identify its exact role. The role of fungi and the need for antifungal coverage, on the other hand, have been investigated extensively in recent years, but at this point, it remains unclear who requires empirical as well as directed therapy.

The skeletal consequences of thyrotoxicosis.

PubMed

Nicholls, Jonathan J; Brassill, Mary Jane; Williams, Graham R; Bassett, J H Duncan

2012-06-01

Euthyroid status is essential for normal skeletal development and the maintenance of adult bone structure and strength. Established thyrotoxicosis has long been recognised as a cause of high bone turnover osteoporosis and fracture but more recent studies have suggested that subclinical hyperthyroidism and long-term suppressive doses of thyroxine (T4) may also result in decreased bone mineral density (BMD) and an increased risk of fragility fracture, particularly in postmenopausal women. Furthermore, large population studies of euthyroid individuals have demonstrated that a hypothalamic-pituitary-thyroid axis set point at the upper end of the normal reference range is associated with reduced BMD and increased fracture susceptibility. Despite these findings, the cellular and molecular mechanisms of thyroid hormone action in bone remain controversial and incompletely understood. In this review, we discuss the role of thyroid hormones in bone and the skeletal consequences of hyperthyroidism.

PNUTS functions as a proto-oncogene by sequestering PTEN

PubMed Central

Kavela, Sridhar; Shinde, Swapnil R; Ratheesh, Raman; Viswakalyan, Kotapalli; Bashyam, Murali D; Gowrishankar, Swarnalata; Vamsy, Mohana; Pattnaik, Sujit; Rao, Subramanyeshwar; Sastry, Regulagadda A; Srinivasulu, Mukta; Chen, Junjie; Maddika, Subbareddy

2012-01-01

PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes such as survival, growth, motility, invasiveness and angiogenesis. While the functions of PTEN have been studied extensively, the regulation of its activity during normal and disease conditions still remains incompletely understood. In this study, we identified the protein phosphatase-1 nuclear targeting subunit PNUTS (PPP1R10) as a PTEN associated protein. PNUTS directly interacted with the lipid-binding domain (C2 domain) of PTEN and sequestered it in the nucleus. Depletion of PNUTS leads to increased apoptosis and reduced cellular proliferation in a PTEN-dependent manner. PNUTS expression was elevated in certain cancers compared to matched normal tissues. Collectively, our studies reveal PNUTS as a novel PTEN regulator and a likely oncogene. PMID:23117887

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output.

PubMed

O'Connell, Ryan M; Chaudhuri, Aadel A; Rao, Dinesh S; Gibson, William S J; Balazs, Alejandro B; Baltimore, David

2010-08-10

The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function screen found that three of these miRNAs conferred a competitive advantage to engrafting hematopoietic cells, whereas other HSC miRNAs attenuated production of blood cells. Overexpression of the most advantageous miRNA, miR-125b, caused a dose-dependent myeloproliferative disorder that progressed to a lethal myeloid leukemia in mice and also enhanced hematopoietic engraftment in human immune system mice. Our study identifies an evolutionarily conserved subset of miRNAs that is expressed in HSCs and functions to modulate hematopoietic output.

SERCA directs cell migration and branching across species and germ layers

PubMed Central

Lansdale, Nick; Navarro, Sonia; Truong, Thai V.; Bower, Dan J.; Featherstone, Neil C.; Connell, Marilyn G.; Al Alam, Denise; Frey, Mark R.; Trinh, Le A.; Fernandez, G. Esteban; Warburton, David; Fraser, Scott E.; Bennett, Daimark; Jesudason, Edwin C.

2017-01-01

ABSTRACT Branching morphogenesis underlies organogenesis in vertebrates and invertebrates, yet is incompletely understood. Here, we show that the sarco-endoplasmic reticulum Ca2+ reuptake pump (SERCA) directs budding across germ layers and species. Clonal knockdown demonstrated a cell-autonomous role for SERCA in Drosophila air sac budding. Live imaging of Drosophila tracheogenesis revealed elevated Ca2+ levels in migratory tip cells as they form branches. SERCA blockade abolished this Ca2+ differential, aborting both cell migration and new branching. Activating protein kinase C (PKC) rescued Ca2+ in tip cells and restored cell migration and branching. Likewise, inhibiting SERCA abolished mammalian epithelial budding, PKC activation rescued budding, while morphogens did not. Mesoderm (zebrafish angiogenesis) and ectoderm (Drosophila nervous system) behaved similarly, suggesting a conserved requirement for cell-autonomous Ca2+ signaling, established by SERCA, in iterative budding. PMID:28821490

Thermodynamics of inequalities: From precariousness to economic stratification

NASA Astrophysics Data System (ADS)

Smerlak, Matteo

2016-01-01

Growing economic inequalities are observed in several countries throughout the world. Following Pareto, the power-law structure of these inequalities has been the subject of much theoretical and empirical work. But their nonequilibrium dynamics, e.g. after a policy change, remains incompletely understood. Here we introduce a thermodynamical theory of inequalities based on the analogy between economic stratification and statistical entropy. Within this framework we identify the combination of upward mobility with precariousness as a fundamental driver of inequality. We formalize this statement by a "second-law" inequality displaying upward mobility and precariousness as thermodynamic conjugate variables. We estimate the time scale for the "relaxation" of the wealth distribution after a sudden change of the after-tax return on capital. Our method can be generalized to gain insight into the dynamics of inequalities in any Markovian model of socioeconomic interactions.

Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations

PubMed Central

Jaureguiberry, Graciana; De la Dure-Molla, Muriel; Parry, David; Quentric, Mickael; Himmerkus, Nina; Koike, Toshiyasu; Poulter, James; Klootwijk, Enriko; Robinette, Steven L.; Howie, Alexander J.; Patel, Vaksha; Figueres, Marie-Lucile; Stanescu, Horia C.; Issler, Naomi; Nicholson, Jeremy K.; Bockenhauer, Detlef; Laing, Christopher; Walsh, Stephen B.; McCredie, David A.; Povey, Sue; Asselin, Audrey; Picard, Arnaud; Coulomb, Aurore; Medlar, Alan J.; Bailleul-Forestier, Isabelle; Verloes, Alain; Le Caignec, Cedric; Roussey, Gwenaelle; Guiol, Julien; Isidor, Bertrand; Logan, Clare; Shore, Roger; Johnson, Colin; Inglehearn, Christopher; Al-Bahlani, Suhaila; Schmittbuhl, Matthieu; Clauss, François; Huckert, Mathilde; Laugel, Virginie; Ginglinger, Emmanuelle; Pajarola, Sandra; Spartà, Giuseppina; Bartholdi, Deborah; Rauch, Anita; Addor, Marie-Claude; Yamaguti, Paulo M.; Safatle, Heloisa P.; Acevedo, Ana Carolina; Martelli-Júnior, Hercílio; dos Santos Netos, Pedro E.; Coletta, Ricardo D.; Gruessel, Sandra; Sandmann, Carolin; Ruehmann, Denise; Langman, Craig B.; Scheinman, Steven J.; Ozdemir-Ozenen, Didem; Hart, Thomas C.; Hart, P. Suzanne; Neugebauer, Ute; Schlatter, Eberhard; Houillier, Pascal; Gahl, William A.; Vikkula, Miikka; Bloch-Zupan, Agnès; Bleich, Markus; Kitagawa, Hiroshi; Unwin, Robert J.; Mighell, Alan; Berdal, Ariane; Kleta, Robert

2013-01-01

Background/Aims Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. Results All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. Conclusions This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis. PMID:23434854

Patent Ductus Arteriosus Ligation and Adverse Outcomes: Causality or Bias?

PubMed Central

Weisz, Dany E.; McNamara, Patrick J.

2014-01-01

Observational studies have associated patent ductus arteriosus (PDA) ligation in preterm infants with increased chronic lung disease (CLD), retinopathy of prematurity, and neurodevelopmental impairment at long-term follow-up. Although the biological rationale for this association is incompletely understood, there is an emerging secular trend toward a permissive approach to the PDA. However, insufficient adjustment for postnatal, pre-ligation confounders, such as intraventricular hemorrhage and the duration and intensity of mechanical ventilation, suggests the presence of residual bias due to confounding by indication, and obliges caution in interpreting the ligation-morbidity relationship. A period of conservative management after failure of medical PDA closure may be considered to reduce the number of infants treated with surgery. Increased mortality and CLD in infants with persistent symptomatic PDA suggests that surgical ligation remains an important treatment modality for preterm infants. PMID:25024972

A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis

PubMed Central

Edens, Brittany M; Yan, Jianhua; Miller, Nimrod; Deng, Han-Xiang; Siddique, Teepu; Ma, Yongchao C

2017-01-01

The etiological underpinnings of amyotrophic lateral sclerosis (ALS) are complex and incompletely understood, although contributions to pathogenesis by regulators of proteolytic pathways have become increasingly apparent. Here, we present a novel variant in UBQLN4 that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. We further demonstrate that the ALS-associated UBQLN4 variant impairs proteasomal function, and identify the Wnt signaling pathway effector beta-catenin as a UBQLN4 substrate. Inhibition of beta-catenin function rescues the UBQLN4 variant-induced motor axon phenotypes. These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways. DOI: http://dx.doi.org/10.7554/eLife.25453.001 PMID:28463112

Adrenomedullin and endocrine control of immune cells during pregnancy.

PubMed

Matson, Brooke C; Caron, Kathleen M

2014-09-01

The immunology of pregnancy is complex and incompletely understood. Aberrant immune activity in the decidua and in the placenta is believed to play a role in diseases of pregnancy, such as infertility, miscarriage, fetal growth restriction and preeclampsia. Here, we briefly review the endocrine control of uterine natural killer cell populations and their functions by the peptide hormone adrenomedullin. Studies in genetic animal models have revealed the critical importance of adrenomedullin dosage at the maternal-fetal interface, with cells from both the maternal and fetal compartments contributing to essential aspects underlying appropriate uterine receptivity, implantation and vascular remodeling of spiral arteries. These basic insights into the crosstalk between the endocrine and immune systems within the maternal-fetal interface may ultimately translate to a better understanding of the functions and consequences of dysregulated adrenomedullin levels in clinically complicated pregnancies.

Mammalian autophagy and the plasma membrane.

PubMed

Pavel, Mariana; Rubinsztein, David C

2017-03-01

Autophagy (literally 'self-eating') is an evolutionarily conserved degradation process where cytoplasmic components are engulfed by vesicles called autophagosomes, which are then delivered to lysosomes, where their contents are degraded. Under stress conditions, such as starvation or oxidative stress, autophagy is upregulated in order to degrade macromolecules and restore the nutrient balance. The source of membranes that participate in the initial formation of phagophores is still incompletely understood and many intracellular structures have been shown to act as lipid donors, including the endoplasmic reticulum, Golgi, nucleus, mitochondria and the plasma membrane. Here, we focus on the contributions of the plasma membrane to autophagosome biogenesis governed by ATG16L1 and ATG9A trafficking, and summarize the physiological and pathological implications of this macroautophagy route, from development and stem cell fate to neurodegeneration and cancer. © 2016 Federation of European Biochemical Societies.

The role of calcium and predation on plate morph evolution in the three-spined stickleback (Gasterosteus aculeatus)

PubMed Central

Smith, Carl; Spence, Rowena; Barber, Iain; Przybylski, Mirosław; Wootton, Robert J

2014-01-01

While the genetic basis to plate morph evolution of the three-spined stickleback (Gasterosteus aculeatus) is well described, the environmental variables that select for different plate and spine morphs are incompletely understood. Using replicate populations of three-spined sticklebacks on North Uist, Scotland, we previously investigated the role of predation pressure and calcium limitation on the adaptive evolution of stickleback morphology and behavior. While dissolved calcium proved a significant predictor of plate and spine morph, predator abundance did not. Ecol. Evol., xxx, 2014 and xxx performed a comparable analysis to our own to address the same question. They failed to detect a significant effect of dissolved calcium on morphological evolution, but did establish a significant effect of predation; albeit in the opposite direction to their prediction. PMID:25478147

Arc expression identifies the lateral amygdala fear memory trace

PubMed Central

Gouty-Colomer, L A; Hosseini, B; Marcelo, I M; Schreiber, J; Slump, D E; Yamaguchi, S; Houweling, A R; Jaarsma, D; Elgersma, Y; Kushner, S A

2016-01-01

Memories are encoded within sparsely distributed neuronal ensembles. However, the defining cellular properties of neurons within a memory trace remain incompletely understood. Using a fluorescence-based Arc reporter, we were able to visually identify the distinct subset of lateral amygdala (LA) neurons activated during auditory fear conditioning. We found that Arc-expressing neurons have enhanced intrinsic excitability and are preferentially recruited into newly encoded memory traces. Furthermore, synaptic potentiation of thalamic inputs to the LA during fear conditioning is learning-specific, postsynaptically mediated and highly localized to Arc-expressing neurons. Taken together, our findings validate the immediate-early gene Arc as a molecular marker for the LA neuronal ensemble recruited during fear learning. Moreover, these results establish a model of fear memory formation in which intrinsic excitability determines neuronal selection, whereas learning-related encoding is governed by synaptic plasticity. PMID:25802982

Posttransplant Intramuscular Injection of PLX-R18 Mesenchymal-Like Adherent Stromal Cells Improves Human Hematopoietic Engraftment in A Murine Transplant Model

PubMed Central

Metheny, Leland; Eid, Saada; Lingas, Karen; Ofir, Racheli; Pinzur, Lena; Meyerson, Howard; Lazarus, Hillard M.; Huang, Alex Y.

2018-01-01

Late-term complications of hematopoietic cell transplantation (HCT) are numerous and include incomplete engraftment. One possible mechanism of incomplete engraftment after HCT is cytokine-mediated suppression or dysfunction of the bone marrow microenvironment. Mesenchymal stromal cells (MSCs) elaborate cytokines that nurture or stimulate the marrow microenvironment by several mechanisms. We hypothesize that the administration of exogenous MSCs may modulate the bone marrow milieu and improve peripheral blood count recovery in the setting of incomplete engraftment. In the current study, we demonstrated that posttransplant intramuscular administration of human placental derived mesenchymal-like adherent stromal cells [PLacental eXpanded (PLX)-R18] harvested from a three-dimensional in vitro culture system improved posttransplant engraftment of human immune compartment in an immune-deficient murine transplantation model. As measured by the percentage of CD45+ cell recovery, we observed improvement in the peripheral blood counts at weeks 6 (8.4 vs. 24.1%, p < 0.001) and 8 (7.3 vs. 13.1%, p < 0.05) and in the bone marrow at week 8 (28 vs. 40.0%, p < 0.01) in the PLX-R18 cohort. As measured by percentage of CD19+ cell recovery, there was improvement at weeks 6 (12.6 vs. 3.8%) and 8 (10.1 vs. 4.1%). These results suggest that PLX-R18 may have a therapeutic role in improving incomplete engraftment after HCT. PMID:29520362

Posttransplant Intramuscular Injection of PLX-R18 Mesenchymal-Like Adherent Stromal Cells Improves Human Hematopoietic Engraftment in A Murine Transplant Model.

PubMed

Metheny, Leland; Eid, Saada; Lingas, Karen; Ofir, Racheli; Pinzur, Lena; Meyerson, Howard; Lazarus, Hillard M; Huang, Alex Y

2018-01-01

Late-term complications of hematopoietic cell transplantation (HCT) are numerous and include incomplete engraftment. One possible mechanism of incomplete engraftment after HCT is cytokine-mediated suppression or dysfunction of the bone marrow microenvironment. Mesenchymal stromal cells (MSCs) elaborate cytokines that nurture or stimulate the marrow microenvironment by several mechanisms. We hypothesize that the administration of exogenous MSCs may modulate the bone marrow milieu and improve peripheral blood count recovery in the setting of incomplete engraftment. In the current study, we demonstrated that posttransplant intramuscular administration of human placental derived mesenchymal-like adherent stromal cells [PLacental eXpanded (PLX)-R18] harvested from a three-dimensional in vitro culture system improved posttransplant engraftment of human immune compartment in an immune-deficient murine transplantation model. As measured by the percentage of CD45 + cell recovery, we observed improvement in the peripheral blood counts at weeks 6 (8.4 vs. 24.1%, p  < 0.001) and 8 (7.3 vs. 13.1%, p  < 0.05) and in the bone marrow at week 8 (28 vs. 40.0%, p  < 0.01) in the PLX-R18 cohort. As measured by percentage of CD19 + cell recovery, there was improvement at weeks 6 (12.6 vs. 3.8%) and 8 (10.1 vs. 4.1%). These results suggest that PLX-R18 may have a therapeutic role in improving incomplete engraftment after HCT.

Steady-state heat conduction in quiescent fluids: Incompleteness of the Navier-Stokes-Fourier equations

NASA Astrophysics Data System (ADS)

Brenner, Howard

2011-10-01

Linear irreversible thermodynamic principles are used to demonstrate, by counterexample, the existence of a fundamental incompleteness in the basic pre-constitutive mass, momentum, and energy equations governing fluid mechanics and transport phenomena in continua. The demonstration is effected by addressing the elementary case of steady-state heat conduction (and transport processes in general) occurring in quiescent fluids. The counterexample questions the universal assumption of equality of the four physically different velocities entering into the basic pre-constitutive mass, momentum, and energy conservation equations. Explicitly, it is argued that such equality is an implicit constitutive assumption rather than an established empirical fact of unquestioned authority. Such equality, if indeed true, would require formal proof of its validity, currently absent from the literature. In fact, our counterexample shows the assumption of equality to be false. As the current set of pre-constitutive conservation equations appearing in textbooks are regarded as applicable both to continua and noncontinua (e.g., rarefied gases), our elementary counterexample negating belief in the equality of all four velocities impacts on all aspects of fluid mechanics and transport processes, continua and noncontinua alike.

Social Interactions under Incomplete Information: Games, Equilibria, and Expectations

NASA Astrophysics Data System (ADS)

Yang, Chao

My dissertation research investigates interactions of agents' behaviors through social networks when some information is not shared publicly, focusing on solutions to a series of challenging problems in empirical research, including heterogeneous expectations and multiple equilibria. The first chapter, "Social Interactions under Incomplete Information with Heterogeneous Expectations", extends the current literature in social interactions by devising econometric models and estimation tools with private information in not only the idiosyncratic shocks but also some exogenous covariates. For example, when analyzing peer effects in class performances, it was previously assumed that all control variables, including individual IQ and SAT scores, are known to the whole class, which is unrealistic. This chapter allows such exogenous variables to be private information and models agents' behaviors as outcomes of a Bayesian Nash Equilibrium in an incomplete information game. The distribution of equilibrium outcomes can be described by the equilibrium conditional expectations, which is unique when the parameters are within a reasonable range according to the contraction mapping theorem in function spaces. The equilibrium conditional expectations are heterogeneous in both exogenous characteristics and the private information, which makes estimation in this model more demanding than in previous ones. This problem is solved in a computationally efficient way by combining the quadrature method and the nested fixed point maximum likelihood estimation. In Monte Carlo experiments, if some exogenous characteristics are private information and the model is estimated under the mis-specified hypothesis that they are known to the public, estimates will be biased. Applying this model to municipal public spending in North Carolina, significant negative correlations between contiguous municipalities are found, showing free-riding effects. The Second chapter "A Tobit Model with Social Interactions under Incomplete Information", is an application of the first chapter to censored outcomes, corresponding to the situation when agents" behaviors are subjected to some binding restrictions. In an interesting empirical analysis for property tax rates set by North Carolina municipal governments, it is found that there is a significant positive correlation among near-by municipalities. Additionally, some private information about its own residents is used by a municipal government to predict others' tax rates, which enriches current empirical work about tax competition. The third chapter, "Social Interactions under Incomplete Information with Multiple Equilibria", extends the first chapter by investigating effective estimation methods when the condition for a unique equilibrium may not be satisfied. With multiple equilibria, the previous model is incomplete due to the unobservable equilibrium selection. Neither conventional likelihoods nor moment conditions can be used to estimate parameters without further specifications. Although there are some solutions to this issue in the current literature, they are based on strong assumptions such as agents with the same observable characteristics play the same strategy. This paper relaxes those assumptions and extends the all-solution method used to estimate discrete choice games to a setting with both discrete and continuous choices, bounded and unbounded outcomes, and a general form of incomplete information, where the existence of a pure strategy equilibrium has been an open question for a long time. By the use of differential topology and functional analysis, it is found that when all exogenous characteristics are public information, there are a finite number of equilibria. With privately known exogenous characteristics, the equilbria can be represented by a compact set in a Banach space and be approximated by a finite set. As a result, a finite-state probability mass function can be used to specify a probability measure for equilibrium selection, which completes the model. From Monte Carlo experiments about two types of binary choice models, it is found that assuming equilibrium uniqueness can bring in estimation biases when the true value of interaction intensity is large and there are multiple equilibria in the data generating process.

Satellite-derived submarine melt rates and mass balance (2011-2015) for Greenland's largest remaining ice tongues

NASA Astrophysics Data System (ADS)

Wilson, Nat; Straneo, Fiammetta; Heimbach, Patrick

2017-12-01

Ice-shelf-like floating extensions at the termini of Greenland glaciers are undergoing rapid changes with potential implications for the stability of upstream glaciers and the ice sheet as a whole. While submarine melting is recognized as a major contributor to mass loss, the spatial distribution of submarine melting and its contribution to the total mass balance of these floating extensions is incompletely known and understood. Here, we use high-resolution WorldView satellite imagery collected between 2011 and 2015 to infer the magnitude and spatial variability of melt rates under Greenland's largest remaining ice tongues - Nioghalvfjerdsbræ (79 North Glacier, 79N), Ryder Glacier (RG), and Petermann Glacier (PG). Submarine melt rates under the ice tongues vary considerably, exceeding 50 m a-1 near the grounding zone and decaying rapidly downstream. Channels, likely originating from upstream subglacial channels, give rise to large melt variations across the ice tongues. We compare the total melt rates to the influx of ice to the ice tongue to assess their contribution to the current mass balance. At Petermann Glacier and Ryder Glacier, we find that the combined submarine and aerial melt approximately balances the ice flux from the grounded ice sheet. At Nioghalvfjerdsbræ the total melt flux (14.2 ± 0.96 km3 a-1 w.e., water equivalent) exceeds the inflow of ice (10.2 ± 0.59 km3 a-1 w.e.), indicating present thinning of the ice tongue.

Exogenous hyalin and sea urchin gastrulation. Part III: Biological activity of hyalin isolated from Lytechinus pictus embryos

PubMed Central

Contreras, Azalia; Vitale, John; Hutchins-Carroll, Virginia; Carroll, Edward J.; Oppenheimer, Steven B.

2008-01-01

Summary Hyalin is a large glycoprotein, consisting of the hyalin repeat domain and non-repeated regions, and is the major component of the hyaline layer in the early sea urchin embryo of Strongylocentrotus purpuratus. The hyalin repeat domain has been identified in proteins from organisms as diverse as bacteria, sea urchins, worms, flies, mice and humans. While the specific function of hyalin and the hyalin repeat domain is incompletely understood, many studies suggest that it has a functional role in adhesive interactions. In part I of this series, we showed that hyalin isolated from the sea urchin S. purpuratus blocked archenteron elongation and attachment to the blastocoel roof occurring during gastrulation in S. purpuratus embryos, (Razinia et al., 2007). The cellular interactions that occur in the sea urchin, recognized by the U.S. National Institutes of Health as a model system, may provide insights into adhesive interactions that occur in human health and disease. In part II of this series, we showed that S. purpuratus hyalin heterospecifically blocked archenteron-ectoderm interaction in Lytechinus pictus embryos (Alvarez et al, 2007). In the current study, we have isolated hyalin from the sea urchin L. pictus and demonstrated that L. pictus hyalin homospecifically blocks archenteron-ectoderm interaction, suggesting a general role for this glycoprotein in mediating a specific set of adhesive interactions. We also found one major difference in hyalin activity in the two sea urchin species involving hyalin influence on gastrulation invagination. PMID:18925979

The first fossil of a bolbitidoid fern belongs to the early-divergent lineages of Elaphoglossum (Dryopteridaceae).

PubMed

Lóriga, Josmaily; Schmidt, Alexander R; Moran, Robbin C; Feldberg, Kathrin; Schneider, Harald; Heinrichs, Jochen

2014-09-01

• Closing gaps in the fossil record and elucidating phylogenetic relationships of mostly incomplete fossils are major challenges in the reconstruction of the diversification of fern lineages through time. The cosmopolitan family Dryopteridaceae represents one of the most species-rich families of leptosporangiate ferns, yet its fossil record is sparse and poorly understood. Here, we describe a fern inclusion in Miocene Dominican amber and investigate its relationships to extant Dryopteridaceae.• The morphology of the fossil was compared with descriptions of extant ferns, resulting in it being tentatively assigned to the bolbitidoid fern genus Elaphoglossum. This assignment was confirmed by reconstructing the evolution of the morphological characters preserved in the inclusion on a molecular phylogeny of 158 extant bolbitidoid ferns. To assess the morphology-based assignment of the fossil to Elaphoglossum, we examined DNA-calibrated divergence time estimates against the age of the amber deposits from which it came.• The fossil belongs to Elaphoglossum and is the first of a bolbitidoid fern. Its assignment to a particular section of Elaphoglossum could not be determined; however, sects. Lepidoglossa, Polytrichia, and Setosa can be discounted because the fossil lacks subulate scales or scales with acicular marginal hairs. Thus, the fossil might belong to either sects. Amygdalifolia, Wrightiana, Elaphoglossum, or Squamipedia or to an extinct lineage.• The discovery of a Miocene Elaphoglossum fossil provides remarkable support to current molecular clock-based estimates of the diversification of these ferns. © 2014 Botanical Society of America, Inc.

Applications of Electrified Dust and Dust Devil Electrodynamics to Martian Atmospheric Electricity

NASA Astrophysics Data System (ADS)

Harrison, R. G.; Barth, E.; Esposito, F.; Merrison, J.; Montmessin, F.; Aplin, K. L.; Borlina, C.; Berthelier, J. J.; Déprez, G.; Farrell, W. M.; Houghton, I. M. P.; Renno, N. O.; Nicoll, K. A.; Tripathi, S. N.; Zimmerman, M.

2016-11-01

Atmospheric transport and suspension of dust frequently brings electrification, which may be substantial. Electric fields of 10 kV m-1 to 100 kV m-1 have been observed at the surface beneath suspended dust in the terrestrial atmosphere, and some electrification has been observed to persist in dust at levels to 5 km, as well as in volcanic plumes. The interaction between individual particles which causes the electrification is incompletely understood, and multiple processes are thought to be acting. A variation in particle charge with particle size, and the effect of gravitational separation explains to, some extent, the charge structures observed in terrestrial dust storms. More extensive flow-based modelling demonstrates that bulk electric fields in excess of 10 kV m-1 can be obtained rapidly (in less than 10 s) from rotating dust systems (dust devils) and that terrestrial breakdown fields can be obtained. Modelled profiles of electrical conductivity in the Martian atmosphere suggest the possibility of dust electrification, and dust devils have been suggested as a mechanism of charge separation able to maintain current flow between one region of the atmosphere and another, through a global circuit. Fundamental new understanding of Martian atmospheric electricity will result from the ExoMars mission, which carries the DREAMS (Dust characterization, Risk Assessment, and Environment Analyser on the Martian Surface)—MicroARES ( Atmospheric Radiation and Electricity Sensor) instrumentation to Mars in 2016 for the first in situ electrical measurements.

Applications of Electrified Dust and Dust Devil Electrodynamics to Martian Atmospheric Electricity

NASA Technical Reports Server (NTRS)

Harrison, R. G.; Barth, E.; Esposito, F.; Merrison, J.; Montmessin, F.; Aplin, K. L.; Borlina, C.; Berthelier, J J.; Deprez, G.; Farrell, William M.;

Management of neuropathic pain following spinal cord injury: now and in the future.

PubMed

Siddall, P J

2009-05-01

To provide an overview of our current understanding of the problem of neuropathic pain following spinal cord injury (SCI) and to suggest possible therapeutic options in the near future. Original research articles, reviews and book chapters on the subject of pain and SCI. Neuropathic pain following SCI has presented a challenge not only for traditional concepts of how pain occurs but also for more recent conceptualizations. We have made substantial progress in identifying the common types of pain that occur following SCI, determining the prevalence and characteristics of pain, investigating some of the pathophysiological changes in the nervous system that may contribute to the presence of neuropathic SCI pain and examining the effectiveness of some treatments. However major challenges remain. We still need to reach consensus on an SCI pain taxonomy; our understanding of mechanisms and the relative contribution of changes in the periphery, spinal cord and brain is incompletely understood; there are few studies that indicate effective treatment options, particularly for neuropathic SCI pain; and treatment of the biological and psychological contributors to pain is often fragmented. Recent studies suggest the potential usefulness of new treatment approaches such as selective pharmacological agents, application of novel neurostimulation techniques and the use of cognitive approaches to modify the pain experience. Our increasing understanding of the problem combined with the promise of these new approaches offers hope for improved management of neuropathic pain following SCI in the near future.

MAX-DOAS observations from ground, ship, and research aircraft: maximizing signal-to-noise to measure 'weak' absorbers

NASA Astrophysics Data System (ADS)

Volkamer, Rainer; Coburn, Sean; Dix, Barbara; Sinreich, Roman

2009-08-01

Multi AXis Differential Optical Absorption Spectroscopy (MAX-DOAS) instruments, as solar straylight satellites, require an accurate characterization and elimination of Fraunhofer lines from solar straylight spectra to measure the atmospheric column abundance of reactive gases that destroy toxic and heat trapping ozone and form climate cooling aerosols, like glyoxal (CHOCHO), iodine oxide (IO), or bromine oxide (BrO). The currently achievable noise levels with state-of-the-art DOAS instruments are limited to δ'DL ~ 10-4 (noise equivalent differential optical density, δ') further noise reductions are typically not straightforward, and the reason for this barrier is not well understood. Here we demonstrate that the nonlinearity of state-of-the-art CCD detectors poses a limitation to accurately characterize Fraunhofer lines; the incomplete elimination of Fraunhofer lines is found to cause residual structures of δ' ~ 10-4, and only partially accounted by fitting of an "offset" spectrum. We have developed a novel software tool, the CU Data Acquisition Code that overcomes this barrier by actively controlling the CCD saturation level, and demonstrates that δ'DL on the order of 10-5 are possible without apparent limitations from the presence of Fraunhofer lines. The software also implements active control of the elevation angle (angle with respect to the horizon) by means of a Motion Compensation System for use with mobile MAX-DOAS deployments from ships and aircraft. Finally, a novel approach to convert slant column densities into line-of-sight averaged concentrations is discussed.

Thermal and Chemical Characterization of Composite Materials. MSFC Center Director's Discretionary Fund Final Report, Project No. ED36-18

NASA Technical Reports Server (NTRS)

Stanley, D. C.; Huff, T. L.

2003-01-01

The purpose of this research effort was to: (1) provide a concise and well-defined property profile of current and developing composite materials using thermal and chemical characterization techniques and (2) optimize analytical testing requirements of materials. This effort applied a diverse array of methodologies to ascertain composite material properties. Often, a single method of technique will provide useful, but nonetheless incomplete, information on material composition and/or behavior. To more completely understand and predict material properties, a broad-based analytical approach is required. By developing a database of information comprised of both thermal and chemical properties, material behavior under varying conditions may be better understood. THis is even more important in the aerospace community, where new composite materials and those in the development stage have little reference data. For example, Fourier transform infrared (FTIR) spectroscopy spectral databases available for identification of vapor phase spectra, such as those generated during experiments, generally refer to well-defined chemical compounds. Because this method renders a unique thermal decomposition spectral pattern, even larger, more diverse databases, such as those found in solid and liquid phase FTIR spectroscopy libraries, cannot be used. By combining this and other available methodologies, a database specifically for new materials and materials being developed at Marshall Space Flight Center can be generated . In addition, characterizing materials using this approach will be extremely useful in the verification of materials and identification of anomalies in NASA-wide investigations.

Coherent Motion of Monolayer Sheets under Confinement and Its Pathological Implications.

PubMed

Soumya, S S; Gupta, Animesh; Cugno, Andrea; Deseri, Luca; Dayal, Kaushik; Das, Dibyendu; Sen, Shamik; Inamdar, Mandar M

2015-12-01

Coherent angular rotation of epithelial cells is thought to contribute to many vital physiological processes including tissue morphogenesis and glandular formation. However, factors regulating this motion, and the implications of this motion if perturbed, remain incompletely understood. In the current study, we address these questions using a cell-center based model in which cells are polarized, motile, and interact with the neighboring cells via harmonic forces. We demonstrate that, a simple evolution rule in which the polarization of any cell tends to orient with its velocity vector can induce coherent motion in geometrically confined environments. In addition to recapitulating coherent rotational motion observed in experiments, our results also show the presence of radial movements and tissue behavior that can vary between solid-like and fluid-like. We show that the pattern of coherent motion is dictated by the combination of different physical parameters including number density, cell motility, system size, bulk cell stiffness and stiffness of cell-cell adhesions. We further observe that perturbations in the form of cell division can induce a reversal in the direction of motion when cell division occurs synchronously. Moreover, when the confinement is removed, we see that the existing coherent motion leads to cell scattering, with bulk cell stiffness and stiffness of cell-cell contacts dictating the invasion pattern. In summary, our study provides an in-depth understanding of the origin of coherent rotation in confined tissues, and extracts useful insights into the influence of various physical parameters on the pattern of such movements.

Kisspeptin modulates sexual and emotional brain processing in humans

PubMed Central

Comninos, Alexander N.; Wall, Matthew B.; Demetriou, Lysia; Shah, Amar J.; Clarke, Sophie A.; Narayanaswamy, Shakunthala; Nesbitt, Alexander; Izzi-Engbeaya, Chioma; Prague, Julia K.; Abbara, Ali; Ratnasabapathy, Risheka; Salem, Victoria; Nijher, Gurjinder M.; Jayasena, Channa N.; Tanner, Mark; Bassett, Paul; Mehta, Amrish; Rabiner, Eugenii A.; Hönigsperger, Christoph; Silva, Meire Ribeiro; Brandtzaeg, Ole Kristian; Wilson, Steven Ray; Brown, Rachel C.; Thomas, Sarah A.; Bloom, Stephen R.; Dhillo, Waljit S.

2017-01-01

BACKGROUND. Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behavior. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviors, and is a likely candidate system for the integration of behavior with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behavior. METHODS. Using a combination of functional neuroimaging and hormonal and psychometric analyses, we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men. RESULTS. We demonstrated that kisspeptin administration enhanced limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin’s enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, kisspeptin administration attenuated negative mood. CONCLUSIONS. Collectively, our data provide evidence of an undescribed role for kisspeptin in integrating sexual and emotional brain processing with reproduction in humans. These results have important implications for our understanding of reproductive biology and are highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function. FUNDING. National Institute for Health Research (NIHR), Wellcome Trust (Ref 080268), and the Medical Research Council (MRC). PMID:28112678

Stress during Adolescence Alters Palatable Food Consumption in a Context-Dependent Manner.

PubMed

Handy, Christine; Yanaga, Stephanie; Reiss, Avery; Zona, Nicole; Robinson, Emily; Saxton, Katherine B

2016-01-01

Food consumption and preferences may be shaped by exposure to stressful environments during sensitive periods in development, and even small changes in consumption can have important effects on long term health. Adolescence is increasingly recognized as a sensitive period, in which adverse experiences can alter development, but the specific programming effects that may occur during adolescence remain incompletely understood. The current study seeks to explore the effects of stress during late adolescence on consumption of a palatable, high-fat, high-sugar food in adulthood-under basal conditions, as well following acute stress. Male Long-Evans rats were exposed to a regimen of variable stress for seven days in late adolescence (PND 45-51). During the stress regimen, stressed animals gained significantly less weight than control animals, but weight in adulthood was unaffected by adolescent stress. Palatable food consumption differed between experimental groups, and the direction of effect depended on context; stressed rats ate significantly more palatable food than controls upon first exposure, but ate less following an acute stressor. Leptin levels and exploratory behaviors did not differ between stressed and non-stressed groups, suggesting that other factors regulate preference for a palatable food. Altered food consumption following adolescent stress suggests that rats remain sensitive to stress during late adolescence, and that adult feeding behavior may be affected by previous adverse experiences. Such programming effects highlight adolescence as a period of plasticity, with the potential to shape long term food consumption patterns and preferences.

Stress during Adolescence Alters Palatable Food Consumption in a Context-Dependent Manner

PubMed Central

Handy, Christine; Yanaga, Stephanie; Reiss, Avery; Zona, Nicole; Robinson, Emily; Saxton, Katherine B.

2016-01-01

Food consumption and preferences may be shaped by exposure to stressful environments during sensitive periods in development, and even small changes in consumption can have important effects on long term health. Adolescence is increasingly recognized as a sensitive period, in which adverse experiences can alter development, but the specific programming effects that may occur during adolescence remain incompletely understood. The current study seeks to explore the effects of stress during late adolescence on consumption of a palatable, high-fat, high-sugar food in adulthood—under basal conditions, as well following acute stress. Male Long-Evans rats were exposed to a regimen of variable stress for seven days in late adolescence (PND 45–51). During the stress regimen, stressed animals gained significantly less weight than control animals, but weight in adulthood was unaffected by adolescent stress. Palatable food consumption differed between experimental groups, and the direction of effect depended on context; stressed rats ate significantly more palatable food than controls upon first exposure, but ate less following an acute stressor. Leptin levels and exploratory behaviors did not differ between stressed and non-stressed groups, suggesting that other factors regulate preference for a palatable food. Altered food consumption following adolescent stress suggests that rats remain sensitive to stress during late adolescence, and that adult feeding behavior may be affected by previous adverse experiences. Such programming effects highlight adolescence as a period of plasticity, with the potential to shape long term food consumption patterns and preferences. PMID:26872268

Genetic therapy for vein bypass graft disease: current perspectives.

PubMed

Simosa, Hector F; Conte, Michael S

2004-01-01

Although continued progress in endovascular technology holds promise for less invasive approaches to arterial diseases, surgical bypass grafting remains the mainstay of therapy for patients with advanced coronary and peripheral ischemia. In the United States, nearly 400,000 coronary and 100,000 lower extremity bypass procedures are performed annually. The autogenous vein, particularly the greater saphenous vein, has proven to be a durable and versatile arterial substitute, with secondary patency rates at 5 years of 70 to 80% in the extremity. However, vein graft failure is a common occurrence that incurs significant morbidity and mortality, and, to date, pharmacologic approaches to prolong vein graft patency have produced limited results. Dramatic advances in genetics, coupled with a rapidly expanding knowledge of the molecular basis of vascular diseases, have set the stage for genetic interventions. The attraction of a genetic approach to vein graft failure is based on the notion that the tissue at risk is readily accessible to the clinician prior to the onset of the pathologic process and the premise that genetic reprogramming of cells in the wall of the vein can lead to an improved healing response. Although the pathophysiology of vein graft failure is incompletely understood, numerous relevant molecular targets have been elucidated. Interventions designed to influence cell proliferation, thrombosis, inflammation, and matrix remodeling at the genetic level have been described, and many have been tested in animal models. Both gene delivery and gene blockade strategies have been investigated, with the latter reaching the stage of advanced clinical trials.

Reporting standards for Bland-Altman agreement analysis in laboratory research: a cross-sectional survey of current practice.

PubMed

Chhapola, Viswas; Kanwal, Sandeep Kumar; Brar, Rekha

2015-05-01

To carry out a cross-sectional survey of the medical literature on laboratory research papers published later than 2012 and available in the common search engines (PubMed, Google Scholar) on the quality of statistical reporting of method comparison studies using Bland-Altman (B-A) analysis. Fifty clinical studies were identified which had undertaken method comparison of laboratory analytes using B-A. The reporting of B-A was evaluated using a predesigned checklist with following six items: (1) correct representation of x-axis on B-A plot, (2) representation and correct definition of limits of agreement (LOA), (3) reporting of confidence interval (CI) of LOA, (4) comparison of LOA with a priori defined clinical criteria, (5) evaluation of the pattern of the relationship between difference (y-axis) and average (x-axis) and (6) measures of repeatability. The x-axis and LOA were presented correctly in 94%, comparison with a priori clinical criteria in 74%, CI reporting in 6%, evaluation of pattern in 28% and repeatability assessment in 38% of studies. There is incomplete reporting of B-A in published clinical studies. Despite its simplicity, B-A appears not to be completely understood by researchers, reviewers and editors of journals. There appear to be differences in the reporting of B-A between laboratory medicine journals and other clinical journals. A uniform reporting of B-A method will enhance the generalizability of results. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Transcriptional Profiling of Metabolic Transitions during Development and Diapause Preparation in the Copepod Calanus finmarchicus.

PubMed

Tarrant, Ann M; Baumgartner, Mark F; Lysiak, Nadine S J; Altin, Dag; Størseth, Trond R; Hansen, Bjørn Henrik

2016-12-01

Calanus finmarchicus, like many other copepods in the family Calanidae, can enter into a facultative diapause during the last juvenile phase (fifth copepodid, C5) to enable survival during unfavorable periods. Diapause is essential to the persistence of Calanus populations and profoundly impacts energy flow within oceanic ecosystems, yet regulation of diapause is not understood in these animals. Transcriptional profiling has begun to provide insight into metabolic changes occurring as C. finmarchicus prepares for and enters into diapause or skips diapause to prepare for the terminal molt. In particular, components of the glycolysis, pentose phosphate and lipid synthesis pathways are upregulated early in the C5 stage when lipid stores are low. Currently, our ability to identify metabolic patterns is limited by the incomplete functional annotation of the C. finmarchicus transcriptome. Such limitations are widespread among studies of non-model organisms and addressing them should be a priority for future research. In addition, integrating the results across multiple emerging complementary transcriptomic studies will provide a more complete picture of copepod physiology than isolated studies. Ultimately, identifying molecular markers of copepod physiology could enable robust identification of animals preparing to enter into diapause and ultimately lead to a greatly improved understanding of diapause regulation. © The Author 2016. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

Immigration, employment relations, and health: Developing a research agenda.

PubMed

Benach, Joan; Muntaner, Carles; Chung, Haejoo; Benavides, Fernando G

2010-04-01

International migration has emerged as a global issue that has transformed the lives of hundreds of millions of persons. Migrant workers contribute to the economic growth of high-income countries often serving as the labour force performing dangerous, dirty and degrading work that nationals are reluctant to perform. Critical examination of the scientific and "grey" literatures on immigration, employment relations and health. Both lay and scientific literatures indicate that public health researchers should be concerned about the health consequences of migration processes. Migrant workers are more represented in dangerous industries and in hazardous jobs, occupations and tasks. They are often hired as labourers in precarious jobs with poverty wages and experience more serious abuse and exploitation at the workplace. Also, analyses document migrant workers' problems of social exclusion, lack of health and safety training, fear of reprisals for demanding better working conditions, linguistic and cultural barriers that minimize the effectiveness of training, incomplete OHS surveillance of foreign workers and difficulty accessing care and compensation when injured. Therefore migrant status can be an important source of occupational health inequalities. Available evidence shows that the employment conditions and associated work organization of most migrant workers are dangerous to their health. The overall impact of immigration on population health, however, still is poorly understood and many mechanisms, pathways and overall health impact are poorly documented. Current limitations highlight the need to engage in explicit analytical, intervention and policy research. (c) 2009 Wiley-Liss, Inc.

Vector-Borne Bacterial Plant Pathogens: Interactions with Hemipteran Insects and Plants

PubMed Central

Perilla-Henao, Laura M.; Casteel, Clare L.

2016-01-01

Hemipteran insects are devastating pests of crops due to their wide host range, rapid reproduction, and ability to transmit numerous plant-infecting pathogens as vectors. While the field of plant–virus–vector interactions has flourished in recent years, plant–bacteria–vector interactions remain poorly understood. Leafhoppers and psyllids are by far the most important vectors of bacterial pathogens, yet there are still significant gaps in our understanding of their feeding behavior, salivary secretions, and plant responses as compared to important viral vectors, such as whiteflies and aphids. Even with an incomplete understanding of plant–bacteria–vector interactions, some common themes have emerged: (1) all known vector-borne bacteria share the ability to propagate in the plant and insect host; (2) particular hemipteran families appear to be incapable of transmitting vector-borne bacteria; (3) all known vector-borne bacteria have highly reduced genomes and coding capacity, resulting in host-dependence; and (4) vector-borne bacteria encode proteins that are essential for colonization of specific hosts, though only a few types of proteins have been investigated. Here, we review the current knowledge on important vector-borne bacterial pathogens, including Xylella fastidiosa, Spiroplasma spp., Liberibacter spp., and ‘Candidatus Phytoplasma spp.’. We then highlight recent approaches used in the study of vector-borne bacteria. Finally, we discuss the application of this knowledge for control and future directions that will need to be addressed in the field of vector–plant–bacteria interactions. PMID:27555855

Disruptions of Host Immunity and Inflammation by Giardia Duodenalis: Potential Consequences for Co-Infections in the Gastro-Intestinal Tract

PubMed Central

Cotton, James A.; Amat, Christina B.; Buret, Andre G.

2015-01-01

Giardia duodenalis (syn. G. intestinalis, or G. lamblia) is a leading cause of waterborne diarrheal disease that infects hundreds of millions of people annually. Research on Giardia has greatly expanded within the last few years, and our understanding of the pathophysiology and immunology on this parasite is ever increasing. At peak infection, Giardia trophozoites induce pathophysiological responses that culminate in the development of diarrheal disease. However, human data has suggested that the intestinal mucosa of Giardia-infected individuals is devoid of signs of overt intestinal inflammation, an observation that is reproduced in animal models. Thus, our understanding of host inflammatory responses to the parasite remain incompletely understood and human studies and experimental data have produced conflicting results. It is now also apparent that certain Giardia infections contain mechanisms capable of modulating their host’s immune responses. As the oral route of Giardia infection is shared with many other gastrointestinal (GI) pathogens, co-infections may often occur, especially in places with poor sanitation and/or improper treatment of drinking water. Moreover, Giardia infections may modulate host immune responses and have been found to protect against the development of diarrheal disease in developing countries. The following review summarizes our current understanding of the immunomodulatory mechanisms of Giardia infections and their consequences for the host, and highlights areas for future research. Potential implications of these immunomodulatory effects during GI co-infection are also discussed. PMID:26569316

Coherent Motion of Monolayer Sheets under Confinement and Its Pathological Implications

PubMed Central

Soumya, S S; Gupta, Animesh; Cugno, Andrea; Deseri, Luca; Dayal, Kaushik; Das, Dibyendu; Sen, Shamik; Inamdar, Mandar M.

2015-01-01

Coherent angular rotation of epithelial cells is thought to contribute to many vital physiological processes including tissue morphogenesis and glandular formation. However, factors regulating this motion, and the implications of this motion if perturbed, remain incompletely understood. In the current study, we address these questions using a cell-center based model in which cells are polarized, motile, and interact with the neighboring cells via harmonic forces. We demonstrate that, a simple evolution rule in which the polarization of any cell tends to orient with its velocity vector can induce coherent motion in geometrically confined environments. In addition to recapitulating coherent rotational motion observed in experiments, our results also show the presence of radial movements and tissue behavior that can vary between solid-like and fluid-like. We show that the pattern of coherent motion is dictated by the combination of different physical parameters including number density, cell motility, system size, bulk cell stiffness and stiffness of cell-cell adhesions. We further observe that perturbations in the form of cell division can induce a reversal in the direction of motion when cell division occurs synchronously. Moreover, when the confinement is removed, we see that the existing coherent motion leads to cell scattering, with bulk cell stiffness and stiffness of cell-cell contacts dictating the invasion pattern. In summary, our study provides an in-depth understanding of the origin of coherent rotation in confined tissues, and extracts useful insights into the influence of various physical parameters on the pattern of such movements. PMID:26691341

Consumption of atmospheric methane by desert soils

USGS Publications Warehouse

Striegl, Robert G.; McConnaughey, T.A.; Thorstenson, D.C.; Weeks, E.P.; Woodward, J.C.

1992-01-01

ATMOSPHERIC concentrations of methane, a greenhouse gas, are increasing at a rate of about 1% yr-1 (refs 1-4). Oxidation by methylotrophic bacteria in soil is the largest terrestrial sink for atmospheric CH4, and is estimated to consume about 30?? 1012 g CH4 yr-1 (refs 4-6). Spatial and temporal variability in the rate of soil CH4 consumption are incompletely understood6-19, as are the apparent inhibitory12,13,18 or enhancing20 effects of changes in land use. Dry deserts, which constitute 20% of total land surface, are not currently included in global soil uptake estimates. Here we describe measurements of the rate of uptake of atmospheric CH4 by undisturbed desert soils. We observed rates as great as 4.38 mg CH4 m-2 day-1; 50% of the measured rates were between 0.24 and 0.92 mg CH4 m2 d-1. Uptake of CH4 by desert soil is enhanced by rainfall after an initial soil-drainage period - opposite to the response of temperate forest soils12. Methane is consumed to a depth of about 2 m, allowing for deep removal of atmospheric CH4 if near-surface conditions are unfavourable for consumption. On the basis of an annual average CH4 consumption rate of 0.66 mg CH4 m-2 d-1, we estimate that the global CH4 sink term needs to be increased by about 7 ?? 1012 g yr-1 to account for the contribution of desert soils.

BANYAN. IX. The Initial Mass Function and Planetary-mass Object Space Density of the TW HYA Association

NASA Astrophysics Data System (ADS)

Gagné, Jonathan; Faherty, Jacqueline K.; Mamajek, Eric E.; Malo, Lison; Doyon, René; Filippazzo, Joseph C.; Weinberger, Alycia J.; Donaldson, Jessica K.; Lépine, Sébastien; Lafrenière, David; Artigau, Étienne; Burgasser, Adam J.; Looper, Dagny; Boucher, Anne; Beletsky, Yuri; Camnasio, Sara; Brunette, Charles; Arboit, Geneviève

2017-02-01

A determination of the initial mass function (IMF) of the current, incomplete census of the 10 Myr-old TW Hya association (TWA) is presented. This census is built from a literature compilation supplemented with new spectra and 17 new radial velocities from ongoing membership surveys, as well as a reanalysis of Hipparcos data that confirmed HR 4334 (A2 Vn) as a member. Although the dominant uncertainty in the IMF remains census incompleteness, a detailed statistical treatment is carried out to make the IMF determination independent of binning while accounting for small number statistics. The currently known high-likelihood members are fitted by a log-normal distribution with a central mass of {0.21}-0.06+0.11 M ⊙ and a characteristic width of {0.8}-0.1+0.2 dex in the 12 M Jup-2 M ⊙ range, whereas a Salpeter power law with α ={2.2}-0.5+1.1 best describes the IMF slope in the 0.1-2 M ⊙ range. This characteristic width is higher than other young associations, which may be due to incompleteness in the current census of low-mass TWA stars. A tentative overpopulation of isolated planetary-mass members similar to 2MASS J11472421-2040204 and 2MASS J11193254-1137466 is identified: this indicates that there might be as many as {10}-5+13 similar members of TWA with hot-start model-dependent masses estimated at ˜5-7 M Jup, most of which would be too faint to be detected in 2MASS. Our new radial velocity measurements corroborate the membership of 2MASS J11472421-2040204, and secure TWA 28 (M8.5 γ), TWA 29 (M9.5 γ), and TWA 33 (M4.5 e) as members. The discovery of 2MASS J09553336-0208403, a young L7-type interloper unrelated to TWA, is also presented.

Inferring duplications, losses, transfers and incomplete lineage sorting with nonbinary species trees.

PubMed

Stolzer, Maureen; Lai, Han; Xu, Minli; Sathaye, Deepa; Vernot, Benjamin; Durand, Dannie

2012-09-15

Gene duplication (D), transfer (T), loss (L) and incomplete lineage sorting (I) are crucial to the evolution of gene families and the emergence of novel functions. The history of these events can be inferred via comparison of gene and species trees, a process called reconciliation, yet current reconciliation algorithms model only a subset of these evolutionary processes. We present an algorithm to reconcile a binary gene tree with a nonbinary species tree under a DTLI parsimony criterion. This is the first reconciliation algorithm to capture all four evolutionary processes driving tree incongruence and the first to reconcile non-binary species trees with a transfer model. Our algorithm infers all optimal solutions and reports complete, temporally feasible event histories, giving the gene and species lineages in which each event occurred. It is fixed-parameter tractable, with polytime complexity when the maximum species outdegree is fixed. Application of our algorithms to prokaryotic and eukaryotic data show that use of an incomplete event model has substantial impact on the events inferred and resulting biological conclusions. Our algorithms have been implemented in Notung, a freely available phylogenetic reconciliation software package, available at http://www.cs.cmu.edu/~durand/Notung. mstolzer@andrew.cmu.edu.

Geomagnetically induced currents: Science, engineering, and applications readiness

NASA Astrophysics Data System (ADS)

Pulkkinen, A.; Bernabeu, E.; Thomson, A.; Viljanen, A.; Pirjola, R.; Boteler, D.; Eichner, J.; Cilliers, P. J.; Welling, D.; Savani, N. P.; Weigel, R. S.; Love, J. J.; Balch, C.; Ngwira, C. M.; Crowley, G.; Schultz, A.; Kataoka, R.; Anderson, B.; Fugate, D.; Simpson, J. J.; MacAlester, M.

2017-07-01

This paper is the primary deliverable of the very first NASA Living With a Star Institute Working Group, Geomagnetically Induced Currents (GIC) Working Group. The paper provides a broad overview of the current status and future challenges pertaining to the science, engineering, and applications of the GIC problem. Science is understood here as the basic space and Earth sciences research that allows improved understanding and physics-based modeling of the physical processes behind GIC. Engineering, in turn, is understood here as the "impact" aspect of GIC. Applications are understood as the models, tools, and activities that can provide actionable information to entities such as power systems operators for mitigating the effects of GIC and government agencies for managing any potential consequences from GIC impact to critical infrastructure. Applications can be considered the ultimate goal of our GIC work. In assessing the status of the field, we quantify the readiness of various applications in the mitigation context. We use the Applications Readiness Level (ARL) concept to carry out the quantification.

Geomagnetically induced currents: Science, engineering, and applications readiness

USGS Publications Warehouse

Pulkkinen, Antti; Bernabeu, E.; Thomson, A.; Viljanen, A.; Pirjola, R.; Boteler, D.; Eichner, J.; Cilliers, P.J.; Welling, D.; Savani, N.P.; Weigel, R.S.; Love, Jeffrey J.; Balch, Christopher; Ngwira, C.M.; Crowley, G.; Schultz, Adam; Kataoka, R.; Anderson, B.; Fugate, D.; Simpson, J.J.; MacAlester, M.

2017-01-01

This paper is the primary deliverable of the very first NASA Living With a Star Institute Working Group, Geomagnetically Induced Currents (GIC) Working Group. The paper provides a broad overview of the current status and future challenges pertaining to the science, engineering, and applications of the GIC problem. Science is understood here as the basic space and Earth sciences research that allows improved understanding and physics-based modeling of the physical processes behind GIC. Engineering, in turn, is understood here as the “impact” aspect of GIC. Applications are understood as the models, tools, and activities that can provide actionable information to entities such as power systems operators for mitigating the effects of GIC and government agencies for managing any potential consequences from GIC impact to critical infrastructure. Applications can be considered the ultimate goal of our GIC work. In assessing the status of the field, we quantify the readiness of various applications in the mitigation context. We use the Applications Readiness Level (ARL) concept to carry out the quantification.

Bone marrow stimulation of the medial femoral condyle produces inferior cartilage and bone repair compared to the trochlea in a rabbit surgical model.

PubMed

Chen, Hongmei; Chevrier, Anik; Hoemann, Caroline D; Sun, Jun; Picard, Genevieve; Buschmann, Michael D

2013-11-01

The influence of the location of cartilage lesions on cartilage repair outcome is incompletely understood. This study compared cartilage and bone repair in medial femoral condylar (MFC) versus femoral trochlear (TR) defects 3 months after bone marrow stimulation in mature rabbits. Intact femurs from adult rabbits served as controls. Results from quantitative histomorphometry and histological scoring showed that bone marrow stimulation produced inferior soft tissue repair in MFC versus TR defects, as indicated by significantly lower % Fill (p = 0.03), a significant increase in collagen type I immunostaining (p < 0.00001) and lower O'Driscoll scores (p < 0.05). 3D micro-CT analysis showed that repaired TR defects regained normal un-operated values of bone volume fraction, trabecular thickness, and trabecular number, whereas in MFC defects the repaired bone architecture appeared immature and less dense compared to intact un-operated MFC controls (p < 0.0001). Severe medial meniscal damage was found in 28% of operated animals and was strongly correlated with (i) low cartilage defect fill, (ii) incomplete bone repair in MFC, and (iii) with a more posterior defect placement in the weight-bearing region. We conclude that the location of cartilage lesions influences cartilage repair, with better outcome in TR versus MFC defects in rabbits. Meniscal degeneration is associated with cartilage damage. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Identification and correction of abnormal, incomplete and mispredicted proteins in public databases.

PubMed

Nagy, Alinda; Hegyi, Hédi; Farkas, Krisztina; Tordai, Hedvig; Kozma, Evelin; Bányai, László; Patthy, László

2008-08-27

Despite significant improvements in computational annotation of genomes, sequences of abnormal, incomplete or incorrectly predicted genes and proteins remain abundant in public databases. Since the majority of incomplete, abnormal or mispredicted entries are not annotated as such, these errors seriously affect the reliability of these databases. Here we describe the MisPred approach that may provide an efficient means for the quality control of databases. The current version of the MisPred approach uses five distinct routines for identifying abnormal, incomplete or mispredicted entries based on the principle that a sequence is likely to be incorrect if some of its features conflict with our current knowledge about protein-coding genes and proteins: (i) conflict between the predicted subcellular localization of proteins and the absence of the corresponding sequence signals; (ii) presence of extracellular and cytoplasmic domains and the absence of transmembrane segments; (iii) co-occurrence of extracellular and nuclear domains; (iv) violation of domain integrity; (v) chimeras encoded by two or more genes located on different chromosomes. Analyses of predicted EnsEMBL protein sequences of nine deuterostome (Homo sapiens, Mus musculus, Rattus norvegicus, Monodelphis domestica, Gallus gallus, Xenopus tropicalis, Fugu rubripes, Danio rerio and Ciona intestinalis) and two protostome species (Caenorhabditis elegans and Drosophila melanogaster) have revealed that the absence of expected signal peptides and violation of domain integrity account for the majority of mispredictions. Analyses of sequences predicted by NCBI's GNOMON annotation pipeline show that the rates of mispredictions are comparable to those of EnsEMBL. Interestingly, even the manually curated UniProtKB/Swiss-Prot dataset is contaminated with mispredicted or abnormal proteins, although to a much lesser extent than UniProtKB/TrEMBL or the EnsEMBL or GNOMON-predicted entries. MisPred works efficiently in identifying errors in predictions generated by the most reliable gene prediction tools such as the EnsEMBL and NCBI's GNOMON pipelines and also guides the correction of errors. We suggest that application of the MisPred approach will significantly improve the quality of gene predictions and the associated databases.

Loss of Humoral and Cellular Immunity to Invasive Nontyphoidal Salmonella during Current or Convalescent Plasmodium falciparum Infection in Malawian Children

PubMed Central

Nyirenda, James T.; Tembo, Dumizulu L.; Storm, Janet; Dube, Queen; Msefula, Chisomo L.; Jambo, Kondwani C.; Mwandumba, Henry C.; Heyderman, Robert S.; Gordon, Melita A.

2017-01-01

ABSTRACT Invasive nontyphoidal Salmonella (iNTS) infections are commonly associated with Plasmodium falciparum infections, but the immunologic basis for this linkage is poorly understood. We hypothesized that P. falciparum infection compromises the humoral and cellular immunity of the host to NTS, which increases the susceptibility of the host to iNTS infection. We prospectively recruited children aged between 6 and 60 months at a Community Health Centre in Blantyre, Malawi, and allocated them to the following groups; febrile with uncomplicated malaria, febrile malaria negative, and nonfebrile malaria negative. Levels of Salmonella enterica serovar Typhimurium-specific serum bactericidal activity (SBA) and whole-blood bactericidal activity (WBBA), complement C3 deposition, and neutrophil respiratory burst activity (NRBA) were measured. Levels of SBA with respect to S. Typhimurium were reduced in febrile P. falciparum-infected children (median, −0.20 log10 [interquartile range {IQR}, −1.85, 0.32]) compared to nonfebrile malaria-negative children (median, −1.42 log10 [IQR, −2.0, −0.47], P = 0.052). In relation to SBA, C3 deposition on S. Typhimurium was significantly reduced in febrile P. falciparum-infected children (median, 7.5% [IQR, 4.1, 15.0]) compared to nonfebrile malaria-negative children (median, 29% [IQR, 11.8, 48.0], P = 0.048). WBBA with respect to S. Typhimurium was significantly reduced in febrile P. falciparum-infected children (median, 0.25 log10 [IQR, −0.73, 1.13], P = 0.0001) compared to nonfebrile malaria-negative children (median, −1.0 log10 [IQR, −1.68, −0.16]). In relation to WBBA, S. Typhimurium-specific NRBA was reduced in febrile P. falciparum-infected children (median, 8.8% [IQR, 3.7, 20], P = 0.0001) compared to nonfebrile malaria-negative children (median, 40.5% [IQR, 33, 65.8]). P. falciparum infection impairs humoral and cellular immunity to S. Typhimurium in children during malaria episodes, which may explain the increased risk of iNTS observed in children from settings of malaria endemicity. The mechanisms underlying humoral immunity impairment are incompletely understood and should be explored further. PMID:28515136

Loss of Humoral and Cellular Immunity to Invasive Nontyphoidal Salmonella during Current or Convalescent Plasmodium falciparum Infection in Malawian Children.

PubMed

Nyirenda, Tonney S; Nyirenda, James T; Tembo, Dumizulu L; Storm, Janet; Dube, Queen; Msefula, Chisomo L; Jambo, Kondwani C; Mwandumba, Henry C; Heyderman, Robert S; Gordon, Melita A; Mandala, Wilson L

2017-07-01

Invasive nontyphoidal Salmonella (iNTS) infections are commonly associated with Plasmodium falciparum infections, but the immunologic basis for this linkage is poorly understood. We hypothesized that P. falciparum infection compromises the humoral and cellular immunity of the host to NTS, which increases the susceptibility of the host to iNTS infection. We prospectively recruited children aged between 6 and 60 months at a Community Health Centre in Blantyre, Malawi, and allocated them to the following groups; febrile with uncomplicated malaria, febrile malaria negative, and nonfebrile malaria negative. Levels of Salmonella enterica serovar Typhimurium-specific serum bactericidal activity (SBA) and whole-blood bactericidal activity (WBBA), complement C3 deposition, and neutrophil respiratory burst activity (NRBA) were measured. Levels of SBA with respect to S Typhimurium were reduced in febrile P. falciparum -infected children (median, -0.20 log10 [interquartile range {IQR}, -1.85, 0.32]) compared to nonfebrile malaria-negative children (median, -1.42 log10 [IQR, -2.0, -0.47], P = 0.052). In relation to SBA, C3 deposition on S Typhimurium was significantly reduced in febrile P. falciparum -infected children (median, 7.5% [IQR, 4.1, 15.0]) compared to nonfebrile malaria-negative children (median, 29% [IQR, 11.8, 48.0], P = 0.048). WBBA with respect to S Typhimurium was significantly reduced in febrile P. falciparum -infected children (median, 0.25 log10 [IQR, -0.73, 1.13], P = 0.0001) compared to nonfebrile malaria-negative children (median, -1.0 log10 [IQR, -1.68, -0.16]). In relation to WBBA, S Typhimurium-specific NRBA was reduced in febrile P. falciparum -infected children (median, 8.8% [IQR, 3.7, 20], P = 0.0001) compared to nonfebrile malaria-negative children (median, 40.5% [IQR, 33, 65.8]). P. falciparum infection impairs humoral and cellular immunity to S Typhimurium in children during malaria episodes, which may explain the increased risk of iNTS observed in children from settings of malaria endemicity. The mechanisms underlying humoral immunity impairment are incompletely understood and should be explored further. Copyright © 2017 Nyirenda et al.

Matriculation Research Report: Incomplete Grades; Data & Analysis.

ERIC Educational Resources Information Center

Gerda, Joe

The policy on incomplete grades at California's College of the Canyons states that incompletes may only be given under circumstances beyond students' control and that students must make arrangements with faculty prior to the end of the semester to clear the incomplete. Failure to complete an incomplete may result in an "F" grade. While…

Management of incomplete abortion in South African public hospitals.

PubMed

Brown, H C; Jewkes, R; Levin, J; Dickson-Tetteh, K; Rees, H

2003-04-01

To describe the current management of incomplete abortion in South African public hospitals and to discuss the extent to which management is clinically appropriate. A multicentre, prospective descriptive study. South African public hospitals that manage gynaecological emergencies. Hospitals were selected using a stratified random sampling method. All women who presented to the above sampled hospitals with incomplete abortion during the three week data collection period in 2000 were included. A data collection sheet was completed at the time of discharge for each woman admitted with a diagnosis of incomplete, complete, missed or inevitable abortion during the study period. Information gathered included demographic data, clinical signs and symptoms at admission, medical management, surgical management, anaestetic management, use of blood products and antibiotics and complications. Three clinical severity categories were used for the purpose of data analysis and interpretation. Detail of medical management, detail of surgical management, use of blood products and antibiotics, methods of analgesia and anaesthesia used, and use of abortifacients. There is a trend towards low cost technology such as the use of manual vacuum aspiration and sedation anaesthesia; however, this is mainly limited to the better resourced tertiary hospitals linked to academic units. The use of antibiotics and blood products has decreased but much of the use is inappropriate. The use of abortifacients does include some use of misoprostol but merely as an adjunct to surgical evacuation. The management of incomplete abortion remains a problem in South Africa, a low income country that is still managing a common clinical problem with costly interventions. The evidence of a trend towards low cost technology is promising, albeit limited to tertiary centres. This study has given us information as how to best address this problem. More training in low cost methods is needed, targeting in particular the district and regional hospitals, and reinforced by skills training focussed mainly on undergraduates and midwife post-abortion care programmes.

A phylogenomic analysis of Marek’s disease virus (MDV) reveals independent paths to virulence in Eurasia and North America

USDA-ARS?s Scientific Manuscript database

Virulence determines the impact a pathogen has on the fitness of its host, yet current understanding of the evolutionary origins and causes of virulence of many pathogens is surprisingly incomplete. Here, we explore the evolution of Marek’s disease virus (MDV), a herpesvirus commonly afflicting chic...

Introduction to the invited issue on carbon allocation of trees and forests

Treesearch

Daniel Epron; Yann Nouvellon; Michael G. Ryan

2012-01-01

Carbon (C) allocation is a major issue in plant ecology, controlling the flows of C fixed in photosynthesis between respiration and biomass production, and between short- and long-lived and aboveground and belowground tissues. Incomplete knowledge of C allocation currently hinders accurate modelling of tree growth and forest ecosystem metabolism (Friedlingstein et al....

Assessing Dimensions of Inquiry Practice by Middle School Science Teachers Engaged in a Professional Development Program

ERIC Educational Resources Information Center

Lakin, Joni M.; Wallace, Carolyn S.

2015-01-01

Inquiry-based teaching promotes students' engagement in problem-solving and investigation as they learn science concepts. Current practice in science teacher education promotes the use of inquiry in the teaching of science. However, the literature suggests that many science teachers hold incomplete or incorrect conceptions of inquiry.…

Teaching Braille Line Tracking Using Stimulus Fading

ERIC Educational Resources Information Center

Scheithauer, Mindy C.; Tiger, Jeffrey H.

2014-01-01

Line tracking is a prerequisite skill for braille literacy that involves moving one's finger horizontally across a line of braille text and identifying when a line ends so the reader may reset his or her finger on the subsequent line. Current procedures for teaching line tracking are incomplete, because they focus on tracking lines with only…

Examining a Higher Education Funding Formula in a Time of Shifting Currents: Kentucky's Benchmark Approach

ERIC Educational Resources Information Center

Wall, Andrew; Frost, Robert; Smith, Ryan; Keeling, Richard

2008-01-01

Although datasets such as the Integrated Postsecondary Data System are available as inputs to higher education funding formulas, these datasets can be unreliable, incomplete, or unresponsive to criteria identified by state education officials. State formulas do not always match the state's economic and human capital goals. This article analyzes…

Juvenile skeletogenesis in anciently diverged sea urchin clades.

PubMed

Gao, Feng; Thompson, Jeffrey R; Petsios, Elizabeth; Erkenbrack, Eric; Moats, Rex A; Bottjer, David J; Davidson, Eric H

2015-04-01

Mechanistic understanding of evolutionary divergence in animal body plans devolves from analysis of those developmental processes that, in forms descendant from a common ancestor, are responsible for their morphological differences. The last common ancestor of the two extant subclasses of sea urchins, i.e., euechinoids and cidaroids, existed well before the Permian/Triassic extinction (252 mya). Subsequent evolutionary divergence of these clades offers in principle a rare opportunity to solve the developmental regulatory events underlying a defined evolutionary divergence process. Thus (i) there is an excellent and fairly dense (if yet incompletely analyzed) fossil record; (ii) cladistically confined features of the skeletal structures of modern euechinoid and cidaroid sea urchins are preserved in fossils of ancestral forms; (iii) euechinoids and cidaroids are among current laboratory model systems in molecular developmental biology (here Strongylocentrotus purpuratus [Sp] and Eucidaris tribuloides [Et]); (iv) skeletogenic specification in sea urchins is uncommonly well understood at the causal level of interactions of regulatory genes with one another, and with known skeletogenic effector genes, providing a ready arsenal of available molecular tools. Here we focus on differences in test and perignathic girdle skeletal morphology that distinguish all modern euechinoid from all modern cidaroid sea urchins. We demonstrate distinct canonical test and girdle morphologies in juveniles of both species by use of SEM and X-ray microtomography. Among the sharply distinct morphological features of these clades are the internal skeletal structures of the perignathic girdle to which attach homologous muscles utilized for retraction and protraction of Aristotles׳ lantern and its teeth. We demonstrate that these structures develop de novo between one and four weeks after metamorphosis. In order to study the underlying developmental processes, a method of section whole mount in situ hybridization was adapted. This method displays current gene expression in the developing test and perignathic girdle skeletal elements of both Sp and Et juveniles. Active, specific expression of the sm37 biomineralization gene in these muscle attachment structures accompanies morphogenetic development of these clade-specific features in juveniles of both species. Skeletogenesis at these clade-specific muscle attachment structures displays molecular earmarks of the well understood embryonic skeletogenic GRN: thus the upstream regulatory gene alx1 and the gene encoding the vegfR signaling receptor are both expressed at the sites where they are formed. This work opens the way to analysis of the alternative spatial specification processes that were installed at the evolutionary divergence of the two extant subclasses of sea urchins. Copyright © 2015 Elsevier Inc. All rights reserved.

A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies.

PubMed

Orr, Miranda E; Sullivan, A Campbell; Frost, Bess

2017-07-01

There are currently no disease-modifying therapies for the treatment of tauopathies, a group of progressive neurodegenerative disorders that are pathologically defined by the presence of tau protein aggregates in the brain. Current challenges for the treatment of tauopathies include the inability to diagnose early and to confidently discriminate between distinct tauopathies in patients, alongside an incomplete understanding of the cellular mechanisms involved in pathogenic tau-induced neuronal death and dysfunction. In this review, we describe current diagnostic and therapeutic strategies, known drivers of pathogenic tau formation, recent contributions to our current mechanistic understanding of how pathogenic tau induces neuronal death, and potential diagnostic and therapeutic approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

Active lamp pulse driver circuit. [optical pumping of laser media

NASA Technical Reports Server (NTRS)

Logan, K. E. (Inventor)

1983-01-01

A flashlamp drive circuit is described which uses an unsaturated transistor as a current mode switch to periodically subject a partially ionized gaseous laser excitation flashlamp to a stable, rectangular pulse of current from an incomplete discharge of an energy storage capacitor. A monostable multivibrator sets the pulse interval, initiating the pulse in response to a flash command by providing a reference voltage to a non-inverting terminal of a base drive amplifier; a tap on an emitter resistor provides a feedback signal sensitive to the current amplitude to an inverting terminal of amplifier, thereby controlling the pulse amplitude. The circuit drives the flashlamp to provide a squarewave current flashlamp discharge.

Cost-Effectiveness of Blood Donation Screening for Trypanosoma cruzi in Mexico

PubMed Central

Sánchez-González, Gilberto; Figueroa-Lara, Alejandro; Elizondo-Cano, Miguel; Wilson, Leslie; Novelo-Garza, Barbara; Valiente-Banuet, Leopoldo; Ramsey, Janine M.

2016-01-01

An estimated 2 million inhabitants are infected with Chagas disease in Mexico, with highest prevalence coinciding with highest demographic density in the southern half of the country. After vector-borne transmission, Trypanosoma cruzi is principally transmitted to humans via blood transfusion. Despite initiation of serological screening of blood donations or donors for T. cruzi since 1990 in most Latin American countries, Mexico only finally included mandatory serological screening nationwide in official Norms in 2012. Most recent regulatory changes and segmented blood services in Mexico may affect compliance of mandatory screening guidelines. The objective of this study was to calculate the incremental cost-effectiveness ratio for total compliance of current guidelines from both Mexican primary healthcare and regular salaried worker health service institutions: the Secretary of Health and the Mexican Institute for Social Security. We developed a bi-modular model to analyze compliance using a decision tree for the most common screening algorithms for each health institution, and a Markov transition model for the natural history of illness and care. The incremental cost effectiveness ratio based on life-years gained is US$ 383 for the Secretary of Health, while the cost for an additional life-year gained is US$ 463 for the Social Security Institute. The results of the present study suggest that due to incomplete compliance of Mexico’s national legislation during 2013 and 2014, the MoH has failed to confirm 15,162 T. cruzi infections, has not prevented 2,347 avoidable infections, and has lost 333,483 life-years. Although there is a vast difference in T. cruzi prevalence between Bolivia and Mexico, Bolivia established mandatory blood screening for T.cruzi in 1996 and until 2002 detected and discarded 11,489 T. cruzi -infected blood units and prevented 2,879 potential infections with their transfusion blood screening program. In the first two years of Mexico’s mandated program, the two primary institutions failed to prevent due to incomplete compliance more potential infections than those gained from the first five years of Bolivia’s program. Full regulatory compliance should be clearly understood as mandatory for the sake of blood security, and its monitoring and analysis in Mexico should be part of the health authority’s responsibility. PMID:27002523

A flexible acquisition cycle for incompletely defined fieldbus protocols.

PubMed

Gaitan, Vasile-Gheorghita; Gaitan, Nicoleta-Cristina; Ungurean, Ioan

2014-05-01

Real time data-acquisition from fieldbuses strongly depends on the network type and protocol used. Currently, there is an impressive number of fieldbuses, some of them are completely defined and others are incompletely defined. In those from the second category, the time variable, the main element in real-time data acquisition, does not appear explicitly. Examples include protocols such as Modbus ASCII/RTU, M-bus, ASCII character-based, and so on. This paper defines a flexible acquisition cycle based on the Master-Slave architecture that can be implemented on a Master station, called a Base Station Gateway (BSG). The BSG can add a timestamp for temporal location of data. It also presents a possible extension for the Modbus protocol, developed as simple and low cost solution based on existing hardware. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

High expression of A-type lamin in the leading front is required for Drosophila thorax closure.

PubMed

Kosakamoto, Hina; Fujisawa, Yuya; Obata, Fumiaki; Miura, Masayuki

2018-05-05

Tissue closure involves the coordinated unidirectional movement of a group of cells without loss of cell-cell contact. However, the molecular mechanisms controlling the tissue closure are not fully understood. Here, we demonstrate that Lamin C, the sole A-type lamin in Drosophila, contributes to the process of thorax closure in pupa. High expression of Lamin C was observed at the leading front of the migrating wing imaginal discs. Live imaging analysis revealed that knockdown of Lamin C in the thorax region affected the coordinated movement of the leading front, resulting in incomplete tissue fusion required for formation of the adult thorax. The closure defect due to knockdown of Lamin C correlated with insufficient accumulation of F-actin at the front. Our study indicates a link between A-type lamin and the cell migration behavior during tissue closure. Copyright © 2018 Elsevier Inc. All rights reserved.

Antibiotic-induced changes in the microbiota disrupt redox dynamics in the gut

PubMed Central

Reese, Aspen T; Cho, Eugenia H; Klitzman, Bruce; Nichols, Scott P; Wisniewski, Natalie A; Villa, Max M; Durand, Heather K; Jiang, Sharon; Midani, Firas S; Nimmagadda, Sai N; O'Connell, Thomas M; Wright, Justin P; Deshusses, Marc A

2018-01-01

How host and microbial factors combine to structure gut microbial communities remains incompletely understood. Redox potential is an important environmental feature affected by both host and microbial actions. We assessed how antibiotics, which can impact host and microbial function, change redox state and how this contributes to post-antibiotic succession. We showed gut redox potential increased within hours of an antibiotic dose in mice. Host and microbial functioning changed under treatment, but shifts in redox potentials could be attributed specifically to bacterial suppression in a host-free ex vivo human gut microbiota model. Redox dynamics were linked to blooms of the bacterial family Enterobacteriaceae. Ecological succession to pre-treatment composition was associated with recovery of gut redox, but also required dispersal from unaffected gut communities. As bacterial competition for electron acceptors can be a key ecological factor structuring gut communities, these results support the potential for manipulating gut microbiota through managing bacterial respiration. PMID:29916366

Hyaline-Vascular Type Castleman's Disease, Sarcoidosis, and Crohns Disease.

PubMed

Gupta, Arjun; Ayyar, Balaji; Zia, Hamid; Chen, Weina; Harris, Samar; Naina, Harris V

2016-06-01

Sarcoidosis and Crohns disease have been associated with increased long term risk of lymphoproliferative disorders, including lymphomas. Newly developed lymphadenopathy in a patient with these disorders should prompt pathological evaluation. Castleman's disease is a lymphoproliferative disorder characterized by enlarged hyperplastic lymph nodes with regressed follicles surrounded by expanded mantle zones of small lymphocytes, and interfollicular vascular proliferation in the hyaline-vascular type. Similar to sarcoidosis and Crohns disease, its etiology is incompletely understood, although immune dysregulation, genetic factors and infectious and environmental factors are thought to play a role in all three diseases. Interleukin-6 is a possible pathological common factor between these three disease processed. Unicentric, hyaline-vascular type Castleman's disease can be treated successfully with complete surgical resection. We report a patient with long history of sarcoidosis and Crohns disease with newly developed lymphadenopathy which was found to be due to Castleman's disease.

Cardiac myofilaments: mechanics and regulation

NASA Technical Reports Server (NTRS)

de Tombe, Pieter P.; Bers, D. M. (Principal Investigator)

2003-01-01

The mechanical properties of the cardiac myofilament are an important determinant of pump function of the heart. This report is focused on the regulation of myofilament function in cardiac muscle. Calcium ions form the trigger that induces activation of the thin filament which, in turn, allows for cross-bridge formation, ATP hydrolysis, and force development. The structure and protein-protein interactions of the cardiac sarcomere that are responsible for these processes will be reviewed. The molecular mechanism that underlies myofilament activation is incompletely understood. Recent experimental approaches have been employed to unravel the mechanism and regulation of myofilament mechanics and energetics by activator calcium and sarcomere length, as well as contractile protein phosphorylation mediated by protein kinase A. Central to these studies is the question whether such factors impact on muscle function simply by altering thin filament activation state, or whether modulation of cross-bridge cycling also plays a part in the responses of muscle to these stimuli.

The origin, function, and diagnostic potential of extracellular microRNAs in human body fluids.

PubMed

Liang, Hongwei; Gong, Fei; Zhang, Suyang; Zhang, Chen-Yu; Zen, Ke; Chen, Xi

2014-01-01

Recently, numerous studies have documented the importance of microRNAs (miRNAs) as an essential cornerstone of the genetic system. Although RNA is usually considered an unstable molecule because of the ubiquitous ribonuclease, miRNAs are now known to circulate in the bloodstream and other body fluids in a stable, cell-free form. Importantly, extracellular miRNAs are aberrantly present in plasma, serum, and other body fluids during the pathogenesis of many diseases and, thus, are promising noninvasive or minimally invasive biomarkers to assess the pathological status of the body. However, the origin and biological function of extracellular miRNAs remains incompletely understood. In this review, we summarize the recent literature on the biogenesis and working models of extracellular miRNAs, and we highlight the impact of extending these ongoing extracellular miRNA studies to clinical applications. © 2013 John Wiley & Sons, Ltd.

Glaucoma surgery and induced astigmatism: a systematic review.

PubMed

Chan, Helen H L; Kong, Yu Xiang G

2017-01-01

The refractive outcomes of glaucoma surgeries, particularly their effect on astigmatism, are incompletely understood. Trabeculectomy is associated with a considerable amount of with-the-rule astigmatic change in the immediate postoperative period. This is followed by a gradual against-the-rule shift. These changes are altered with the use of mitomycin C (MMC). Non-penetrating surgery such as deep sclerectomy is also associated with a similar or smaller degree of induced astigmatism. Minimally invasive glaucoma surgery appears to be astigmatically neutral. There is no clear evidence regarding refractive outcomes of glaucoma drainage device surgery. Induced astigmatism may account for a reduction in unaided visual acuity in the early postoperative period following a successful trabeculectomy. These changes appear to stabilise at 3 months, and it would be prudent to defer the prescription of new glasses until this time. If sequential cataract surgery is to be performed, toric intraocular lenses can be a useful option for astigmatic correction.

Decision Making: from Neuroscience to Psychiatry

PubMed Central

Lee, Daeyeol

2013-01-01

Adaptive behaviors increase the likelihood of survival and reproduction and improve the quality of life. However, it is often difficult to identify optimal behaviors in real life due to the complexity of the decision maker’s environment and social dynamics. As a result, although many different brain areas and circuits are involved in decision making, evolutionary and learning solutions adopted by individual decision makers sometimes produce suboptimal outcomes. Although these problems are exacerbated in numerous neurological and psychiatric disorders, their underlying neurobiological causes remain incompletely understood. In this review, theoretical frameworks in economics and machine learning and their applications in recent behavioral and neurobiological studies are summarized. Examples of such applications in clinical domains are also discussed for substance abuse, Parkinson’s disease, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, and autism. Findings from these studies have begun to lay the foundations necessary to improve diagnostics and treatment for various neurological and psychiatric disorders. PMID:23622061

Poreless eggshells

PubMed Central

Lin, Haifan; Matzuk, Martin M.

2015-01-01

The oocyte is the sole source of the female genetic material that will be fertilized by sperm to form an embryo. Many extrinsic and intrinsic factors are critical for oocyte development and survival; however, these mediators are incompletely understood. In this issue of the JCI, Weinberg-Shukron et al. uncover a novel recessive missense mutation in the gene encoding nucleoporin-107 (NUP107) that results in abnormal ovarian development. Recapitulation of the human mutation in the Drosophila NUP107 ortholog resulted in poor follicular development and demonstrated an evolutionarily conserved and ovary-specific role of NUP107. While NUP107 is required for nuclear pore complex function in somatic cells of flies and women, this specific amino acid change appears only to be disruptive in the ovary. All together, these findings imply that missense mutations in other genes could be specifically disruptive of ovarian or testicular function, while leaving extragonadal function intact. PMID:26485282

Aquaporins-2 and -4 regulate glycogen metabolism and survival during hyposmotic-anoxic stress in Caenorhabditis elegans

PubMed Central

LaMacchia, John C.

2015-01-01

Periods of oxygen deprivation can lead to ion and water imbalances in affected tissues that manifest as swelling (edema). Although oxygen deprivation-induced edema is a major contributor to injury in clinical ischemic diseases such as heart attack and stroke, the pathophysiology of this process is incompletely understood. In the present study we investigate the impact of aquaporin-mediated water transport on survival in a Caenorhabditis elegans model of edema formation during complete oxygen deprivation (anoxia). We find that nematodes lacking aquaporin water channels in tissues that interface with the surrounding environment display decreased edema formation and improved survival rates in anoxia. We also find that these animals have significantly reduced demand for glycogen as an energetic substrate during anoxia. Together, our data suggest that reductions in membrane water permeability may be sufficient to induce a hypometabolic state during oxygen deprivation that reduces injury and extends survival limits. PMID:26017147

Therapeutic targeting of HES1 transcriptional programs in T-ALL

PubMed Central

Schnell, Stephanie A.; Ambesi-Impiombato, Alberto; Sanchez-Martin, Marta; Belver, Laura; Xu, Luyao; Qin, Yue; Kageyama, Ryoichiro

2015-01-01

Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival. Mechanistically, we demonstrate that HES1 directly downregulates the expression of BBC3, the gene encoding the PUMA BH3-only proapoptotic factor in T-cell acute lymphoblastic leukemia. Finally, we identify perhexiline, a small-molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1-induced leukemias in vitro and in vivo. PMID:25784680

Adenosine and Ischemic Preconditioning

PubMed Central

Liang, Bruce T.; Swierkosz, Tomasz A.; Herrmann, Howard C.; Kimmel, Stephen; Jacobson, Kenneth A.

2012-01-01

Adenosine is released in large amounts during myocardial ischemia and is capable of exerting potent cardioprotective effects in the heart. Although these observations on adenosine have been known for a long time, how adenosine acts to achieve its anti-ischemic effect remains incompletely understood. However, recent advances on the chemistry and pharmacology of adenosine receptor ligands have provided important and novel information on the function of adenosine receptor subtypes in the cardiovascular system. The development of model systems for the cardiac actions of adenosine has yielded important insights into its mechanism of action and have begun to elucidate the sequence of signalling events from receptor activation to the actual exertion of its cardioprotective effect. The present review will focus on the adenosine receptors that mediate the potent anti-ischemic effect of adenosine, new ligands at the receptors, potential molecular signalling mechanisms downstream of the receptor, mediators for cardioprotection, and possible clinical applications in cardiovascular disorders. PMID:10607860

Poroelastic Mechanical Effects of Hemicelluloses on Cellulosic Hydrogels under Compression

PubMed Central

Lopez-Sanchez, Patricia; Cersosimo, Julie; Wang, Dongjie; Flanagan, Bernadine; Stokes, Jason R.; Gidley, Michael J.

2015-01-01

Hemicelluloses exhibit a range of interactions with cellulose, the mechanical consequences of which in plant cell walls are incompletely understood. We report the mechanical properties of cell wall analogues based on cellulose hydrogels to elucidate the contribution of xyloglucan or arabinoxylan as examples of two hemicelluloses displaying different interactions with cellulose. We subjected the hydrogels to mechanical pressures to emulate the compressive stresses experienced by cell walls in planta. Our results revealed that the presence of either hemicellulose increased the resistance to compression at fast strain rates. However, at slow strain rates, only xyloglucan increased composite strength. This behaviour could be explained considering the microstructure and the flow of water through the composites confirming their poroelastic nature. In contrast, small deformation oscillatory rheology showed that only xyloglucan decreased the elastic moduli. These results provide evidence for contrasting roles of different hemicelluloses in plant cell wall mechanics and man-made cellulose-based composite materials. PMID:25794048

Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587.

PubMed

Figueroa, Javier; Phillips, Lynette M; Shahar, Tal; Hossain, Anwar; Gumin, Joy; Kim, Hoon; Bean, Andrew J; Calin, George A; Fueyo, Juan; Walters, Edgar T; Kalluri, Raghu; Verhaak, Roel G; Lang, Frederick F

2017-11-01

Tumor-stromal communications impact tumorigenesis in ways that are incompletely understood. Here, we show that glioma-associated human mesenchymal stem cells (GA-hMSC), a newly identified stromal component of glioblastoma, release exosomes that increase the proliferation and clonogenicity of tumor-initiating glioma stem-like cells (GSC). This event leads to a significantly greater tumor burden and decreased host survival compared with untreated GSCs in orthotopic xenografts. Analysis of the exosomal content identified miR-1587 as a mediator of the exosomal effects on GSCs, in part via downregulation of the tumor-suppressive nuclear receptor corepressor NCOR1. Our results illuminate the tumor-supporting role for GA-hMSCs by identifying GA-hMSC-derived exosomes in the intercellular transfer of specific miRNA that enhance the aggressiveness of glioblastoma. Cancer Res; 77(21); 5808-19. ©2017 AACR . ©2017 American Association for Cancer Research.

Protective Efficacy of Serially Up-Ranked Subdominant CD8+ T Cell Epitopes against Virus Challenges

PubMed Central

Roshorm, Yaowaluck; Bridgeman, Anne; Létourneau, Sven; Liljeström, Peter; Potash, Mary Jane; Volsky, David J.; McMichael, Andrew J.; Hanke, Tomáš

2011-01-01

Immunodominance in T cell responses to complex antigens like viruses is still incompletely understood. Some data indicate that the dominant responses to viruses are not necessarily the most protective, while other data imply that dominant responses are the most important. The issue is of considerable importance to the rational design of vaccines, particularly against variable escaping viruses like human immunodeficiency virus type 1 and hepatitis C virus. Here, we showed that sequential inactivation of dominant epitopes up-ranks the remaining subdominant determinants. Importantly, we demonstrated that subdominant epitopes can induce robust responses and protect against whole viruses if they are allowed at least once in the vaccination regimen to locally or temporally dominate T cell induction. Therefore, refocusing T cell immune responses away from highly variable determinants recognized during natural virus infection towards subdominant, but conserved regions is possible and merits evaluation in humans. PMID:21625575

Bacterial pneumonia as an influenza complication.

PubMed

Martin-Loeches, Ignacio; van Someren Gréve, Frank; Schultz, Marcus J

2017-04-01

The pathogenesis and impact of coinfection, in particular bacterial coinfection, in influenza are incompletely understood. This review summarizes results from studies on bacterial coinfection in the recent pandemic influenza outbreak. Systemic immune mechanisms play a key role in the development of coinfection based on the complexity of the interaction of the host and the viral and bacterial pathogens. Several studies were performed to determine the point prevalence of bacterial coinfection in influenza. Coinfection in influenza is frequent in critically ill patients with Streptococcus pneumoniae being the most frequent bacterial pathogen and higher rates of potentially resistant pathogens over the years. Bacterial pneumonia is certainly an influenza complication. The recent epidemiology findings have helped to partially resolve the contribution of different pathogens. Immunosuppression is a risk factor for bacterial coinfection in influenza, and the epidemiology of coinfection has changed over the years during the last influenza pandemic, and these recent findings should be taken into account during present outbreaks.

Lack of involvement of lipocortin 1 in dexamethasone suppression of IL-1 release

PubMed Central

Rickard, D.; Goulding, N. J.

1993-01-01

The annexin lipocortin 1 is reported to mediate some anti-inflammatory effects of glucocorticoids, but the mechanisms of this mediation are incompletely understood. The involvement of lipocortin 1 in glucocorticoid inhibition of monocyte interleukin 1β (IL-1β) release has been investigated. Treatment of peripheral blood monocytes with 2 μg/ml lipopolysaccharide potently increased IL–1β release (p = 0.001) and dexamethasone (10−7 M) significantly reduced both resting and stimulated IL-1β release (p = 0.009). A neutralizing monoclonal antibody to lipocortin 1 (0.5–50.0 μg/ml) was unable to inhibit this effect and recombinant lipocortin 1 (2 × 10−6 M) and 188aa lipocortin 1 fragment (10−8−10−6 M) had no effect. It is concluded that lipocortin 1 is not involved in the inhibition of monocyte IL-1β release by glucocorticoids. PMID:18475502

Identification of genetic elements in metabolism by high-throughput mouse phenotyping.

PubMed

Rozman, Jan; Rathkolb, Birgit; Oestereicher, Manuela A; Schütt, Christine; Ravindranath, Aakash Chavan; Leuchtenberger, Stefanie; Sharma, Sapna; Kistler, Martin; Willershäuser, Monja; Brommage, Robert; Meehan, Terrence F; Mason, Jeremy; Haselimashhadi, Hamed; Hough, Tertius; Mallon, Ann-Marie; Wells, Sara; Santos, Luis; Lelliott, Christopher J; White, Jacqueline K; Sorg, Tania; Champy, Marie-France; Bower, Lynette R; Reynolds, Corey L; Flenniken, Ann M; Murray, Stephen A; Nutter, Lauryl M J; Svenson, Karen L; West, David; Tocchini-Valentini, Glauco P; Beaudet, Arthur L; Bosch, Fatima; Braun, Robert B; Dobbie, Michael S; Gao, Xiang; Herault, Yann; Moshiri, Ala; Moore, Bret A; Kent Lloyd, K C; McKerlie, Colin; Masuya, Hiroshi; Tanaka, Nobuhiko; Flicek, Paul; Parkinson, Helen E; Sedlacek, Radislav; Seong, Je Kyung; Wang, Chi-Kuang Leo; Moore, Mark; Brown, Steve D; Tschöp, Matthias H; Wurst, Wolfgang; Klingenspor, Martin; Wolf, Eckhard; Beckers, Johannes; Machicao, Fausto; Peter, Andreas; Staiger, Harald; Häring, Hans-Ulrich; Grallert, Harald; Campillos, Monica; Maier, Holger; Fuchs, Helmut; Gailus-Durner, Valerie; Werner, Thomas; Hrabe de Angelis, Martin

2018-01-18

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.

APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages

PubMed Central

Sharma, Shraddha; Patnaik, Santosh K.; Thomas Taggart, R.; Kannisto, Eric D.; Enriquez, Sally M.; Gollnick, Paul; Baysal, Bora E.

2015-01-01

The extent, regulation and enzymatic basis of RNA editing by cytidine deamination are incompletely understood. Here we show that transcripts of hundreds of genes undergo site-specific C>U RNA editing in macrophages during M1 polarization and in monocytes in response to hypoxia and interferons. This editing alters the amino acid sequences for scores of proteins, including many that are involved in pathogenesis of viral diseases. APOBEC3A, which is known to deaminate cytidines of single-stranded DNA and to inhibit viruses and retrotransposons, mediates this RNA editing. Amino acid residues of APOBEC3A that are known to be required for its DNA deamination and anti-retrotransposition activities were also found to affect its RNA deamination activity. Our study demonstrates the cellular RNA editing activity of a member of the APOBEC3 family of innate restriction factors and expands the understanding of C>U RNA editing in mammals. PMID:25898173

Neurons for hunger and thirst transmit a negative-valence teaching signal.

PubMed

Betley, J Nicholas; Xu, Shengjin; Cao, Zhen Fang Huang; Gong, Rong; Magnus, Christopher J; Yu, Yang; Sternson, Scott M

2015-05-14

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.

CaMKII in Vascular Signalling: "Friend or Foe"?

PubMed

Ebenebe, Obialunanma V; Heather, Alison; Erickson, Jeffrey R

2018-05-01

Signalling mechanisms within and between cells of the vasculature enable function and maintain homeostasis. However, a number of these mechanisms also contribute to the pathophysiology of vascular disease states. The multifunctional signalling molecule calcium/calmodulin-dependent kinase II (CaMKII) has been shown to have critical functional effects in many tissue types. For example, CaMKII is known to have a dual role in cardiac physiology and pathology. The function of CaMKII within the vasculature is incompletely understood, but emerging evidence points to potential physiological and pathological roles. This review discusses the evidence for CaMKII signalling within the vasculature, with the aim to better understand both positive and potentially deleterious effects of CaMKII activation in vascular tissue. Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Poroelastic mechanical effects of hemicelluloses on cellulosic hydrogels under compression.

PubMed

Lopez-Sanchez, Patricia; Cersosimo, Julie; Wang, Dongjie; Flanagan, Bernadine; Stokes, Jason R; Gidley, Michael J

2015-01-01

Hemicelluloses exhibit a range of interactions with cellulose, the mechanical consequences of which in plant cell walls are incompletely understood. We report the mechanical properties of cell wall analogues based on cellulose hydrogels to elucidate the contribution of xyloglucan or arabinoxylan as examples of two hemicelluloses displaying different interactions with cellulose. We subjected the hydrogels to mechanical pressures to emulate the compressive stresses experienced by cell walls in planta. Our results revealed that the presence of either hemicellulose increased the resistance to compression at fast strain rates. However, at slow strain rates, only xyloglucan increased composite strength. This behaviour could be explained considering the microstructure and the flow of water through the composites confirming their poroelastic nature. In contrast, small deformation oscillatory rheology showed that only xyloglucan decreased the elastic moduli. These results provide evidence for contrasting roles of different hemicelluloses in plant cell wall mechanics and man-made cellulose-based composite materials.

Opportunities in proteomics to understand hepatitis C and HIV coinfection.

PubMed

Meissner, Eric G; Suffredini, Anthony F; Kottilil, Shyamasundaran

2012-08-01

Antiretroviral therapy has significantly reduced morbidity and mortality associated with HIV infection. However, coinfection with HCV results in a more complicated disease course for both infections. HIV infection dramatically impacts the natural history of chronic liver disease due to HCV. Coinfected patients not on antiretroviral therapy for HIV develop liver fibrosis and cirrhosis at a faster rate, clear acute infection less commonly and respond to IFN-α-based therapy for chronic infection less often than HCV-monoinfected patients. The interaction between these two viruses, the immune system and the fibrotic machinery of the liver remains incompletely understood. In this review, we discuss recent advances in proteomics as applied to HCV and HIV and highlight issues in coinfection that are amenable to further discovery through proteomic approaches. We focus on clinical predictors of liver fibrosis and treatment outcome as these have the greatest potential clinical applicability.

Essential role for fibrillin-2 in zebrafish notochord and vascular morphogenesis.

PubMed

Gansner, John M; Madsen, Erik C; Mecham, Robert P; Gitlin, Jonathan D

2008-10-01

Recent studies demonstrate that lysyl oxidase cuproenzymes are critical for zebrafish notochord formation, but the molecular mechanisms of copper-dependent notochord morphogenesis are incompletely understood. We, therefore, conducted a forward genetic screen for zebrafish mutants that exhibit notochord sensitivity to lysyl oxidase inhibition, yielding a mutant with defects in notochord and vascular morphogenesis, puff daddygw1 (pfdgw1). Meiotic mapping and cloning reveal that the pfdgw1 phenotype results from disruption of the gene encoding the extracellular matrix protein fibrillin-2, and the spatiotemporal expression of fibrillin-2 is consistent with the pfdgw1 phenotype. Furthermore, each aspect of the pfdgw1 phenotype is recapitulated by morpholino knockdown of fibrillin-2. Taken together, the data reveal a genetic interaction between fibrillin-2 and the lysyl oxidases in notochord formation and demonstrate the importance of fibrillin-2 in specific early developmental processes in zebrafish. Copyright (c) 2008 Wiley-Liss, Inc.

Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle.

PubMed

Barrientos, Tomasa; Laothamatas, Indira; Koves, Timothy R; Soderblom, Erik J; Bryan, Miles; Moseley, M Arthur; Muoio, Deborah M; Andrews, Nancy C

2015-11-01

Transferrin receptor (Tfr1) is ubiquitously expressed, but its roles in non-hematopoietic cells are incompletely understood. We used a tissue-specific conditional knockout strategy to ask whether skeletal muscle required Tfr1 for iron uptake. We found that iron assimilation via Tfr1 was critical for skeletal muscle metabolism, and that iron deficiency in muscle led to dramatic changes, not only in muscle, but also in adipose tissue and liver. Inactivation of Tfr1 incapacitated normal energy production in muscle, leading to growth arrest and a muted attempt to switch to fatty acid β oxidation, using up fat stores. Starvation signals stimulated gluconeogenesis in the liver, but amino acid substrates became limiting and hypoglycemia ensued. Surprisingly, the liver was also iron deficient, and production of the iron regulatory hormone hepcidin was depressed. Our observations reveal a complex interaction between iron homeostasis and metabolism that has implications for metabolic and iron disorders.

Region effects influence local tree species diversity.

PubMed

Ricklefs, Robert E; He, Fangliang

2016-01-19

Global patterns of biodiversity reflect both regional and local processes, but the relative importance of local ecological limits to species coexistence, as influenced by the physical environment, in contrast to regional processes including species production, dispersal, and extinction, is poorly understood. Failure to distinguish regional influences from local effects has been due, in part, to sampling limitations at small scales, environmental heterogeneity within local or regional samples, and incomplete geographic sampling of species. Here, we use a global dataset comprising 47 forest plots to demonstrate significant region effects on diversity, beyond the influence of local climate, which together explain more than 92% of the global variation in local forest tree species richness. Significant region effects imply that large-scale processes shaping the regional diversity of forest trees exert influence down to the local scale, where they interact with local processes to determine the number of coexisting species.

Depression, Stress, and Anhedonia: Toward a Synthesis and Integrated Model

PubMed Central

Pizzagalli, Diego A.

2014-01-01

Depression is a significant public health problem, but its etiology and pathophysiology remain poorly understood. Such incomplete understanding likely arises from the fact that depression encompasses a heterogeneous set of disorders. To overcome these limitations, renewed interest in intermediate phenotypes (endophenotypes) has resurfaced, and anhedonia has emerged as one of the most promising endophenotypes of depression. Here, a heuristic model is presented postulating that anhedonia arises from dysfunctional interactions between stress and brain reward systems. To this end, we review and integrate three bodies of independent literature investigating the role of (1) anhedonia, (2) dopamine, and (3) stress in depression. In a fourth section, we summarize animal data indicating that stress negatively affect mesocorticolimbic dopaminergic pathways critically implicated in incentive motivation and reinforcement learning. In the last section, we provide a synthesis of these four literatures, present initial evidence consistent with our model, and discuss directions for future research. PMID:24471371

Biological roles of cysteine proteinases in the pathogenesis of Trichomonas vaginalis

PubMed Central

Hernández, Hilda M.; Marcet, Ricardo; Sarracent, Jorge

2014-01-01

Human trichomonosis, infection with Trichomonas vaginalis, is the most common non-viral sexually transmitted disease in the world. The host-parasite interaction and pathophysiological processes of trichomonosis remain incompletely understood. This review focuses on the advancements reached in the area of the pathogenesis of T. vaginalis, especially in the role of the cysteine proteinases. It highlights various approaches made in this field and lists a group of trichomonad cysteine proteinases involved in diverse processes such as invasion of the mucous layer, cytoadherence, cytotoxicity, cytoskeleton disruption of red blood cells, hemolysis, and evasion of the host immune response. A better understanding of the biological roles of cysteine proteinases in the pathogenesis of this parasite could be used in the identification of new chemotherapeutic targets. An additional advantage could be the development of a vaccine in order to reduce transmission of T. vaginalis. PMID:25348828

Zinc and Zinc Transporters: Novel Regulators of Ventricular Myocardial Development.

PubMed

Lin, Wen; Li, Deqiang

2018-06-01

Ventricular myocardial development is a well-orchestrated process involving different cardiac structures, multiple signal pathways, and myriad proteins. Dysregulation of this important developmental event can result in cardiomyopathies, such as left ventricle non-compaction, which affect the pediatric population and the adults. Human and mouse studies have shed light upon the etiology of some cardiomyopathy cases and highlighted the contribution of both genetic and environmental factors. However, the regulation of ventricular myocardial development remains incompletely understood. Zinc is an essential trace metal with structural, enzymatic, and signaling function. Perturbation of zinc homeostasis has resulted in developmental and physiological defects including cardiomyopathy. In this review, we summarize several mechanisms by which zinc and zinc transporters can impact the regulation of ventricular myocardial development. Based on our review, we propose that zinc deficiency and mutations of zinc transporters may underlie some cardiomyopathy cases especially those involving ventricular myocardial development defects.

Regulation of anoikis by Deleted in Breast Cancer-1 (DBC1) through NF-κB

PubMed Central

Park, Sun Hee; Riley, Philip; Frisch, Steven M

2013-01-01

Anoikis-resistance of tumor cells is critical for anchorage-independent growth and metastasis. The inflammatory-response transcription factor NF-κB contributes to anoikis-resistance and tumor progression through mechanisms that are understood incompletely. Deleted in Breast Cancer-1 protein (KIAA1967) is over-expressed in several tumor types, and correlates with a poorer prognosis in some cases. We report here that DBC1 suppressed anoikis in normal epithelial and breast cancer cell lines. DBC1 interacted with IKK-β, stimulating its kinase activity, promoting NF-κB transcriptional activity through the phosphorylation of relA serine-536 and enhancing the expression of the NF-κB target genes, c-FLIP and bcl-xl. Our results indicate that DBC1 is an important co-factor for the control of the IKK-β-NF-κB signaling pathway that regulates anoikis. PMID:23588592

New findings on venous thrombogenesis

PubMed Central

Byrnes, James R.; Wolberg, Alisa S.

2017-01-01

Summary Venous thrombosis (VT) is the third most common cause of cardiovascular death worldwide. Complications from VT and pulmonary embolism are the leading cause of lost disability-adjusted life years. Risks include genetic (e.g., non-O blood group, activated protein C resistance, hyperprothrombinemia) and acquired (e.g., age, surgery, cancer, pregnancy, immobilisation, female hormone use) factors. Pathophysiologic mechanisms that promote VT are incompletely understood, but involve abnormalities in blood coagulability, vessel function, and flow (so-called Virchow’s Triad). Epidemiologic studies of humans, animal models, and biochemical and biophysical investigations have revealed contributions from extrinsic, intrinsic, and common pathways of coagulation, endothelial cells, leukocytes, red blood cells, platelets, cell-derived microvesicles, stasis-induced changes in vascular cells, and blood rheology. Knowledge of these mechanisms may yield new therapeutic targets. Characterisation of mechanisms that mediate VT formation and stability, particularly in aging, are needed to advance understanding of VT. PMID:27878206

Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease

PubMed Central

Uderhardt, Stefan; Ackermann, Jochen A.; Fillep, Tobias; Hammond, Victoria J.; Willeit, Johann; Stark, Konstantin; Rossaint, Jan; Schubert, Irene; Mielenz, Dirk; Dietel, Barbara; Raaz-Schrauder, Dorette; Ay, Cihan; Thaler, Johannes; Heim, Christian; Collins, Peter W.; Schabbauer, Gernot; Mackman, Nigel; Voehringer, David; Nadler, Jerry L.; Lee, James J.; Massberg, Steffen; Rauh, Manfred; O’Donnell, Valerie B.

2017-01-01

Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase–derived hydroxyeicosatetraenoic acid–phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease. PMID:28566277

Mitochondria localize to injured axons to support regeneration

PubMed Central

Han, Sung Min; Baig, Huma S.; Hammarlund, Marc

2016-01-01

SUMMARY Axon regeneration is essential to restore the nervous system after axon injury. However, the neuronal cell biology that underlies axon regeneration is incompletely understood. Here we use in vivo single-neuron analysis to investigate the relationship between nerve injury, mitochondrial localization, and axon regeneration. Mitochondria translocate into injured axons, so that average mitochondria density increases after injury. Moreover, single-neuron analysis reveals that axons that fail to increase mitochondria have poor regeneration. Experimental alterations to axonal mitochondrial distribution or mitochondrial respiratory chain function result in corresponding changes to regeneration outcomes. Axonal mitochondria are specifically required for growth cone migration, identifying a key energy challenge for injured neurons. Finally, mitochondrial localization to the axon after injury is regulated in part by dual-leucine zipper kinase-1 (DLK-1), a conserved regulator of axon regeneration. These data identify regulation of axonal mitochondria as a new cell biological mechanism that helps determine the regenerative response of injured neurons. PMID:28009276

CXCR4+ granulocytes reflect fungal cystic fibrosis lung disease.

PubMed

Carevic, Melanie; Singh, Anurag; Rieber, Nikolaus; Eickmeier, Olaf; Griese, Matthias; Hector, Andreas; Hartl, Dominik

2015-08-01

Cystic fibrosis airways are frequently colonised with fungi. However, the interaction of these fungi with immune cells and the clinical relevance in cystic fibrosis lung disease are incompletely understood.We characterised granulocytes in airway fluids and peripheral blood from cystic fibrosis patients with and without fungal colonisation, non-cystic fibrosis disease controls and healthy control subjects cross-sectionally and longitudinally and correlated these findings with lung function parameters.Cystic fibrosis patients with chronic fungal colonisation by Aspergillus fumigatus were characterised by an accumulation of a distinct granulocyte subset, expressing the HIV coreceptor CXCR4. Percentages of airway CXCR4(+) granulocytes correlated with lung disease severity in patients with cystic fibrosis.These studies demonstrate that chronic fungal colonisation with A. fumigatus in cystic fibrosis patients is associated with CXCR4(+) airway granulocytes, which may serve as a potential biomarker and therapeutic target in fungal cystic fibrosis lung disease. Copyright ©ERS 2015.

Metabolic Catastrophe in Mice Lacking Transferrin Receptor in Muscle

PubMed Central

Barrientos, Tomasa; Laothamatas, Indira; Koves, Timothy R.; Soderblom, Erik J.; Bryan, Miles; Moseley, M. Arthur; Muoio, Deborah M.; Andrews, Nancy C.

2015-01-01

Transferrin receptor (Tfr1) is ubiquitously expressed, but its roles in non-hematopoietic cells are incompletely understood. We used a tissue-specific conditional knockout strategy to ask whether skeletal muscle required Tfr1 for iron uptake. We found that iron assimilation via Tfr1 was critical for skeletal muscle metabolism, and that iron deficiency in muscle led to dramatic changes, not only in muscle, but also in adipose tissue and liver. Inactivation of Tfr1 incapacitated normal energy production in muscle, leading to growth arrest and a muted attempt to switch to fatty acid β oxidation, using up fat stores. Starvation signals stimulated gluconeogenesis in the liver, but amino acid substrates became limiting and hypoglycemia ensued. Surprisingly, the liver was also iron deficient, and production of the iron regulatory hormone hepcidin was depressed. Our observations reveal a complex interaction between iron homeostasis and metabolism that has implications for metabolic and iron disorders. PMID:26870796

Quantum space and quantum completeness

NASA Astrophysics Data System (ADS)

Jurić, Tajron

2018-05-01

Motivated by the question whether quantum gravity can "smear out" the classical singularity we analyze a certain quantum space and its quantum-mechanical completeness. Classical singularity is understood as a geodesic incompleteness, while quantum completeness requires a unique unitary time evolution for test fields propagating on an underlying background. Here the crucial point is that quantum completeness renders the Hamiltonian (or spatial part of the wave operator) to be essentially self-adjoint in order to generate a unique time evolution. We examine a model of quantum space which consists of a noncommutative BTZ black hole probed by a test scalar field. We show that the quantum gravity (noncommutative) effect is to enlarge the domain of BTZ parameters for which the relevant wave operator is essentially self-adjoint. This means that the corresponding quantum space is quantum complete for a larger range of BTZ parameters rendering the conclusion that in the quantum space one observes the effect of "smearing out" the singularity.

The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Signaling by Confining Linker for Activation of T Cells (LAT) Activation via TRAF6 Protein*

PubMed Central

Yang, Yin; Wu, Songfang; Wang, Yu; Pan, Shuang; Lan, Bei; Liu, Yaohui; Zhang, Liming; Leng, Qianli; Chen, Da; Zhang, Cuizhu; He, Bin; Cao, Youjia

2015-01-01

Herpes simplex virus 1 (HSV-1) is the most prevalent human virus and causes global morbidity because the virus is able to infect multiple cell types. Remarkably, HSV infection switches between lytic and latent cycles, where T cells play a critical role. However, the precise way of virus-host interactions is incompletely understood. Here we report that HSV-1 productively infected Jurkat T-cells and inhibited antigen-induced T cell receptor activation. We discovered that HSV-1-encoded Us3 protein interrupted TCR signaling and interleukin-2 production by inactivation of the linker for activation of T cells. This study unveils a mechanism by which HSV-1 intrudes into early events of TCR-mediated cell signaling and may provide novel insights into HSV infection, during which the virus escapes from host immune surveillance. PMID:25907557

Molecular and cellular mechanisms of pulmonary fibrosis

PubMed Central

2012-01-01

Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease. PMID:22824096

On chirality of slime mould.

PubMed

Dimonte, Alice; Adamatzky, Andrew; Erokhin, Victor; Levin, Michael

2016-02-01

Left-right patterning and lateralised behaviour is an ubiquitous aspect of plants and animals. The mechanisms linking cellular chirality to the large-scale asymmetry of multicellular structures are incompletely understood, and it has been suggested that the chirality of living cells is hardwired in their cytoskeleton. We examined the question of biased asymmetry in a unique organism: the slime mould Physarum polycephalum, which is unicellular yet possesses macroscopic, complex structure and behaviour. In laboratory experiment using a T-shape, we found that Physarum turns right in more than 74% of trials. The results are in agreement with previously published studies on asymmetric movement of muscle cells, neutrophils, liver cells and growing neural filaments, and for the first time reveal the presence of consistently-biased laterality in the fungi kingdom. Exact mechanisms of the slime mould's direction preference remain unknown. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone

PubMed Central

Zhao, Liangliang; Hadziahmetovic, Majda; Wang, Chenguang; Xu, Xueying; Song, Ying; Jinnah, H.A.; Wodzinska, Jolanta; Iacovelli, Jared; Wolkow, Natalie; Krajacic, Predrag; Weissberger, Alyssa Cwanger; Connelly, John; Spino, Michael; Lee, Michael K.; Connor, James; Giasson, Benoit; Harris, Z. Leah; Dunaief, Joshua L.

2016-01-01

Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. PMID:26303407

Competing phases, phase separation, and coexistence in the extended one-dimensional bosonic Hubbard model

DOE PAGES

Batrouni, G. G.; Rousseau, V. G.; Scalettar, R. T.; ...

2014-11-17

Here, we study the phase diagram of the one-dimensional bosonic Hubbard model with contact (U) and near neighbor (V ) interactions focusing on the gapped Haldane insulating (HI) phase which is characterized by an exotic nonlocal order parameter. The parameter regime (U, V and μ) where this phase exists and how it competes with other phases such as the supersolid (SS) phase, is incompletely understood. We use the Stochastic Green Function quantum Monte Carlo algorithm as well as the density matrix renormalization group to map out the phase diagram. The HI exists only at = 1, the SS phase existsmore » for a very wide range of parameters (including commensurate fillings) and displays power law decay in the one body Green function were our main conclusions. Additionally, we show that at fixed integer density, the system exhibits phase separation in the (U, V ) plane.« less

Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart.

PubMed

Xu, Wenjing; Barrientos, Tomasa; Mao, Lan; Rockman, Howard A; Sauve, Anthony A; Andrews, Nancy C

2015-10-20

Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but cardiac iron utilization is incompletely understood. We hypothesized that the transferrin receptor (Tfr1) might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in vivo. Surprisingly, we found that decreased iron, due to inactivation of Tfr1, was associated with severe cardiac consequences. Mice lacking Tfr1 in the heart died in the second week of life and had cardiomegaly, poor cardiac function, failure of mitochondrial respiration, and ineffective mitophagy. The phenotype could only be rescued by aggressive iron therapy, but it was ameliorated by administration of nicotinamide riboside, an NAD precursor. Our findings underscore the importance of both Tfr1 and iron in the heart, and may inform therapy for patients with heart failure. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Gamma-ray astronomy

NASA Technical Reports Server (NTRS)

Ramaty, R.; Lingenfelter, R. E.

1982-01-01

Cosmic gamma rays, the physical processes responsible for their production and the astrophysical sites from which they were seen are reported. The bulk of the observed gamma ray emission is in the photon energy range from about 0.1 MeV to 1 GeV, where observations are carried out above the atmosphere. There are also, however, gamma ray observations at higher energies obtained by detecting the Cerenkov light produced by the high energy photons in the atmosphere. Gamma ray emission was observed from sources as close as the Sun and the Moon and as distant as the quasar 3C273, as well as from various other galactic and extragalactic sites. The radiation processes also range from the well understood, e.g. energetic particle interactions with matter, to the still incompletely researched, such as radiation transfer in optically thick electron positron plasmas in intense neutron star magnetic fields.

A dynamically coupled allosteric network underlies binding cooperativity in Src kinase

PubMed Central

Foda, Zachariah H.; Shan, Yibing; Kim, Eric T.; Shaw, David E.; Seeliger, Markus A.

2015-01-01

Protein tyrosine kinases are attractive drug targets because many human diseases are associated with the deregulation of kinase activity. However, how the catalytic kinase domain integrates different signals and switches from an active to an inactive conformation remains incompletely understood. Here we identify an allosteric network of dynamically coupled amino acids in Src kinase that connects regulatory sites to the ATP- and substrate-binding sites. Surprisingly, reactants (ATP and peptide substrates) bind with negative cooperativity to Src kinase while products (ADP and phosphopeptide) bind with positive cooperativity. We confirm the molecular details of the signal relay through the allosteric network by biochemical studies. Experiments on two additional protein tyrosine kinases indicate that the allosteric network may be largely conserved among these enzymes. Our work provides new insights into the regulation of protein tyrosine kinases and establishes a potential conduit by which resistance mutations to ATP-competitive kinase inhibitors can affect their activity. PMID:25600932

A review of brain circuitries involved in stuttering

PubMed Central

Craig-McQuaide, Anna; Akram, Harith; Zrinzo, Ludvic; Tripoliti, Elina

2014-01-01

Stuttering has been the subject of much research, nevertheless its etiology remains incompletely understood. This article presents a critical review of the literature on stuttering, with particular reference to the role of the basal ganglia (BG). Neuroimaging and lesion studies of developmental and acquired stuttering, as well as pharmacological and genetic studies are discussed. Evidence of structural and functional changes in the BG in those who stutter indicates that this motor speech disorder is due, at least in part, to abnormal BG cues for the initiation and termination of articulatory movements. Studies discussed provide evidence of a dysfunctional hyperdopaminergic state of the thalamocortical pathways underlying speech motor control in stuttering. Evidence that stuttering can improve, worsen or recur following deep brain stimulation for other indications is presented in order to emphasize the role of BG in stuttering. Further research is needed to fully elucidate the pathophysiology of this speech disorder, which is associated with significant social isolation. PMID:25452719

Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes

PubMed Central

Das, Hiranmoy; Kumar, Ajay; Lin, Zhiyong; Patino, Willmar D.; Hwang, Paul M.; Feinberg, Mark W.; Majumder, Pradip K.; Jain, Mukesh K.

2006-01-01

The mechanisms regulating activation of monocytes remain incompletely understood. Herein we provide evidence that Kruppel-like factor 2 (KLF2) inhibits proinflammatory activation of monocytes. In vitro, KLF2 expression in monocytes is reduced by cytokine activation or differentiation. Consistent with this observation, KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. Adenoviral overexpression of KLF2 inhibits the LPS-mediated induction of proinflammatory factors, cytokines, and chemokines and reduces phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-κB and activator protein 1, in part by means of recruitment of transcriptional coactivator p300/CBP-associated factor. These observations identify KLF2 as a novel negative regulator of monocytic activation. PMID:16617118

Epidemiology of ovarian cancer.

PubMed

Permuth-Wey, Jennifer; Sellers, Thomas A

2009-01-01

Ovarian cancer represents the sixth most commonly diagnosed cancer among women in the world, and causes more deaths per year than any other cancer of the female reproductive system. Despite the high incidence and mortality rates, the etiology of this disease is poorly understood. Established risk factors for ovarian cancer include age and having a family history of the disease, while protective factors include increasing parity, oral contraceptive use, and oophorectomy. Lactation, incomplete pregnancies, and surgeries such as hysterectomy and tubal ligation may confer a weak protective effect against ovarian cancer. Infertility may contribute to ovarian cancer risk among nulliparous women. Other possible risk factors for ovarian cancer include postmenopausal hormone-replacement therapy and lifestyle factors such as cigarette smoking and alcohol consumption. Many of the causes of ovarian cancer are yet to be identified. Additional research is needed to better understand the etiology of this deadly disease.

Improved understanding of the pathophysiology of atrial fibrillation through the lens of discrete pathological pathways

PubMed Central

Balouch, Muhammad A.; Kolek, Matthew J.; Darbar, Dawood

2014-01-01

Atrial fibrillation (AF) is a common disorder with a complex and incompletely understood pathophysiology. Genetic approaches to understanding the pathophysiology of AF have led to the identification of several biological pathways important in the pathogenesis of the arrhythmia. These include pathways important for cardiac development, generation and propagation of atrial electrical impulses, and atrial remodeling and fibrosis. While common and rare genetic variants in these pathways are associated with increased susceptibility to AF, they differ substantially among patients with lone versus typical AF. Furthermore, how these pathways converge to a final common clinical phenotype of AF is unclear and might also vary among different patient populations. Here, we review the contemporary knowledge of AF pathogenesis and discuss how derangement in cardiac development, ion channel dysfunction, and promotion of atrial fibrosis may contribute to this common and important clinical disorder. PMID:25054116

Smallpox virus plaque phenotypes: genetic, geographical and case fatality relationships.

PubMed

Olson, Victoria A; Karem, Kevin L; Smith, Scott K; Hughes, Christine M; Damon, Inger K

2009-04-01

Smallpox (infection with Orthopoxvirus variola) remains a feared illness more than 25 years after its eradication. Historically, case-fatality rates (CFRs) varied between outbreaks (<1 to approximately 40 %), the reasons for which are incompletely understood. The extracellular enveloped virus (EEV) form of orthopoxvirus progeny is hypothesized to disseminate infection. Investigations with the closely related Orthopoxvirus vaccinia have associated increased comet formation (EEV production) with increased mouse mortality (pathogenicity). Other vaccinia virus genetic manipulations which affect EEV production inconsistently support this association. However, antisera against vaccinia virus envelope protect mice from lethal challenge, further supporting a critical role for EEV in pathogenicity. Here, we show that the increased comet formation phenotypes of a diverse collection of variola viruses associate with strain phylogeny and geographical origin, but not with increased outbreak-related CFRs; within clades, there may be an association of plaque size with CFR. The mechanisms for variola virus pathogenicity probably involves multiple host and pathogen factors.

Uncertainty, learning, and the optimal management of wildlife

USGS Publications Warehouse

Williams, B.K.

2001-01-01

Wildlife management is limited by uncontrolled and often unrecognized environmental variation, by limited capabilities to observe and control animal populations, and by a lack of understanding about the biological processes driving population dynamics. In this paper I describe a comprehensive framework for management that includes multiple models and likelihood values to account for structural uncertainty, along with stochastic factors to account for environmental variation, random sampling, and partial controllability. Adaptive optimization is developed in terms of the optimal control of incompletely understood populations, with the expected value of perfect information measuring the potential for improving control through learning. The framework for optimal adaptive control is generalized by including partial observability and non-adaptive, sample-based updating of model likelihoods. Passive adaptive management is derived as a special case of constrained adaptive optimization, representing a potentially efficient suboptimal alternative that nonetheless accounts for structural uncertainty.

Functional abdominal pain syndrome.

PubMed

Clouse, Ray E; Mayer, Emeran A; Aziz, Qasim; Drossman, Douglas A; Dumitrascu, Dan L; Mönnikes, Hubert; Naliboff, Bruce D

2006-04-01

Functional abdominal pain syndrome (FAPS) differs from the other functional bowel disorders; it is less common, symptoms largely are unrelated to food intake and defecation, and it has higher comorbidity with psychiatric disorders. The etiology and pathophysiology are incompletely understood. Because FAPS likely represents a heterogeneous group of disorders, peripheral neuropathic pain mechanisms, alterations in endogenous pain modulation systems, or both may be involved in any one patient. The diagnosis of FAPS is made on the basis of positive symptom criteria and a longstanding history of symptoms; in the absence of alarm symptoms, an extensive diagnostic evaluation is not required. Management is based on a therapeutic physician-patient relationship and empirical treatment algorithms using various classes of centrally acting drugs, including antidepressants and anticonvulsants. The choice, dose, and combination of drugs are influenced by psychiatric comorbidities. Psychological treatment options include psychotherapy, relaxation techniques, and hypnosis. Refractory FAPS patients may benefit from a multidisciplinary pain clinic approach.

Risk factors for community-acquired bacterial meningitis.

PubMed

Lundbo, Lene Fogt; Benfield, Thomas

2017-06-01

Bacterial meningitis is a significant burden of disease and mortality in all age groups worldwide despite the development of effective conjugated vaccines. The pathogenesis of bacterial meningitis is based on complex and incompletely understood host-pathogen interactions. Some of these are pathogen-specific, while some are shared between different bacteria. We searched the database PubMed to identify host risk factors for bacterial meningitis caused by the pathogens Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type b, because they are three most common causative bacteria beyond the neonatal period. We describe a number of risk factors; including socioeconomic factors, age, genetic variation of the host and underlying medical conditions associated with increased susceptibility to invasive bacterial infections in both children and adults. As conjugated vaccines are available for these infections, it is of utmost importance to identify high risk patients to be able to prevent invasive disease.

Inflammatory Mediators of Hepatic Steatosis

PubMed Central

Hijona, Elizabeth; Hijona, Lander; Arenas, Juan I.; Bujanda, Luis

2010-01-01

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a world-wide public health problem. NAFLD represents a spectrum of disease ranging from “simple steatosis”, which is considered relatively benign, to nonalcoholic steatohepatitis and to NAFLD-associated cirrhosis and end-stage liver disease. The etiology of NAFLD and its progression is complex and remains incompletely understood. The progression of the disease involves many factors. Apart from the two hits, the accumulation of TG and the development of fibrosis and necroinflammatory processes, exit numerous molecules associated with these two hits. Among them we can highlight the pro-inflammatory molecules and adiponectins. This review focuses on the growing evidence from both experimental and human studies suggesting a central role of cytokines in the pathogenesis of NAFLD. We review the role of cytokines as key regulators of insulin sensitivity and hepatic lipid overloading, liver injury and inflammation, and fibrosis with an emphasis on potential therapeutic implications. PMID:20300479

Current-induced switching of magnetic molecules on topological insulator surfaces

NASA Astrophysics Data System (ADS)

Locane, Elina; Brouwer, Piet W.

2017-03-01

Electrical currents at the surface or edge of a topological insulator are intrinsically spin polarized. We show that such surface or edge currents can be used to switch the orientation of a molecular magnet weakly coupled to the surface or edge of a topological insulator. For the edge of a two-dimensional topological insulator as well as for the surface of a three-dimensional topological insulator the application of a well-chosen surface or edge current can lead to a complete polarization of the molecule if the molecule's magnetic anisotropy axis is appropriately aligned with the current direction. For a generic orientation of the molecule a nonzero but incomplete polarization is obtained. We calculate the probability distribution of the magnetic states and the switching rates as a function of the applied current.

Transcranial direct current stimulation (tDCS) Paired with massed practice training to promote adaptive plasticity and motor recovery in chronic incomplete tetraplegia: a pilot study.

PubMed

Potter-Baker, Kelsey A; Janini, Daniel P; Lin, Yin-Liang; Sankarasubramanian, Vishwanath; Cunningham, David A; Varnerin, Nicole M; Chabra, Patrick; Kilgore, Kevin L; Richmond, Mary Ann; Frost, Frederick S; Plow, Ela B

2017-08-07

Objective Our goal was to determine if pairing transcranial direct current stimulation (tDCS) with rehabilitation for two weeks could augment adaptive plasticity offered by these residual pathways to elicit longer-lasting improvements in motor function in incomplete spinal cord injury (iSCI). Design Longitudinal, randomized, controlled, double-blinded cohort study. Setting Cleveland Clinic Foundation, Cleveland, Ohio, USA. Participants Eight male subjects with chronic incomplete motor tetraplegia. Interventions Massed practice (MP) training with or without tDCS for 2 hrs, 5 times a week. Outcome Measures We assessed neurophysiologic and functional outcomes before, after and three months following intervention. Neurophysiologic measures were collected with transcranial magnetic stimulation (TMS). TMS measures included excitability, representational volume, area and distribution of a weaker and stronger muscle motor map. Functional assessments included a manual muscle test (MMT), upper extremity motor score (UEMS), action research arm test (ARAT) and nine hole peg test (NHPT). Results We observed that subjects receiving training paired with tDCS had more increased strength of weak proximal (15% vs 10%), wrist (22% vs 10%) and hand (39% vs. 16%) muscles immediately and three months after intervention compared to the sham group. Our observed changes in muscle strength were related to decreases in strong muscle map volume (r=0.851), reduced weak muscle excitability (r=0.808), a more focused weak muscle motor map (r=0.675) and movement of weak muscle motor map (r=0.935). Conclusion Overall, our results encourage the establishment of larger clinical trials to confirm the potential benefit of pairing tDCS with training to improve the effectiveness of rehabilitation interventions for individuals with SCI. Trial Registration NCT01539109.

Academic Airframe Icing Perspective

NASA Technical Reports Server (NTRS)

Bragg, Mike; Rothmayer, Alric; Thompson, David

2009-01-01

2-D ice accretion and aerodynamics reasonably well understood for engineering applications To significantly improve our current capabilities we need to understand 3-D: a) Important ice accretion physics and modeling not well understood in 3-D; and b) Aerodynamics unsteady and 3-D especially near stall. Larger systems issues important and require multidisciplinary team approach

Why physician-assisted suicide perpetuates the idolatory of medicine.

PubMed

Cherry, Mark J

2003-01-01

Adequate response to physician-assisted suicide and euthanasia depends on fundamental philosophical and theological issues, including the character of an appropriate philosophically and theologically anchored anthropology, where the central element of traditional Christian anthropology is that humans are created to worship God. As I will argue, Christian morality and moral epistemology must be nested within and understood through this background Christian anthropology. As a result, I will argue that physician-assisted suicide and euthanasia can only be one-sidedly and inadequately appreciated through rational appeal to central values, such as "human dignity" and "self determination", or through "sola scriptura" biblical interpretation, or individual judgments of conscience. Adequately addressing physician-assisted suicide and euthanasia will depend on a more fundamental spiritual-therapeutic approach. This cluster of moral, epistemological, anthropological, and bioethical claims will be explored by drawing on the texts of St. Basil the Great, St. Maximos the Confessor, and St. Isaac the Syrian. Their reflections on medicine, the human good, and its relationship to worship, spiritual therapy, and God will be used as a basis to indicate a broader philosophical perspective, which will be needed to avoid a one-sided, incomplete approach to the challenges of physician-assisted suicide and euthanasia. Medical morality, I argue, is best understood within categories that transcend the right, the good, the just, and the virtuous; namely, the holy.

Pandemic influenza: certain uncertainties

PubMed Central

Morens, David M.; Taubenberger, Jeffery K.

2011-01-01

SUMMARY For at least five centuries, major epidemics and pandemics of influenza have occurred unexpectedly and at irregular intervals. Despite the modern notion that pandemic influenza is a distinct phenomenon obeying such constant (if incompletely understood) rules such as dramatic genetic change, cyclicity, “wave” patterning, virus replacement, and predictable epidemic behavior, much evidence suggests the opposite. Although there is much that we know about pandemic influenza, there appears to be much more that we do not know. Pandemics arise as a result of various genetic mechanisms, have no predictable patterns of mortality among different age groups, and vary greatly in how and when they arise and recur. Some are followed by new pandemics, whereas others fade gradually or abruptly into long-term endemicity. Human influenza pandemics have been caused by viruses that evolved singly or in co-circulation with other pandemic virus descendants and often have involved significant transmission between, or establishment of, viral reservoirs within other animal hosts. In recent decades, pandemic influenza has continued to produce numerous unanticipated events that expose fundamental gaps in scientific knowledge. Influenza pandemics appear to be not a single phenomenon but a heterogeneous collection of viral evolutionary events whose similarities are overshadowed by important differences, the determinants of which remain poorly understood. These uncertainties make it difficult to predict influenza pandemics and, therefore, to adequately plan to prevent them. PMID:21706672

Imaging the Reconstruction of True and False Memories Using Sensory Reactivation and the Misinformation Paradigms

ERIC Educational Resources Information Center

Stark, Craig E. L.; Okado, Yoko; Loftus, Elizabeth F.

2010-01-01

Many current theories of false memories propose that, when we retrieve a memory, we are not reactivating a veridical, fixed representation of a past event, but are rather reactivating incomplete fragments that may be accurate or distorted and may have arisen from other events. By presenting the two phases of the misinformation paradigm in…

Self-Efficacy and Vicarious Learning in Doctoral Studies at a Distance

ERIC Educational Resources Information Center

Kozar, Olga; Lum, Juliet F.; Benson, Phil

2015-01-01

Even though there are increasing numbers of PhD students in the distance mode, our current understanding of PhD candidature at a distance is limited and incomplete. On the one end of the spectrum are accounts of unhappy and isolated doctoral students who are separated from communities of practice. At the same time, literature offers accounts of…

Examining the Use of Internal Defect Information for Information-Augmented Hardwood Log Breakdown

Treesearch

Luis G. Occeña; Daniel L. Schmoldt; Suraphan Thawornwong

1997-01-01

In present-day hardwood sawmills, log breakdown is hampered by incomplete information about log geometry and internal features. When internal log scanning becomes operational, it will remove this roadblock and provide a complete view of each logâs interior. It is not currently obvious, however, how dramatically this increased level of information will improve log...

Retirement financial planning and the RN: an integrative literature review.

PubMed

Keele, Shanna; Alpert, Patricia T

2013-11-01

This integrative literature review examined the current research on RN retirement. The review identified 3 critical gaps in knowledge: (a) minimal knowledge regarding the economic impact on RN retirement, (b) incomplete information regarding the demographics of RN retirement, and (c) a scarcity of prospective longitudinal RN workforce studies. Future research must address these gaps to better address RN workforce sustainability.

Retirement Financial Planning and the RN: An Integrative Literature Review.

PubMed

Keele, Shanna; Alpert, Patricia T

2015-10-01

This integrative literature review examined the current research on RN retirement. The review identified 3 critical gaps in knowledge: (a) minimal knowledge regarding the economic impact on RN retirement, (b) incomplete information regarding the demographics of RN retirement, and (c) a scarcity of prospective longitudinal RN workforce studies. Future research must address these gaps to better address RN workforce sustainability.

A Systemic View of the Learning and Differentiation of Scientific Concepts: The Case of Electric Current and Voltage Revisited

ERIC Educational Resources Information Center

Koponen, Ismo T.; Kokkonen, Tommi

2014-01-01

In learning conceptual knowledge in physics, a common problem is the incompleteness of a learning process, where students' personal, often undifferentiated concepts take on more scientific and differentiated form. With regard to such concept learning and differentiation, this study proposes a systemic view in which concepts are considered as…

Some Families of the Incomplete H-Functions and the Incomplete \\overline H -Functions and Associated Integral Transforms and Operators of Fractional Calculus with Applications

NASA Astrophysics Data System (ADS)

Srivastava, H. M.; Saxena, R. K.; Parmar, R. K.

2018-01-01

Our present investigation is inspired by the recent interesting extensions (by Srivastava et al. [35]) of a pair of the Mellin-Barnes type contour integral representations of their incomplete generalized hypergeometric functions p γ q and p Γ q by means of the incomplete gamma functions γ( s, x) and Γ( s, x). Here, in this sequel, we introduce a family of the relatively more general incomplete H-functions γ p,q m,n ( z) and Γ p,q m,n ( z) as well as their such special cases as the incomplete Fox-Wright generalized hypergeometric functions p Ψ q (γ) [ z] and p Ψ q (Γ) [ z]. The main object of this paper is to study and investigate several interesting properties of these incomplete H-functions, including (for example) decomposition and reduction formulas, derivative formulas, various integral transforms, computational representations, and so on. We apply some substantially general Riemann-Liouville and Weyl type fractional integral operators to each of these incomplete H-functions. We indicate the easilyderivable extensions of the results presented here that hold for the corresponding incomplete \\overline H -functions as well. Potential applications of many of these incomplete special functions involving (for example) probability theory are also indicated.

Assessment of predictive performance in incomplete data by combining internal validation and multiple imputation.

PubMed

Wahl, Simone; Boulesteix, Anne-Laure; Zierer, Astrid; Thorand, Barbara; van de Wiel, Mark A

2016-10-26

Missing values are a frequent issue in human studies. In many situations, multiple imputation (MI) is an appropriate missing data handling strategy, whereby missing values are imputed multiple times, the analysis is performed in every imputed data set, and the obtained estimates are pooled. If the aim is to estimate (added) predictive performance measures, such as (change in) the area under the receiver-operating characteristic curve (AUC), internal validation strategies become desirable in order to correct for optimism. It is not fully understood how internal validation should be combined with multiple imputation. In a comprehensive simulation study and in a real data set based on blood markers as predictors for mortality, we compare three combination strategies: Val-MI, internal validation followed by MI on the training and test parts separately, MI-Val, MI on the full data set followed by internal validation, and MI(-y)-Val, MI on the full data set omitting the outcome followed by internal validation. Different validation strategies, including bootstrap und cross-validation, different (added) performance measures, and various data characteristics are considered, and the strategies are evaluated with regard to bias and mean squared error of the obtained performance estimates. In addition, we elaborate on the number of resamples and imputations to be used, and adopt a strategy for confidence interval construction to incomplete data. Internal validation is essential in order to avoid optimism, with the bootstrap 0.632+ estimate representing a reliable method to correct for optimism. While estimates obtained by MI-Val are optimistically biased, those obtained by MI(-y)-Val tend to be pessimistic in the presence of a true underlying effect. Val-MI provides largely unbiased estimates, with a slight pessimistic bias with increasing true effect size, number of covariates and decreasing sample size. In Val-MI, accuracy of the estimate is more strongly improved by increasing the number of bootstrap draws rather than the number of imputations. With a simple integrated approach, valid confidence intervals for performance estimates can be obtained. When prognostic models are developed on incomplete data, Val-MI represents a valid strategy to obtain estimates of predictive performance measures.

Retinal Wave Patterns Are Governed by Mutual Excitation among Starburst Amacrine Cells and Drive the Refinement and Maintenance of Visual Circuits

PubMed Central

Xu, Hong-Ping; Burbridge, Timothy J.; Ye, Meijun; Chen, Minggang; Ge, Xinxin; Zhou, Z. Jimmy

2016-01-01

Retinal waves are correlated bursts of spontaneous activity whose spatiotemporal patterns are critical for early activity-dependent circuit elaboration and refinement in the mammalian visual system. Three separate developmental wave epochs or stages have been described, but the mechanism(s) of pattern generation of each and their distinct roles in visual circuit development remain incompletely understood. We used neuroanatomical, in vitro and in vivo electrophysiological, and optical imaging techniques in genetically manipulated mice to examine the mechanisms of wave initiation and propagation and the role of wave patterns in visual circuit development. Through deletion of β2 subunits of nicotinic acetylcholine receptors (β2-nAChRs) selectively from starburst amacrine cells (SACs), we show that mutual excitation among SACs is critical for Stage II (cholinergic) retinal wave propagation, supporting models of wave initiation and pattern generation from within a single retinal cell type. We also demonstrate that β2-nAChRs in SACs, and normal wave patterns, are necessary for eye-specific segregation. Finally, we show that Stage III (glutamatergic) retinal waves are not themselves necessary for normal eye-specific segregation, but elimination of both Stage II and Stage III retinal waves dramatically disrupts eye-specific segregation. This suggests that persistent Stage II retinal waves can adequately compensate for Stage III retinal wave loss during the development and refinement of eye-specific segregation. These experiments confirm key features of the “recurrent network” model for retinal wave propagation and clarify the roles of Stage II and Stage III retinal wave patterns in visual circuit development. SIGNIFICANCE STATEMENT Spontaneous activity drives early mammalian circuit development, but the initiation and patterning of activity vary across development and among modalities. Cholinergic “retinal waves” are initiated in starburst amacrine cells and propagate to retinal ganglion cells and higher-order visual areas, but the mechanism responsible for creating their unique and critical activity pattern is incompletely understood. We demonstrate that cholinergic wave patterns are dictated by recurrent connectivity within starburst amacrine cells, and retinal ganglion cells act as “readouts” of patterned activity. We also show that eye-specific segregation occurs normally without glutamatergic waves, but elimination of both cholinergic and glutamatergic waves completely disrupts visual circuit development. These results suggest that each retinal wave pattern during development is optimized for concurrently refining multiple visual circuits. PMID:27030771

Failsafe modes in incomplete minority game

NASA Astrophysics Data System (ADS)

Yao, Xiaobo; Wan, Shaolong; Chen, Wen

2009-09-01

We make a failsafe extension to the incomplete minority game model, give a brief analysis on how incompleteness will effect system efficiency. Simulations that limited incompleteness in strategies can improve the system efficiency. Among three failsafe modes, the “Back-to-Best” mode brings most significant improvement and keeps the system efficiency in a long range of incompleteness. A simple analytic formula has a trend which matches simulation results. The IMMG model is used to study the effect of distribution, and we find that there is one junction point in each series of curves, at which system efficiency is not influenced by the distribution of incompleteness. When pIbar > the concentration of incompleteness weakens the effect. On the other side of , concentration will be helpful. When pI is close to zero agents using incomplete strategies have on average better profits than those using standard strategies, and the “Back-to-Best” agents have a wider range of pI to win.

A Review of Auditory Prediction and Its Potential Role in Tinnitus Perception.

PubMed

Durai, Mithila; O'Keeffe, Mary G; Searchfield, Grant D

2018-06-01

The precise mechanisms underlying tinnitus perception and distress are still not fully understood. A recent proposition is that auditory prediction errors and related memory representations may play a role in driving tinnitus perception. It is of interest to further explore this. To obtain a comprehensive narrative synthesis of current research in relation to auditory prediction and its potential role in tinnitus perception and severity. A narrative review methodological framework was followed. The key words Prediction Auditory, Memory Prediction Auditory, Tinnitus AND Memory, Tinnitus AND Prediction in Article Title, Abstract, and Keywords were extensively searched on four databases: PubMed, Scopus, SpringerLink, and PsychINFO. All study types were selected from 2000-2016 (end of 2016) and had the following exclusion criteria applied: minimum age of participants <18, nonhuman participants, and article not available in English. Reference lists of articles were reviewed to identify any further relevant studies. Articles were short listed based on title relevance. After reading the abstracts and with consensus made between coauthors, a total of 114 studies were selected for charting data. The hierarchical predictive coding model based on the Bayesian brain hypothesis, attentional modulation and top-down feedback serves as the fundamental framework in current literature for how auditory prediction may occur. Predictions are integral to speech and music processing, as well as in sequential processing and identification of auditory objects during auditory streaming. Although deviant responses are observable from middle latency time ranges, the mismatch negativity (MMN) waveform is the most commonly studied electrophysiological index of auditory irregularity detection. However, limitations may apply when interpreting findings because of the debatable origin of the MMN and its restricted ability to model real-life, more complex auditory phenomenon. Cortical oscillatory band activity may act as neurophysiological substrates for auditory prediction. Tinnitus has been modeled as an auditory object which may demonstrate incomplete processing during auditory scene analysis resulting in tinnitus salience and therefore difficulty in habituation. Within the electrophysiological domain, there is currently mixed evidence regarding oscillatory band changes in tinnitus. There are theoretical proposals for a relationship between prediction error and tinnitus but few published empirical studies. American Academy of Audiology.

Stem Cell Genetic Therapy for Fanconi Anemia - A New Hope.

PubMed

Hanenberg, Helmut; Roellecke, Katharina; Wiek, Constanze

2017-01-01

Fanconi anemia (FA) is a rare inherited DNA disorder clinically characterized by congenital malformations, progressive bone marrow failure, and cancer susceptibility. Due to a strong survival advantage of spontaneously corrected 'normal' hematopoietic stem cells (HSCs) in a few patients, FA is considered a model disorder for genetic correction of autologous stem cells, where genetically corrected stem cells and their progeny have a strong in vivo selective advantage, ultimately leading to normal hematopoiesis. Despite these apparently ideal circumstances, three HSC gene therapy trials with gammaretroviral vectors (stage I) designed to cure the hematological manifestation of FA completely failed to provide long-term clinical benefits for patients, predominantly due to the combination of insufficient gene transfer technologies and incompletely understood FA HSC pathobiology. Currently, FA gene therapy is in stage II where, based on an improved understanding of the cellular defects in FA HSCs, consequently adapted transduction protocols are being used in two phase I/II trials for in vitro genetic correction of FANCA-deficient hematopoietic stem cells. These results are eagerly awaited. Independent from the outcome of these studies, technologies are already available that seem highly attractive for testing in FA. In stage III, this would ultimately include targeted in vivo correction of autologous HSCs by overexpression of nonintegrating lentiviral vectors with scaffold/matrix attachment region elements using specific envelopes as pseudotypes. Although currently still challenging, in a few years in vivo genome editing approaches will be readily available in stage IV, in which the delivery of the editing machinery/ complex is targeted to the autologous FA HSCs by the nonintegrating lentiviral vectors established in stage III. Even low levels of corrected stem cells will then quickly repopulate the entire hematopoiesis of the patient. We therefore are sanguine that in the future, genetic therapy can be used clinically for the correction of FA HSCs in the standard care of FA patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Cardiovascular Toxicity of Illicit Anabolic-Androgenic Steroid Use

PubMed Central

Baggish, Aaron L.; Weiner, Rory B.; Kanayama, Gen; Hudson, James I.; Lu, Michael T.; Hoffmann, Udo; Pope, Harrison G.

2017-01-01

Background Millions of individuals have used illicit anabolic-androgenic steroids (AAS), but the long-term cardiovascular associations of these drugs remains incompletely understood. Methods Employing a cross-sectional cohort design, we recruited 140 experienced male weightlifters aged 34–54 years, comprising 86 men reporting at least 2 years of cumulative lifetime AAS use and 54 non-using men. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: left ventricular (LV) systolic function (left ventricular ejection fraction [LVEF]), LV diastolic function (early relaxation velocity [E´]), and coronary atherosclerosis (coronary artery plaque volume). Results Compared to non-users, AAS users demonstrated relatively reduced LV systolic function (mean±SD LVEF = 52±11% vs. 63±8%; P<0.001) and diastolic function (E´ = 9.3±2.4 cm/s vs. 11.1±2.0 cm/s; P<0.001). Users currently taking AAS at the time of evaluation (N = 58) showed significantly reduced LV systolic (LVEF = 49±10% vs. 58±10%; P<0.001) and diastolic function (E´ = 8.9±2.4 cm/s vs. 10.1±2.4 cm/s; P=0.035) compared to users currently off-drug (N = 28). Additionally, AAS users demonstrated higher coronary artery plaque volume then nonusers (median [interquartile range] 3 [0, 174] mL3 vs. 0 [0, 69] mL3, P = 0.012). Lifetime AAS dose was strongly associated with coronary atherosclerotic burden (increase [95% confidence interval] in rank of plaque volume for each 10-year increase in cumulative duration of AAS use: 0.60 SD units [0.16 to 1.03 SD units]; P = 0.008). Conclusions Long-term AAS use appears to be associated with myocardial dysfunction and accelerated coronary atherosclerosis. These forms of AAS-associated adverse cardiovascular phenotypes may represent a previously under-recognized public-health problem. PMID:28533317

Simulation of nonstationary phenomena in atmospheric-pressure glow discharge

NASA Astrophysics Data System (ADS)

Korolev, Yu. D.; Frants, O. B.; Nekhoroshev, V. O.; Suslov, A. I.; Kas'yanov, V. S.; Shemyakin, I. A.; Bolotov, A. V.

2016-06-01

Nonstationary processes in atmospheric-pressure glow discharge manifest themselves in spontaneous transitions from the normal glow discharge into a spark. In the experiments, both so-called completed transitions in which a highly conductive constricted channel arises and incomplete transitions accompanied by the formation of a diffuse channel are observed. A model of the positive column of a discharge in air is elaborated that allows one to interpret specific features of the discharge both in the stationary stage and during its transition into a spark and makes it possible to calculate the characteristic oscillatory current waveforms for completed transitions into a spark and aperiodic ones for incomplete transitions. The calculated parameters of the positive column in the glow discharge mode agree well with experiment. Data on the densities of the most abundant species generated in the discharge (such as atomic oxygen, metastable nitrogen molecules, ozone, nitrogen oxides, and negative oxygen ions) are presented.

The recognition of emotional expression in prosopagnosia: decoding whole and part faces.

PubMed

Stephan, Blossom Christa Maree; Breen, Nora; Caine, Diana

2006-11-01

Prosopagnosia is currently viewed within the constraints of two competing theories of face recognition, one highlighting the analysis of features, the other focusing on configural processing of the whole face. This study investigated the role of feature analysis versus whole face configural processing in the recognition of facial expression. A prosopagnosic patient, SC made expression decisions from whole and incomplete (eyes-only and mouth-only) faces where features had been obscured. SC was impaired at recognizing some (e.g., anger, sadness, and fear), but not all (e.g., happiness) emotional expressions from the whole face. Analyses of his performance on incomplete faces indicated that his recognition of some expressions actually improved relative to his performance on the whole face condition. We argue that in SC interference from damaged configural processes seem to override an intact ability to utilize part-based or local feature cues.

Simulation of nonstationary phenomena in atmospheric-pressure glow discharge

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

Korolev, Yu. D., E-mail: korolev@lnp.hcei.tsc.ru; Frants, O. B.; Nekhoroshev, V. O.

2016-06-15

Nonstationary processes in atmospheric-pressure glow discharge manifest themselves in spontaneous transitions from the normal glow discharge into a spark. In the experiments, both so-called completed transitions in which a highly conductive constricted channel arises and incomplete transitions accompanied by the formation of a diffuse channel are observed. A model of the positive column of a discharge in air is elaborated that allows one to interpret specific features of the discharge both in the stationary stage and during its transition into a spark and makes it possible to calculate the characteristic oscillatory current waveforms for completed transitions into a spark andmore » aperiodic ones for incomplete transitions. The calculated parameters of the positive column in the glow discharge mode agree well with experiment. Data on the densities of the most abundant species generated in the discharge (such as atomic oxygen, metastable nitrogen molecules, ozone, nitrogen oxides, and negative oxygen ions) are presented.« less

Clinical trial transparency: many gains but access to evidence for new medicines remains imperfect.

PubMed

Mintzes, Barbara; Lexchin, Joel; Quintano, Ancella Santos

2015-01-01

Although selective and incomplete publication is widely acknowledged to be a problem, full access to clinical trial data remains illusive. Authors' personal files, key documents from Food and Drug Administration and European Medicines Agency and focussed searches of PubMed. Existing sources of information provide an incomplete overview of scientific research. Persistent arguments about commercial confidentiality and the potential difficulties in de-identifying raw data can block important progress. Current industry efforts are voluntary and only partially satisfy the need for complete data. Requirements for trial registration are increasing. Important regulatory changes in particular in Europe have the potential to result in the release of more information. Documenting the effects of prospective trial registration and requirements for proactive clinical trial publication on healthcare decisions, public health and rational resource allocation. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Adherence to guidelines for cardiovascular screening in current high school preparticipation evaluation forms.

PubMed

Rausch, Christopher M; Phillips, George C

2009-10-01

We compared the content of the cardiac screening questions on US state high school athletic association preparticipation evaluation forms with current consensus recommendations. We reviewed the high school athletic association's approved, recommended, or required sports preparticipation form from each of the 50 US states and the District of Columbia, and compared the content of the personal and family history components with current recommendations for cardiac screening questions. We found that 85% of the preparticipation forms in current use contain all elements of the formerly recommended guidelines, but only 17% contain all elements of the new consensus guidelines. We conclude that although there appears to be some improvement in the content of the preparticipation forms in current use compared with previous studies, the vast majority of these forms are incomplete compared with current consensus guidelines.

Incomplete Protection against Dengue Virus Type 2 Re-infection in Peru.

PubMed

Forshey, Brett M; Reiner, Robert C; Olkowski, Sandra; Morrison, Amy C; Espinoza, Angelica; Long, Kanya C; Vilcarromero, Stalin; Casanova, Wilma; Wearing, Helen J; Halsey, Eric S; Kochel, Tadeusz J; Scott, Thomas W; Stoddard, Steven T

2016-02-01

Nearly half of the world's population is at risk for dengue, yet no licensed vaccine or anti-viral drug is currently available. Dengue is caused by any of four dengue virus serotypes (DENV-1 through DENV-4), and infection by a DENV serotype is assumed to provide life-long protection against re-infection by that serotype. We investigated the validity of this fundamental assumption during a large dengue epidemic caused by DENV-2 in Iquitos, Peru, in 2010-2011, 15 years after the first outbreak of DENV-2 in the region. We estimated the age-dependent prevalence of serotype-specific DENV antibodies from longitudinal cohort studies conducted between 1993 and 2010. During the 2010-2011 epidemic, active dengue cases were identified through active community- and clinic-based febrile surveillance studies, and acute inapparent DENV infections were identified through contact tracing studies. Based on the age-specific prevalence of DENV-2 neutralizing antibodies, the age distribution of DENV-2 cases was markedly older than expected. Homologous protection was estimated at 35.1% (95% confidence interval: 0%-65.2%). At the individual level, pre-existing DENV-2 antibodies were associated with an incomplete reduction in the frequency of symptoms. Among dengue cases, 43% (26/66) exhibited elevated DENV-2 neutralizing antibody titers for years prior to infection, compared with 76% (13/17) of inapparent infections (age-adjusted odds ratio: 4.2; 95% confidence interval: 1.1-17.7). Our data indicate that protection from homologous DENV re-infection may be incomplete in some circumstances, which provides context for the limited vaccine efficacy against DENV-2 in recent trials. Further studies are warranted to confirm this phenomenon and to evaluate the potential role of incomplete homologous protection in DENV transmission dynamics.

Tbx1 regulates oral epithelial adhesion and palatal development

PubMed Central

Funato, Noriko; Nakamura, Masataka; Richardson, James A.; Srivastava, Deepak; Yanagisawa, Hiromi

2012-01-01

Cleft palate, the most frequent congenital craniofacial birth defect, is a multifactorial condition induced by the interaction of genetic and environmental factors. In addition to complete cleft palate, a large number of human cases involve soft palate cleft and submucosal cleft palate. However, the etiology of these forms of cleft palate has not been well understood. T-box transcriptional factor (Tbx) family of transcriptional factors has distinct roles in a wide range of embryonic differentiation or response pathways. Here, we show that genetic disruption of Tbx1, a major candidate gene for the human congenital disorder 22q11.2 deletion syndrome (Velo-cardio-facial/DiGeorge syndrome), led to abnormal epithelial adhesion between the palate and mandible in mouse, resulting in various forms of cleft palate similar to human conditions. We found that hyperproliferative epithelium failed to undergo complete differentiation in Tbx1-null mice (Tbx1−/−). Inactivation of Tbx1 specifically in the keratinocyte lineage (Tbx1KCKO) resulted in an incomplete cleft palate confined to the anterior region of the palate. Interestingly, Tbx1 overexpression resulted in decreased cell growth and promoted cell-cycle arrest in MCF7 epithelial cells. These findings suggest that Tbx1 regulates the balance between proliferation and differentiation of keratinocytes and is essential for palatal fusion and oral mucosal differentiation. The impaired adhesion separation of the oral epithelium together with compromised palatal mesenchymal growth is an underlying cause for various forms of cleft palate phenotypes in Tbx1−/− mice. Our present study reveals new pathogenesis of incomplete and submucous cleft palate during mammalian palatogenesis. PMID:22371266

Dynamic Motor Compensations with Permanent, Focal Loss of Forelimb Force after Cervical Spinal Cord Injury

PubMed Central

López-Dolado, Elisa; Lucas-Osma, Ana M.

2013-01-01

Abstract Incomplete cervical lesion is the most common type of human spinal cord injury (SCI) and causes permanent paresis of arm muscles, a phenomenon still incompletely understood in physiopathological and neuroanatomical terms. We performed spinal cord hemisection in adult rats at the caudal part of the segment C6, just rostral to the bulk of triceps brachii motoneurons, and analyzed the forces and kinematics of locomotion up to 4 months postlesion to determine the nature of motor function loss and recovery. A dramatic (50%), immediate and permanent loss of extensor force occurred in the forelimb but not in the hind limb of the injured side, accompanied by elbow and wrist kinematic impairments and early adaptations of whole-body movements that initially compensated the balance but changed continuously over the follow-up period to allow effective locomotion. Overuse of both contralateral legs and ipsilateral hind leg was evidenced since 5 days postlesion. Ipsilateral foreleg deficits resulted mainly from interruption of axons that innervate the spinal cord segments caudal to the lesion, because chronic loss (about 35%) of synapses was detected at C7 while only 14% of triceps braquii motoneurons died, as assessed by synaptophysin immunohistochemistry and retrograde neural tracing, respectively. We also found a large pool of propriospinal neurons projecting from C2–C5 to C7 in normal rats, with topographical features similar to the propriospinal premotoneuronal system of cats and primates. Thus, concurrent axotomy at C6 of brain descending axons and cervical propriospinal axons likely hampered spontaneous recovery of the focal neurological impairments. PMID:23249275

Aeromagnetic and aeromagnetic-based geologic maps of the Coastal Belt, Franciscan Complex, northern California

USGS Publications Warehouse

Langenheim, V.E.; Jachens, R.C.; McLaughlin, R.J.

2011-01-01

The Coastal belt of the Franciscan Complex represents a Late Cretaceous to Miocene accretionary prism and overlying slope deposits. Its equivalents may extend from the offshore outer borderland of southern California to north of the Mendocino Triple Junction under the Eel River Basin and in the offshore of Cascadia. The Coastal belt is exposed on land in northern California, yet its structure and stratigraphy are incompletely known because of discontinuous exposure, structural disruption, and lithologically non-distinctive clastic rocks. The intent of this report is to make available, in map form, aeromagnetic data covering the Coastal belt that provide a new dataset to aid in mapping, understanding, and interpreting the incompletely understood geology and structure in northern California.The newly merged aeromagnetic data over the Coastal belt of the Franciscan Complex reveal long, linear anomalies that indicate remarkably coherent structure within a terrane where mapping at the surface indicates complex deformation and that has been described as "broken formation" and, even locally as "mélange". The anomalies in the Coastal belt are primarily sourced by volcanic-rich graywackes and exotic blocks of basalt. Some anomalies along the contact of the Coastal belt with the Central belt are likely caused by local interleaving of components of the Coast Ranges ophiolite. These data can be used to map additional exotic blocks within the Coastal belt and to distinguish lithologically indistinct graywackes within the Coastal terrane. Using anomaly asymmetry allows projection of these "layers" into the subsurface. This analysis indicates predominant northeast dips consistent with tectonic interleaving of blocks within a subduction zone.

Excessive coupling of the salience network with intrinsic neurocognitive brain networks during rectal distension in adolescents with irritable bowel syndrome: a preliminary report

PubMed Central

Liu, Xiaolin; Silverman, Alan; Kern, Mark; Ward, B. Douglas; Li, Shi-Jiang; Shaker, Reza; Sood, Manu R.

2015-01-01

Background The neural network mechanisms underlying visceral hypersensitivity in irritable bowel syndrome (IBS) are incompletely understood. It has been proposed that an intrinsic salience network plays an important role in chronic pain and IBS symptoms. Using neuroimaging, we examined brain responses to rectal distension in adolescent IBS patients, focusing on determining the alteration of salience network integrity in IBS and its functional implications in current theoretical frameworks. We hypothesized that (1) brain responses to visceral stimulation in adolescents are similar to those in adults, and (2) IBS is associated with an altered salience network interaction with other neurocognitive networks, particularly the default mode network (DMN) and executive control network (ECN), as predicted by the theoretical models. Methods IBS patients and controls received subliminal and liminal rectal distension during imaging. Stimulus-induced brain activations were determined. Salience network integrity was evaluated by functional connectivity of its seed regions activated by rectal distension in the insular and cingulate cortices. Key Results Compared with controls, IBS patients demonstrated greater activation to rectal distension in neural structures of the homeostatic afferent and emotional arousal networks, especially the anterior cingulate and insular cortices. Greater brain responses to liminal vs. subliminal distension were observed in both groups. Particularly, IBS is uniquely associated with an excessive coupling of the salience network with the DMN and ECN in their key frontal and parietal node areas. Conclusions & Inferences Our study provided consistent evidence supporting the theoretical predictions of altered salience network functioning as a neuropathological mechanism of IBS symptoms. PMID:26467966

Personalised immunomodulating treatments for Graves' disease: fact or fiction?

PubMed

Struja, Tristan Mirko; Kutz, Alexander; Fischli, Stefan; Meier, Christian; Müller, Beat; Schütz, Philipp

2017-08-14

Although Graves' disease has been recognised for more than 100 years, its physiopathological mechanisms are incompletely understood. Treatment strategies today mainly focus on suppression of thyroid hormone production by use of antithyroid drugs or radio-iodine, but neglect the underlying immunological mechanisms. Although Graves' disease is often seen as a prototype for an autoimmune mechanism, it is more likely to be a heterogeneous syndrome showing characteristics of both autoimmunity and immunodeficiency. The interplay of these two mechanisms may well characterise the physiopathology of this disease and its complications. Immunodeficiency may be either genetically determined or secondarily acquired. Various triggering events lead to autoimmunity with stimulation of the thyroid gland resulting in the clinical syndrome of hyperthyroidism. Also, relapse risk differs from patient to patient and can be estimated from clinical parameters incorporated into the Graves' Recurrent Events After Therapy (GREAT) score. Accurate risk stratification may help to distinguish high-risk patients for whom a more definitive treatment approach should be used from others where there is a high probability that the disease will recover with medical treatment alone. Several smaller trials having found positive effects of immunosuppressive drugs on recurrence risk in Graves' disease; therefoore, there is great potential in the use of novel immunomodulating drugs in addition to the currently used antithyroid drugs for the successful treatment of this condition. Further in-depth exploration of susceptibility, triggering factors and immunological mechanisms has the potential to improve treatment of Graves' disease, with more personalised, risk-adapted treatment strategies based on the different physiopathological concepts of this heterogeneous condition.

The phylogenetic relationships among non-diplomystid catfishes as inferred from mitochondrial cytochrome b sequences; the search for the ictalurid sister taxon (Otophysi: Siluriformes).

PubMed

Hardman, Michael

2005-12-01

The relationships among families of catfishes are poorly understood and have yet to be the subject of a comprehensive investigation with molecular data. Existing phylogenetic hypotheses are based on morphological data and incompletely resolved. This study analyzed complete sequences of mitochondrial gene cytochrome b for 170 species from 29 of 33 extant families, and focused on the relationships of Ictaluridae to other catfishes. In addition to previous phylogenetic studies, the fossil record, paleogeography, biogeography, and distribution of extant catfish families collectively suggest the location (if extant) of the ictalurid sister taxon to be Northern or Eastern Asia. Of the extant catfishes currently native to this area and included in this analysis, parsimony and Bayesian likelihood analyses recovered Cranoglanis bouderius as the most proximal sister taxon of Ictaluridae. Seemingly, ictalurids and cranoglanidids represent another biogeographic component linking freshwater fishes of North America and eastern Asia, e.g., catostomids and paddlefishes. The results coupled with present-day catfish distributions and inferences from the fossil record collectively suggest the ancestor of Ictaluridae to have invaded freshwaters of North America at the close of the Cretaceous through northeastern Asia and northwestern North America. Other superfamilial nodes supported the results of previous phylogenetic studies of narrower taxonomic scope. Several novel relationships were recovered (including a clade composed of Pimelodidae, Pseudopimelodidae, and Heptapteridae) and these along with sources of systematic error are discussed. A broad sampling of Bagridae permitted an examination of intergeneric relationships within this family and in light of recent morphological and molecular studies.

Analysis of microtubule growth dynamics arising from altered actin network structure and contractility in breast tumor cells

NASA Astrophysics Data System (ADS)

Ory, Eleanor C.; Bhandary, Lekhana; E Boggs, Amanda; Chakrabarti, Kristi R.; Parker, Joshua; Losert, Wolfgang; Martin, Stuart S.

2017-04-01

The periphery of epithelial cells is shaped by opposing cytoskeletal physical forces generated predominately by two dynamic force generating systems—growing microtubule ends push against the boundary from the cell center, and the actin cortex contracts the attached plasma membrane. Here we investigate how changes to the structure and dynamics of the actin cortex alter the dynamics of microtubules. Current drugs target actin polymerization and contraction to reduce cell division and invasiveness; however, the impacts on microtubule dynamics remain incompletely understood. Using human MCF-7 breast tumor cells expressing GFP-tagged microtubule end-binding-protein-1 (EB1) and coexpression of cytoplasmic fluorescent protein mCherry, we map the trajectories of growing microtubule ends and cytoplasmic boundary respectively. Based on EB1 tracks and cytoplasmic boundary outlines, we calculate the speed, distance from cytoplasmic boundary, and straightness of microtubule growth. Actin depolymerization with Latrunculin-A reduces EB1 growth speed as well as allows the trajectories to extend beyond the cytoplasmic boundary. Blebbistatin, a direct myosin-II inhibitor, reduced EB1 speed and yielded less straight EB1 trajectories. Inhibiting signaling upstream of myosin-II contractility via the Rho-kinase inhibitor, Y-27632, altered EB1 dynamics differently from Blebbistatin. These results indicate that reduced actin cortex integrity can induce distinct alterations in microtubule dynamics. Given recent findings that tumor stem cell characteristics are increased by drugs which reduce actin contractility or stabilize microtubules, it remains important to clearly define how cytoskeletal drugs alter the interactions between these two filament systems in tumor cells.

Hypertension in pregnancy: Taking cues from pathophysiology for clinical practice.

PubMed

Sava, Ruxandra I; March, Keith L; Pepine, Carl J

2018-02-01

Pregnancy-related hypertension (PHTN) syndromes are a frequent and potentially deadly complication of pregnancy, while also negatively impacting the lifelong health of the mother and child. PHTN appears in women likely to develop hypertension later in life, with the stress of pregnancy unmasking a subclinical hypertensive phenotype. However, distinguishing between PHTN and chronic hypertension is essential for optimal management. Preeclampsia (PE) is linked to potentially severe outcomes and lacks effective treatments due to poorly understood mechanisms. Inadequate remodeling of spiral uterine arteries (SUAs), the cornerstone of PE pathophysiology, leads to hypoperfusion of the developing placenta. In normal pregnancies, extravillous trophoblast (EVT) cells assume an invasive phenotype and invade SUAs, transforming them into large conduits. Decidual natural killer cells play an essential role, mediating materno-fetal immune tolerance, inducing early SUA remodeling and regulating EVT invasiveness. Notch signaling is important in EVT phenotypic switch and is dysregulated in PE. The hypoxic placenta releases antiangiogenic and proinflammatory factors that converge upon maternal endothelium, inducing endothelial dysfunction, hypertension, and organ damage. Hypoxia-inducible factor 1-α is upstream of such molecules, whereas endothelin-1 is a major effector. We also describe important genetic links and evidence of incomplete materno-fetal immune tolerance, with PE patients presenting with autoantibodies, lower T reg , and higher T h 17 cells. Thus, PE manifestations arise as a consequence of mal-placentation or/and because of a predisposition of the maternal vascular bed to excessively react to pathogenic molecules. From this pathophysiological basis, we provide current and propose future therapeutic directions for PE. © 2018 Wiley Periodicals, Inc.

Alzheimer Disease: Scientific Breakthroughs and Translational Challenges.

PubMed

Caselli, Richard J; Beach, Thomas G; Knopman, David S; Graff-Radford, Neill R

2017-06-01

Alzheimer disease (AD) was originally conceived as a rare disease that caused presenile dementia but has come to be understood as the most prevalent cause of dementia at any age worldwide. It has an extended preclinical phase characterized by sequential changes in imaging and cerebrospinal fluid biomarkers with subtle memory decline beginning more than a decade before the emergence of symptomatic memory loss heralding the beginning of the mild cognitive impairment stage. The apolipoprotein E ε4 allele is a prevalent and potent risk factor for AD that has facilitated research into its preclinical phase. Cerebral Aβ levels build from preclinical through early dementia stages followed by hyperphosphorylated tau-related pathology, the latter driving cognitive deficits and dementia severity. Structural and molecular imaging can now recapitulate the neuropathology of AD antemortem. Autosomal dominant forms of early-onset familial AD gave rise to the amyloid hypothesis of AD, which, in turn, has led to therapeutic trials of immunotherapy designed to clear cerebral amyloid, but to date results have been disappointing. Genome-wide association studies have identified multiple additional risk factors, but to date none have yielded an effective alternate therapeutic target. Current and future trials aimed at presymptomatic individuals either harboring cerebral amyloid or at genetically high risk offer the hope that earlier intervention might yet succeed where trials in patients with established dementia have failed. A major looming challenge will be that of expensive, incompletely effective disease-modifying therapy: who and when to treat, and how to pay for it. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Urine specific gravity as an indicator of dehydration in Olympic combat sport athletes; considerations for research and practice.

PubMed

Zubac, Damir; Reale, Reid; Karnincic, Hrvoje; Sivric, Anamaria; Jelaska, Igor

2018-05-10

Urine specific gravity (U SG ) is the most commonly reported biochemical marker used in research and applied settings to detect fluid deficits in athletes, including those participating in combat sports. Despite the popularity of its use, there has been a growing debate regarding the diagnostic accuracy and the applicability of U SG in characterizing whole-body fluid status and fluctuations. Moreover, recent investigations report universally high prevalence of hypohydration (∼90%) via U SG assessment in combat sport athletes, often in spite of stable body-mass. Given the widespread use in both research and practice, and its use in a regulatory sense as a 'hydration test' in combat sports as a means to detect dehydration at the time of weigh-in; understanding the limitations and applicability of U SG assessment is of paramount importance. Inconsistencies in findings of U SG readings, possibly as a consequence of diverse methodological research approaches and/or overlooked confounding factors, preclude a conclusive position stand within current combat sports research and practice. Thus the primary aim of this paper is to critically review the literature regarding U SG assessment of hydration status in combat sports research and practice. When taken on balance, the existing literature suggests: the use of laboratory derived benchmarks in applied settings, inconsistent sampling methodologies, the incomplete picture of how various confounding factors affect end-point readings, and the still poorly understood potential of renal adaptation to dehydration in combat athletes; make the utility of hydration assessment via U SG measurement quite problematic, particularly when diet and training is not controlled.

High Presence of Extracellular Hemoglobin in the Periventricular White Matter Following Preterm Intraventricular Hemorrhage

PubMed Central

Ley, David; Romantsik, Olga; Vallius, Suvi; Sveinsdóttir, Kristbjörg; Sveinsdóttir, Snjolaug; Agyemang, Alex A.; Baumgarten, Maria; Mörgelin, Matthias; Lutay, Nataliya; Bruschettini, Matteo; Holmqvist, Bo; Gram, Magnus

2016-01-01

Severe cerebral intraventricular hemorrhage (IVH) in preterm infants continues to be a major clinical problem, occurring in about 15–20% of very preterm infants. In contrast to other brain lesions the incidence of IVH has not been reduced over the last decade, but actually slightly increased. Currently over 50% of surviving infants develop post-hemorrhagic ventricular dilatation and about 35% develop severe neurological impairment, mainly cerebral palsy and intellectual disability. To date there is no therapy available to prevent infants from developing either hydrocephalus or serious neurological disability. It is known that blood rapidly accumulates within the ventricles following IVH and this leads to disruption of normal anatomy and increased local pressure. However, the molecular mechanisms causing brain injury following IVH are incompletely understood. We propose that extracellular hemoglobin is central in the pathophysiology of periventricular white matter damage following IVH. Using a preterm rabbit pup model of IVH the distribution of extracellular hemoglobin was characterized at 72 h following hemorrhage. Evaluation of histology, histochemistry, hemoglobin immunolabeling and scanning electron microscopy revealed presence of extensive amounts of extracellular hemoglobin, i.e., not retained within erythrocytes, in the periventricular white matter, widely distributed throughout the brain. Furthermore, double immunolabeling together with the migration and differentiation markers polysialic acid neural cell adhesion molecule (PSA-NCAM) demonstrates that a significant proportion of the extracellular hemoglobin is distributed in areas of the periventricular white matter with high extracellular plasticity. In conclusion, these findings support that extracellular hemoglobin may contribute to the pathophysiological processes that cause irreversible damage to the immature brain following IVH. PMID:27536248

Remodeling is a more important determinant of lumen size than atheroma burden in left main coronary artery disease.

PubMed

Berry, Colin; Noble, Stéphane; Ibrahim, Reda; Grégoire, Jean; Levesque, Sylvie; L'allier, Philippe L; Tardif, Jean-Claude

2010-07-01

Left main coronary artery (LMCA) disease influences survival; however, the predictors of LMCA changes over time are incompletely understood. Paired intravascular ultrasound (IVUS) and core laboratory analyses were performed in a standardized fashion in 207 subjects (mean +/- SD age 58 +/- 10 years, 80% men). The average follow-up duration was 18 months (range 12-24 months). The IVUS measurements were first obtained at the smallest lumen area and the largest plaque area at follow-up and the corresponding positions in the LMCA were then measured at baseline. The LMCA percentage of atheroma area at baseline was 38.2% +/- 11.8%, and 133 patients (64%) experienced an increase in percentage of atheroma area. Change in lumen area correlated positively with change in total vessel area (R = 0.85, P < .0001) and negatively with change in percentage of atheroma area (R = -0.58, P < .0001). Change in plaque area correlated well with change in total vessel area (R = 0.64, P < .0001) but only weakly with change in lumen area (r = 0.14, P = .039). Although LMCA length correlated negatively with baseline lumen area and total vessel area, it did not correlate with their changes over time. On multivariable analyses, current smoking predicted an increase in percentage of atheroma area (P = .0013) and plaque area (P = .0041). Height negatively predicted change in percentage of atheroma area (P = .001). The LMCA lumen dimensions are more tightly linked with remodeling than with atheroma progression/regression. Copyright (c) 2010 Mosby, Inc. All rights reserved.

Cardiovascular Redox and Ox Stress Proteomics

PubMed Central

Kumar, Vikas; Calamaras, Timothy Dean; Haeussler, Dagmar; Colucci, Wilson Steven; Cohen, Richard Alan; McComb, Mark Errol; Pimentel, David

2012-01-01

Abstract Significance: Oxidative post-translational modifications (OPTMs) have been demonstrated as contributing to cardiovascular physiology and pathophysiology. These modifications have been identified using antibodies as well as advanced proteomic methods, and the functional importance of each is beginning to be understood using transgenic and gene deletion animal models. Given that OPTMs are involved in cardiovascular pathology, the use of these modifications as biomarkers and predictors of disease has significant therapeutic potential. Adequate understanding of the chemistry of the OPTMs is necessary to determine what may occur in vivo and which modifications would best serve as biomarkers. Recent Advances: By using mass spectrometry, advanced labeling techniques, and antibody identification, OPTMs have become accessible to a larger proportion of the scientific community. Advancements in instrumentation, database search algorithms, and processing speed have allowed MS to fully expand on the proteome of OPTMs. In addition, the role of enzymatically reversible OPTMs has been further clarified in preclinical models. Critical Issues: The identification of OPTMs suffers from limitations in analytic detection based on the methodology, instrumentation, sample complexity, and bioinformatics. Currently, each type of OPTM requires a specific strategy for identification, and generalized approaches result in an incomplete assessment. Future Directions: Novel types of highly sensitive MS instrumentation that allow for improved separation and detection of modified proteins and peptides have been crucial in the discovery of OPTMs and biomarkers. To further advance the identification of relevant OPTMs in advanced search algorithms, standardized methods for sample processing and depository of MS data will be required. Antioxid. Redox Signal. 17, 1528–1559. PMID:22607061

Persistent Atrial Fibrillation Ablation using the Tip-Versatile Ablation Catheter.

PubMed

Davies, Edward J; Clayton, Ben; Lines, Ian; Haywood, Guy A

2016-07-01

The mechanisms by which persistent atrial fibrillation (PsAF) develops are incompletely understood. Consequently, the optimal strategy for the ablative management of PsAF remains debated. Current methods are often time consuming, complex and non-reproducible. We assessed the Tip-Versatile Ablation Catheter (T-VAC) technique, a rapidly delivered, empirical technique based on the box-set concept using duty-cycled linear catheter ablation technology. Forty-four procedures in 40 patients undergoing PsAF ablation with the novel technique were prospectively entered onto a database: 27 de novo. Primary endpoint was freedom from arrhythmia at over two-year follow-up. Secondary endpoints were time to first arrhythmia recurrence, freedom from atrial fibrillation (AF) on and off antiarrhythmic drugs (AAD), procedural and fluoroscopy duration and complication rate. At mean follow-up of 33 months, absolute freedom from arrhythmia recurrence was 45% in the de novo group. Overall, at 33 (IQR 24-63) months, 60% of de novo patients were in sustained normal sinus rhythm and a further 15% reported only occasional paroxysms of AF at long-term follow-up. Procedure time was 192±25 mins, total energy delivered 2239±883s and fluoroscopy time was 60±10mins. In selected patients with persistent AF, a long-term rate of 60% arrhythmia free survival off AAD can be achieved using this novel T-VAC technique. Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Children and adults minimise activated muscle volume by selecting gait parameters that balance gross mechanical power and work demands.

PubMed

Hubel, Tatjana Y; Usherwood, James R

2015-09-01

Terrestrial locomotion on legs is energetically expensive. Compared with cycling, or with locomotion in swimming or flying animals, walking and running are highly uneconomical. Legged gaits that minimise mechanical work have previously been identified and broadly match walking and running at appropriate speeds. Furthermore, the 'cost of muscle force' approaches are effective in relating locomotion kinetics to metabolic cost. However, few accounts have been made for why animals deviate from either work-minimising or muscle-force-minimising strategies. Also, there is no current mechanistic account for the scaling of locomotion kinetics with animal size and speed. Here, we report measurements of ground reaction forces in walking children and adult humans, and their stance durations during running. We find that many aspects of gait kinetics and kinematics scale with speed and size in a manner that is consistent with minimising muscle activation required for the more demanding between mechanical work and power: spreading the duration of muscle action reduces activation requirements for power, at the cost of greater work demands. Mechanical work is relatively more demanding for larger bipeds--adult humans--accounting for their symmetrical M-shaped vertical force traces in walking, and relatively brief stance durations in running compared with smaller bipeds--children. The gaits of small children, and the greater deviation of their mechanics from work-minimising strategies, may be understood as appropriate for their scale, not merely as immature, incompletely developed and energetically sub-optimal versions of adult gaits. © 2015. Published by The Company of Biologists Ltd.

Critical role of the axonal guidance cue EphrinB2 in lung growth, angiogenesis, and repair.

PubMed

Vadivel, Arul; van Haaften, Tim; Alphonse, Rajesh S; Rey-Parra, Gloria-Juliana; Ionescu, Lavinia; Haromy, Al; Eaton, Farah; Michelakis, Evangelos; Thébaud, Bernard

2012-03-01

Lung diseases characterized by alveolar damage currently lack efficient treatments. The mechanisms contributing to normal and impaired alveolar growth and repair are incompletely understood. Axonal guidance cues (AGC) are molecules that guide the outgrowth of axons to their targets. Among these AGCs, members of the Ephrin family also promote angiogenesis, cell migration, and organogenesis outside the nervous system. The role of Ephrins during alveolar growth and repair is unknown. We hypothesized that EphrinB2 promotes alveolar development and repair. We used in vitro and in vivo manipulation of EphrinB2 signaling to assess the role of this AGC during normal and impaired lung development. In vivo EphrinB2 knockdown using intranasal siRNA during the postnatal stage of alveolar development in rats arrested alveolar and vascular growth. In a model of O(2)-induced arrested alveolar growth in newborn rats, air space enlargement, loss of lung capillaries, and pulmonary hypertension were associated with decreased lung EphrinB2 and receptor EphB4 expression. In vitro, EphrinB2 preserved alveolar epithelial cell viability in O(2), decreased O(2)-induced alveolar epithelial cell apoptosis, and accelerated alveolar epithelial cell wound healing, maintained lung microvascular endothelial cell viability, and proliferation and vascular network formation. In vivo, treatment with intranasal EphrinB2 decreased alveolar epithelial and endothelial cell apoptosis, preserved alveolar and vascular growth in hyperoxic rats, and attenuated pulmonary hypertension. The AGC EphrinB2 may be a new therapeutic target for lung repair and pulmonary hypertension.

Long-term changes in lower tropospheric baseline ozone concentrations: Comparing chemistry-climate models and observations at northern midlatitudes

NASA Astrophysics Data System (ADS)

Parrish, D. D.; Lamarque, J.-F.; Naik, V.; Horowitz, L.; Shindell, D. T.; Staehelin, J.; Derwent, R.; Cooper, O. R.; Tanimoto, H.; Volz-Thomas, A.; Gilge, S.; Scheel, H.-E.; Steinbacher, M.; Fröhlich, M.

2014-05-01

Two recent papers have quantified long-term ozone (O3) changes observed at northern midlatitude sites that are believed to represent baseline (here understood as representative of continental to hemispheric scales) conditions. Three chemistry-climate models (NCAR CAM-chem, GFDL-CM3, and GISS-E2-R) have calculated retrospective tropospheric O3 concentrations as part of the Atmospheric Chemistry and Climate Model Intercomparison Project and Coupled Model Intercomparison Project Phase 5 model intercomparisons. We present an approach for quantitative comparisons of model results with measurements for seasonally averaged O3 concentrations. There is considerable qualitative agreement between the measurements and the models, but there are also substantial and consistent quantitative disagreements. Most notably, models (1) overestimate absolute O3 mixing ratios, on average by 5 to 17 ppbv in the year 2000, (2) capture only 50% of O3 changes observed over the past five to six decades, and little of observed seasonal differences, and (3) capture 25 to 45% of the rate of change of the long-term changes. These disagreements are significant enough to indicate that only limited confidence can be placed on estimates of present-day radiative forcing of tropospheric O3 derived from modeled historic concentration changes and on predicted future O3 concentrations. Evidently our understanding of tropospheric O3, or the incorporation of chemistry and transport processes into current chemical climate models, is incomplete. Modeled O3 trends approximately parallel estimated trends in anthropogenic emissions of NOx, an important O3 precursor, while measured O3 changes increase more rapidly than these emission estimates.

49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

Code of Federal Regulations, 2014 CFR

2014-10-01

... manufacturing operation on the incomplete vehicle. (3) Identification of the incomplete vehicle(s) to which the document applies. The identification shall be by vehicle identification number (VIN) or groups of VINs to... 49 Transportation 6 2014-10-01 2014-10-01 false Requirements for incomplete vehicle manufacturers...

49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

Code of Federal Regulations, 2011 CFR

2011-10-01

... manufacturing operation on the incomplete vehicle. (3) Identification of the incomplete vehicle(s) to which the document applies. The identification shall be by vehicle identification number (VIN) or groups of VINs to... 49 Transportation 6 2011-10-01 2011-10-01 false Requirements for incomplete vehicle manufacturers...

49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

Code of Federal Regulations, 2010 CFR

2010-10-01

... manufacturing operation on the incomplete vehicle. (3) Identification of the incomplete vehicle(s) to which the document applies. The identification shall be by vehicle identification number (VIN) or groups of VINs to... 49 Transportation 6 2010-10-01 2010-10-01 false Requirements for incomplete vehicle manufacturers...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 6 2012-10-01 2012-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 6 2010-10-01 2010-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 6 2014-10-01 2014-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 6 2013-10-01 2013-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

49 CFR 529.4 - Requirements for incomplete automobile manufacturers.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 6 2011-10-01 2011-10-01 false Requirements for incomplete automobile... AUTOMOBILES § 529.4 Requirements for incomplete automobile manufacturers. (a) Except as provided in paragraph (c) of this section, §§ 529.5 and 529.6, each incomplete automobile manufacturer is considered, with...

The Federal Budget: Current and Upcoming Issues

DTIC Science & Technology

2009-11-25

90 Milton Friedman , Capitalism and Freedom (Chicago: Univ. of Chicago Press, 1962), pp. 75-84. The Federal Budget...deficit, according to some budget experts, gives an incomplete view of the government’s fiscal condition because it includes Social Security surpluses...MSR/; “A New Era of Responsibility : Renewing America’s Promise,” February 26, 2009. A detailed discussion of how the FY2009 deficit has changed since

Hall current effects in the Lewis magnetohydrodynamic generator

NASA Technical Reports Server (NTRS)

Nichols, L. D.; Sovie, R. J.

1972-01-01

Data obtained in a magnetohydrodynamic generator are compared with theoretical values calculated by using the Dzung theory. The generator was operated with cesium-seeded argon as the working fluid. The gas temperature varied from 1800 to 2100 K, the gas pressure from 19 to 22 N/sq cm, the Mach number from 0.3 to 0.5, and the magnetic field strength from 0.2 to 1.6 T. The analysis indicates that there is incomplete seed vaporization and that Hall current shorting paths (through the working fluid to ground at both the entrance and exit of the channel) limit generator performance.

CLCA1 and TMEM16A: the link towards a potential cure for airway diseases.

PubMed

Brett, Tom J

2015-10-01

The hallmark traits of chronic obstructive airway diseases are inflammation, airway constriction due to hyperreactivity and mucus overproduction. The current common treatments for asthma and chronic obstructive pulmonary disease target the first two traits with none currently targeting mucus overproduction. The main source of obstructive mucus production is mucus cell metaplasia (MCM), the transdifferentiation of airway epithelial cells into mucus-producing goblet cells, in the small airways. Our current understanding of MCM is profusely incomplete. Few of the molecular players involved in driving MCM in humans have been identified and for many of those that have, their functions and mechanisms are unknown. This fact has limited the development of therapeutics that target mucus overproduction by inhibiting MCM. Current work in the field is aiming to change that.

A Study of Incomplete Abortion Following Medical Method of Abortion (MMA).

PubMed

Pawde, Anuya A; Ambadkar, Arun; Chauhan, Anahita R

2016-08-01

Medical method of abortion (MMA) is a safe, efficient, and affordable method of abortion. However, incomplete abortion is a known side effect. To study incomplete abortion due to medication abortion and compare to spontaneous incomplete abortion and to study referral practices and prescriptions in cases of incomplete abortion following MMA. Prospective observational study of 100 women with first trimester incomplete abortion, divided into two groups (spontaneous or following MMA), was administered a questionnaire which included information regarding onset of bleeding, treatment received, use of medications for abortion, its prescription, and administration. Comparison of two groups was done using Fisher exact test (SPSS 21.0 software). Thirty percent of incomplete abortions were seen following MMA; possible reasons being self-administration or prescription by unregistered practitioners, lack of examination, incorrect dosage and drugs, and lack of follow-up. Complications such as collapse, blood requirement, and fever were significantly higher in these patients compared to spontaneous abortion group. The side effects of incomplete abortions following MMA can be avoided by the following standard guidelines. Self medication, over- the-counter use, and prescription by unregistered doctors should be discouraged and reported, and need of follow-up should be emphasized.

Estimate of true incomplete exchanges using fluorescence in situ hybridization with telomere probes

NASA Technical Reports Server (NTRS)

Wu, H.; George, K.; Yang, T. C.

1998-01-01

PURPOSE: To study the frequency of true incomplete exchanges in radiation-induced chromosome aberrations. MATERIALS AND METHODS: Human lymphocytes were exposed to 2 Gy and 5 Gy of gamma-rays. Chromosome aberrations were studied using the fluorescence in situ hybridization (FISH) technique with whole chromosome-specific probes, together with human telomere probes. Chromosomes 2 and 4 were chosen in the present study. RESULTS: The percentage of incomplete exchanges was 27% when telomere signals were not considered. After excluding false incomplete exchanges identified by the telomere signals, the percentage of incomplete exchanges decreased to 11%. Since telomere signals appear on about 82% of the telomeres, the percentage of true incomplete exchanges should be even lower and was estimated to be 3%. This percentage was similar for chromosomes 2 and 4 and for doses of both 2 Gy and 5 Gy. CONCLUSIONS: The percentage of true incomplete exchanges is significantly lower in gamma-irradiated human lymphocytes than the frequencies reported in the literature.

Effective Time Management in Battalion Task Force Operations

DTIC Science & Technology

1993-06-01

at the National Training Center is used to isolate areas that are symptomatic of time management deficiencies and to establish that a problem of...managing exists within task force operations. This study establishes that time management is a problem and that current doctrinal references offer...incomplete time management guidance. This study then suggests a variety of techniques and procedures to improve the problem. This study concludes time can be

Argonne Geothermal Geochemical Database v2.0

DOE Data Explorer

Harto, Christopher

2013-05-22

A database of geochemical data from potential geothermal sources aggregated from multiple sources as of March 2010. The database contains fields for the location, depth, temperature, pH, total dissolved solids concentration, chemical composition, and date of sampling. A separate tab contains data on non-condensible gas compositions. The database contains records for over 50,000 wells, although many entries are incomplete. Current versions of source documentation are listed in the dataset.

Parallel image reconstruction for 3D positron emission tomography from incomplete 2D projection data

NASA Astrophysics Data System (ADS)

Guerrero, Thomas M.; Ricci, Anthony R.; Dahlbom, Magnus; Cherry, Simon R.; Hoffman, Edward T.

1993-07-01

The problem of excessive computational time in 3D Positron Emission Tomography (3D PET) reconstruction is defined, and we present an approach for solving this problem through the construction of an inexpensive parallel processing system and the adoption of the FAVOR algorithm. Currently, the 3D reconstruction of the 610 images of a total body procedure would require 80 hours and the 3D reconstruction of the 620 images of a dynamic study would require 110 hours. An inexpensive parallel processing system for 3D PET reconstruction is constructed from the integration of board level products from multiple vendors. The system achieves its computational performance through the use of 6U VME four i860 processor boards, the processor boards from five manufacturers are discussed from our perspective. The new 3D PET reconstruction algorithm FAVOR, FAst VOlume Reconstructor, that promises a substantial speed improvement is adopted. Preliminary results from parallelizing FAVOR are utilized in formulating architectural improvements for this problem. In summary, we are addressing the problem of excessive computational time in 3D PET image reconstruction, through the construction of an inexpensive parallel processing system and the parallelization of a 3D reconstruction algorithm that uses the incomplete data set that is produced by current PET systems.

Semantic Borders and Incomplete Understanding.

PubMed

Silva-Filho, Waldomiro J; Dazzani, Maria Virgínia

2016-03-01

In this article, we explore a fundamental issue of Cultural Psychology, that is our "capacity to make meaning", by investigating a thesis from contemporary philosophical semantics, namely, that there is a decisive relationship between language and rationality. Many philosophers think that for a person to be described as a rational agent he must understand the semantic content and meaning of the words he uses to express his intentional mental states, e.g., his beliefs and thoughts. Our argument seeks to investigate the thesis developed by Tyler Burge, according to which our mastery or understanding of the semantic content of the terms which form our beliefs and thoughts is an "incomplete understanding". To do this, we discuss, on the one hand, the general lines of anti-individualism or semantic externalism and, on the other, criticisms of the Burgean notion of incomplete understanding - one radical and the other moderate. We defend our understanding that the content of our beliefs must be described in the light of the limits and natural contingencies of our cognitive capacities and the normative nature of our rationality. At heart, anti-individualism leads us to think about the fact that we are social creatures, living in contingent situations, with important, but limited, cognitive capacities, and that we receive the main, and most important, portion of our knowledge simply from what others tell us. Finally, we conclude that this discussion may contribute to the current debate about the notion of borders.

Cross-face nerve grafting for reanimation of incomplete facial paralysis: quantitative outcomes using the FACIAL CLIMA system and patient satisfaction.

PubMed

Hontanilla, Bernardo; Marre, Diego; Cabello, Alvaro

2014-01-01

Although in most cases Bell palsy resolves spontaneously, approximately one-third of patients will present sequela including facial synkinesis and paresis. Currently, the techniques available for reanimation of these patients include hypoglossal nerve transposition, free muscle transfer, and cross-face nerve grafting (CFNG). Between December 2008 and March 2012, eight patients with incomplete unilateral facial paralysis were reanimated with two-stage CFNG. Gender, age at surgery, etiology of paralysis denervation time, donor and recipient nerves, presence of facial synkinesis, and follow-up were registered. Commissural excursion and velocity and patient satisfaction were evaluated with the FACIAL CLIMA and a questionnaire, respectively. Mean age at surgery was 33.8 ± 11.5 years; mean time of denervation was 96.6 ± 109.8 months. No complications requiring surgery were registered. Follow-up period ranged from 7 to 33 months with a mean of 19 ± 9.7 months. FACIAL CLIMA showed improvement of both commissural excursion and velocity greater than 75% in 4 patients, greater than 50% in 2 patients, and less than 50% in the remaining two patients. Qualitative evaluation revealed a high grade of satisfaction in six patients (75%). Two-stage CFNG is a reliable technique for reanimation of incomplete facial paralysis with a high grade of patient satisfaction. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Influence of incomplete fusion on complete fusion at energies above the Coulomb barrier

NASA Astrophysics Data System (ADS)

Shuaib, Mohd; Sharma, Vijay R.; Yadav, Abhishek; Sharma, Manoj Kumar; Singh, Pushpendra P.; Singh, Devendra P.; Kumar, R.; Singh, R. P.; Muralithar, S.; Singh, B. P.; Prasad, R.

2017-10-01

In the present work, excitation functions of several reaction residues in the system 19F+169Tm, populated via the complete and incomplete fusion processes, have been measured using off-line γ-ray spectroscopy. The analysis of excitation functions has been done within the framework of statistical model code pace4. The excitation functions of residues populated via xn and pxn channels are found to be in good agreement with those estimated by the theoretical model code, which confirms the production of these residues solely via complete fusion process. However, a significant enhancement has been observed in the cross-sections of residues involving α-emitting channels as compared to the theoretical predictions. The observed enhancement in the cross-sections has been attributed to the incomplete fusion processes. In order to have a better insight into the onset and strength of incomplete fusion, the incomplete fusion strength function has been deduced. At present, there is no theoretical model available which can satisfactorily explain the incomplete fusion reaction data at energies ≈4-6 MeV/nucleon. In the present work, the influence of incomplete fusion on complete fusion in the 19F+169Tm system has also been studied. The measured cross-section data may be important for the development of reactor technology as well. It has been found that the incomplete fusion strength function strongly depends on the α-Q value of the projectile, which is found to be in good agreement with the existing literature data. The analysis strongly supports the projectile-dependent mass-asymmetry systematics. In order to study the influence of Coulomb effect ({Z}{{P}}{Z}{{T}}) on incomplete fusion, the deduced strength function for the present work is compared with the nearby projectile-target combinations. The incomplete fusion strength function is found to increase linearly with {Z}{{P}}{Z}{{T}}, indicating a strong influence of Coulomb effect in the incomplete fusion reactions.

The Stratigraphic Incompleteness of Submarine Channels

NASA Astrophysics Data System (ADS)

Vendettuoli, D.; Clare, M. A.; Hughes Clarke, J. E.; Cartigny, M.; Vellinga, A. J.; Talling, P.; Hizzett, J. L.; Hage, S.; Waltham, D.; Hubbard, S. M.

2017-12-01

Turbidity currents transport prodigious quantities of sediment across the world's oceans through submarine channels. These flows damage strategically important seafloor infrastructure and their deposits host major oil and gas reservoirs. We therefore need to understand these flows, but their very powerful nature makes direct monitoring challenging. Most studies to date focus on the deposits that turbidity currents leave behind in the sedimentological record. However, deposits of individual flows are likely to be reworked by successive flows, but it is unclear as to what extent. How complete is the stratigraphy of these deposits? What percentage of flow deposits are preserved in the rock record? Are some events better preserved than others, and if so, why? We address these questions by re-analysing the most detailed time-lapse mapping yet of a turbidity current system. This field dataset comes from the fjord-head Squamish Delta in British Columbia, Canada where Hughes Clarke (2016) collected 93 near-daily repeat surveys in 2011. These surveys revealed the seafloor response to more than 100 turbidity currents. Here we use temporal changes in seabed elevation to understand patterns of deposition and erosion. We calculate the total thickness of sediment deposited at each location, and document the percentage of sediment that is preserved (i.e. stratigraphic completeness) at multiple time-steps over the surveyed period. The average stratigraphic completeness across the delta near submarine channels is <1%, but this is highly spatially variable. Some levees record up to 40% completeness. The low value is largely due to upstream migrating bedforms that constantly rework previously emplaced sediments. Surprisingly, even at the terminal lobes, stratigraphic completeness is typically <5%. These results provide new insights into the evolution of submarine channels and why their deposits produce a highly incomplete record of submarine flows.

Using an improved understanding of current climate variability to develop increased drought resilience in UK irrigated agriculture

NASA Astrophysics Data System (ADS)

Holman, I.; Rey Vicario, D.

2016-12-01

Improving community preparedness for climate change can be supported by developing resilience to past events, focused on those changes of particular relevance (such as floods and droughts). However, communities' perceptions of impacts and risk can be influenced by an incomplete appreciation of historical baseline climate variability. This can arise from a number of factors including individual's age, access to long term data records and availability of local knowledge. For example, the most significant recent drought in the UK occurred in 1976/77 but does it represent the worst drought that did occur (or could have occurred) without climate change? We focus on the east of England where most irrigated agriculture is located and where many local farmers interviewed were either not in business then or have an incomplete memory of the impacts of the drought. This paper describes a comparison of an annual agroclimatic indicator closely linked to irrigation demand (maximum Potential Soil Moisture Deficit) calculated from three sources of long term observational and simulated historical weather data with recent data. These long term datasets include gridded measured / calculated datasets of precipitation and reference evapotranspiration; a dynamically downscaled 20th Century Re-analysis dataset, and two Regional Climate Model ensemble datasets (FutureFlows and the MaRIUS event set) which each provide between 110 and 3000 years of baseline weather. The comparison shows that the long term datasets provide a wider characterisation of current climate variability and affect the perception of current drought frequency and severity. The paper will show that using a more comprehensive understanding of current climate variability and drought risk as a basis for adapting irrigated systems to droughts can provide substantial increased resilience to (uncertain) climate change.

Transcranial direct current stimulation (tDCS) of the primary motor cortex and robot-assisted arm training in chronic incomplete cervical spinal cord injury: A proof of concept sham-randomized clinical study.

PubMed

Yozbatiran, Nuray; Keser, Zafer; Davis, Matthew; Stampas, Argyrios; O'Malley, Marcia K; Cooper-Hay, Catherine; Frontera, Joel; Fregni, Felipe; Francisco, Gerard E

2016-07-15

After cervical spinal cord injury, current options for treatment of upper extremity motor functions have been limited to traditional approaches. However, there is a substantial need to explore more rigorous alternative treatments to facilitate motor recovery. To demonstrate whether anodal-primary motor cortex (M1) excitability enhancement (with cathodal-supra orbital area) (atDCS) combined with robot-assisted arm training (R-AAT) will provide greater improvement in contralateral arm and hand motor functions compared to sham stimulation (stDCS) and R-AAT in patients with chronic, incomplete cervical spinal cord injury (iCSCI). In this parallel-group, double-blinded, randomized and sham-controlled trial, nine participants with chronic iCSCI (AIS C and D level) were randomized to receive 10 sessions of atDCS or stDSC combined with R-AAT. Feasibility and tolerability was assessed with attrition rate and occurrence of adverse events, Changes in arm and hand function were assessed with Jebson Taylor Hand Function Test (JTHFT). Amount of Use Scale of Motor Activity Log (AOU-MAL), American Spinal Injury Association Upper Extremity Motor Score and Modified Ashworth Scale (MAS) at baseline, after treatment, and at two-month follow-up. None of the participants missed a treatment session or dropped-out due to adverse events related to the treatment protocol. Participants tended to perform better in JTHFT and AOU-MAL after treatment. Active group at post-treatment and two-month follow-up demonstrated better arm and hand performance compared to sham group. These preliminary findings support that modulating excitatory input of the corticospinal tracts on spinal circuits may be a promising strategy in improving arm and hand functions in persons with incomplete tetraplegia. Further study is needed to explore the underlying mechanisms of recovery.

Amyloidosis in a Captive Zebra Finch (Taeniopygia guttata) Research Colony

PubMed Central

Shientag, Lisa J; Garlick, David S; Galati, Erin

2016-01-01

Five birds in a captive zebra finch research colony were diagnosed with systemic amyloidosis within a 7-mo period by means of postmortem Congo red staining and green birefringence under polarized light. The liver was the most frequently and usually the most seriously affected organ, followed by the spleen and then the kidney. All 5 birds had been clinically affected with various inflammatory, infectious, and neoplastic conditions associated with amyloid A (AA) amyloidosis in humans and animals. Immunohistochemistry using antisera against duck AA protein revealed that tissues from 2 of the 5 birds were positive for the presence of AA protein and systemic inflammation-associated amyloidosis. Although the development of AA amyloidosis has been associated with chronic inflammation, trauma, and various infectious and neoplastic diseases as well as possible genetic predispositions and stresses linked to overcrowding, the root causes for individual cases of AA amyloidosis are incompletely understood. As far as we know, this report is the first description of AA amyloidosis in captive, research zebra finches. PMID:27298248

Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity.

PubMed

Shirakawa, Kotaro; Wang, Lan; Man, Na; Maksimoska, Jasna; Sorum, Alexander W; Lim, Hyung W; Lee, Intelly S; Shimazu, Tadahiro; Newman, John C; Schröder, Sebastian; Ott, Melanie; Marmorstein, Ronen; Meier, Jordan; Nimer, Stephen; Verdin, Eric

2016-05-31

Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-κB activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs.

Silk Self-Assembly Mechanisms and Control-From Thermodynamics to Kinetics

PubMed Central

Lu, Qiang; Zhu, Hesun; Zhang, Cencen; Zhang, Feng; Zhang, Bing; Kaplan, David L.

2012-01-01

Silkworms and spiders generate fibres that exhibit high strength and extensibility. The underlying mechanisms involved in processing silk proteins into fiber form remain incompletely understood, resulting in the failure to fully recapitulate the remarkable properties of native fibers in vitro from regenerated silk solutions. In the present study, the extensibility and high strength of regenerated silks were achieved by mimicking the natural spinning process. Conformational transitions inside micelles, followed by aggregation of micelles and their stabilization as they relate to the metastable structure of silk are described. Subsequently, the mechanisms to control the formation of nanofibrous structures were elucidated. The results clarify that the self-assembly of silk in aqueous solution is a thermodynamically driven process where kinetics also play a key role. Four key factors, molecular mobility, charge, hydrophilic interactions and concentration underlie the process. Adjusting these factors can balance nanostructure and conformational composition, and be used to achieve silk-based materials with properties comparable to native fibers. These mechanisms suggest new directions to design silk-based multifunctional materials. PMID:22320432

Structural basis of the 9-fold symmetry of centrioles.

PubMed

Kitagawa, Daiju; Vakonakis, Ioannis; Olieric, Natacha; Hilbert, Manuel; Keller, Debora; Olieric, Vincent; Bortfeld, Miriam; Erat, Michèle C; Flückiger, Isabelle; Gönczy, Pierre; Steinmetz, Michel O

2011-02-04

The centriole, and the related basal body, is an ancient organelle characterized by a universal 9-fold radial symmetry and is critical for generating cilia, flagella, and centrosomes. The mechanisms directing centriole formation are incompletely understood and represent a fundamental open question in biology. Here, we demonstrate that the centriolar protein SAS-6 forms rod-shaped homodimers that interact through their N-terminal domains to form oligomers. We establish that such oligomerization is essential for centriole formation in C. elegans and human cells. We further generate a structural model of the related protein Bld12p from C. reinhardtii, in which nine homodimers assemble into a ring from which nine coiled-coil rods radiate outward. Moreover, we demonstrate that recombinant Bld12p self-assembles into structures akin to the central hub of the cartwheel, which serves as a scaffold for centriole formation. Overall, our findings establish a structural basis for the universal 9-fold symmetry of centrioles. Copyright © 2011 Elsevier Inc. All rights reserved.

Gentle reenergization of electrons in merging galaxy clusters

PubMed Central

de Gasperin, Francesco; Intema, Huib T.; Shimwell, Timothy W.; Brunetti, Gianfranco; Brüggen, Marcus; Enßlin, Torsten A.; van Weeren, Reinout J.; Bonafede, Annalisa; Röttgering, Huub J. A.

2017-01-01

Galaxy clusters are the most massive constituents of the large-scale structure of the universe. Although the hot thermal gas that pervades galaxy clusters is relatively well understood through observations with x-ray satellites, our understanding of the nonthermal part of the intracluster medium (ICM) remains incomplete. With Low-Frequency Array (LOFAR) and Giant Metrewave Radio Telescope (GMRT) observations, we have identified a phenomenon that can be unveiled only at extremely low radio frequencies and offers new insights into the nonthermal component. We propose that the interplay between radio-emitting plasma and the perturbed intracluster medium can gently reenergize relativistic particles initially injected by active galactic nuclei. Sources powered through this mechanism can maintain electrons at higher energies than radiative aging would allow. If this mechanism is common for aged plasma, a population of mildly relativistic electrons can be accumulated inside galaxy clusters providing the seed population for merger-induced reacceleration mechanisms on larger scales such as turbulence and shock waves. PMID:28983512

Ultrasound screening of periarticular soft tissue abnormality around metal-on-metal bearings.

PubMed

Nishii, Takashi; Sakai, Takashi; Takao, Masaki; Yoshikawa, Hideki; Sugano, Nobuhiko

2012-06-01

Although metal hypersensitivity or pseudotumors are concerns for metal-on-metal (MoM) bearings, detailed pathologies of patterns, severity, and incidence of periprosthetic soft tissue lesions are incompletely understood. We examined the potential of ultrasound for screening of periarticular soft tissue lesions around MoM bearings. Ultrasound examinations were conducted in 88 hips (79 patients) with MoM hip resurfacings or MoM total hip arthroplasties with a large femoral head. Four qualitative ultrasound patterns were shown, including normal pattern in 69 hips, joint-expansion pattern in 11 hips, cystic pattern in 5 hips, and mass pattern in 3 hips. Hips with the latter 3 abnormal patterns showed significantly higher frequency of clinical symptoms, without significant differences of sex, duration of implantation, head sizes, and cup abduction/anteversion angles, compared with hips with normal pattern. Ultrasound examination provides sensitive screening of soft tissue reactions around MoM bearings and may be useful in monitoring progression and defining treatment for periarticular soft tissue abnormalities. Copyright © 2012 Elsevier Inc. All rights reserved.

Observation, Inference, and Imagination: Elements of Edgar Allan Poe's Philosophy of Science

NASA Astrophysics Data System (ADS)

Gelfert, Axel

2014-03-01

Edgar Allan Poe's standing as a literary figure, who drew on (and sometimes dabbled in) the scientific debates of his time, makes him an intriguing character for any exploration of the historical interrelationship between science, literature and philosophy. His sprawling `prose-poem' Eureka (1848), in particular, has sometimes been scrutinized for anticipations of later scientific developments. By contrast, the present paper argues that it should be understood as a contribution to the raging debates about scientific methodology at the time. This methodological interest, which is echoed in Poe's `tales of ratiocination', gives rise to a proposed new mode of—broadly abductive—inference, which Poe attributes to the hybrid figure of the `poet-mathematician'. Without creative imagination and intuition, Science would necessarily remain incomplete, even by its own standards. This concern with imaginative (abductive) inference ties in nicely with his coherentism, which grants pride of place to the twin virtues of Simplicity and Consistency, which must constrain imagination lest it degenerate into mere fancy.

Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase

PubMed Central

Jiang, Tao; Yu, Kuai

2017-01-01

From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca2+ binding stimulates its open conformation by altering the structure of transmembrane helices that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl- channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca2+-activated Cl- channel convert it into a robust scramblase. PMID:28917060

Transcranial electric stimulation (tES) and NeuroImaging: the state-of-the-art, new insights and prospects in basic and clinical neuroscience.

PubMed

Soekadar, Surjo R; Herring, Jim Don; McGonigle, David

2016-10-15

Transcranial electric stimulation (tES) of the brain has attracted an increased interest in recent years. Yet, despite remarkable research efforts to date, the underlying neurobiological mechanisms of tES' effects are still incompletely understood. This Special Issue aims to provide a comprehensive and up-to-date overview of the state-of-the-art in studies combining tES and neuroimaging, while introducing most recent insights and outlining future prospects related to this new and rapidly growing field. The findings reported here combine methodological advancements with insights into the underlying mechanisms of tES itself. At the same time, they also point to the many caveats and specific challenges associated with such studies, which can arise from both technical and biological sources. Besides promising to advance basic neuroscience, combined tES and neuroimaging studies may also substantially change previous conceptions about the methods of action of electric or magnetic stimulation on the brain. Copyright © 2016. Published by Elsevier Inc.

Alteration of the RANKL/RANK/OPG System in Periprosthetic Osteolysis with Septic Loosening.

PubMed

Wang, Long; Dai, Zixun; Xie, Jie; Liao, Hao; Lv, Cheng; Hu, Yihe

2016-02-01

The pathogenesis of periprosthetic osteolysis with septic loosening remains incompletely understood. The purpose of this study was to investigate whether expression of the RANKL/RANK/OPG system is altered in septic interface membranes (SIMs). Seventeen cases with a SIM, 26 cases with an aseptic interface membrane (AIM), and 12 cases with a normal synovium (NS) were assessed. Scanning and transmission electron microscopy (SEM and TEM, respectively) were used to observe the microscopic morphology of three tissue conditions. Differences in RANKL, RANK, and OPG expression at the mRNA level were assessed by real-time quantitative PCR, and differences at the protein level were assessed by immunohistochemical staining and Western blotting. SEM showed wear debris widely distributed on the AIM surface, and TEM showed Bacillus activity in the SIM. RANKL expression and the RANKL/OPG ratio were significantly increased in SIMs. Imbalance in the RANKL/RANK/OPG system is related to periprosthetic osteolysis with septic loosening but is not the only possible pathogenic mechanism.

SAS-1 Is a C2 Domain Protein Critical for Centriole Integrity in C. elegans

PubMed Central

Delattre, Marie; Balestra, Fernando R.; Blanchoud, Simon; Finger, Susanne; Knott, Graham; Müller-Reichert, Thomas; Gönczy, Pierre

2014-01-01

Centrioles are microtubule-based organelles important for the formation of cilia, flagella and centrosomes. Despite progress in understanding the underlying assembly mechanisms, how centriole integrity is ensured is incompletely understood, including in sperm cells, where such integrity is particularly critical. We identified C. elegans sas-1 in a genetic screen as a locus required for bipolar spindle assembly in the early embryo. Our analysis reveals that sperm-derived sas-1 mutant centrioles lose their integrity shortly after fertilization, and that a related defect occurs when maternal sas-1 function is lacking. We establish that sas-1 encodes a C2 domain containing protein that localizes to centrioles in C. elegans, and which can bind and stabilize microtubules when expressed in human cells. Moreover, we uncover that SAS-1 is related to C2CD3, a protein required for complete centriole formation in human cells and affected in a type of oral-facial-digital (OFD) syndrome. PMID:25412110

HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/β-Catenin Signaling Pathway.

PubMed

Wang, Yongdi; Liao, Jinxu; Tang, Shao-Jun; Shu, Jianhong; Zhang, Wenping

2017-06-01

HIV-1 gp120 plays a critical role in the pathogenesis of HIV-associated pain, but the underlying molecular mechanisms are incompletely understood. This study aims to determine the effect and possible mechanism of HIV-1 gp120 on BDNF expression in BV2 cells (a murine-derived microglial cell line). We observed that gp120 (10 ng/ml) activated BV2 cells in cultures and upregulated proBDNF/mBDNF. Furthermore, gp120-treated BV2 also accumulated Wnt3a and β-catenin, suggesting the activation of the Wnt/β-catenin pathway. We demonstrated that activation of the pathway by Wnt3a upregulated BDNF expression. In contrast, inhibition of the Wnt/β-catenin pathway by either DKK1 or IWR-1 attenuated BDNF upregulation induced by gp120 or Wnt3a. These findings collectively suggest that gp120 stimulates BDNF expression in BV2 cells via the Wnt/β-catenin signaling pathway.

A review of the immunomodulatory role of dietary tryptophan in livestock and poultry.

PubMed

Bai, Miaomiao; Liu, Hongnan; Xu, Kang; Oso, Abimbola Oladele; Wu, Xin; Liu, Gang; Tossou, Myrlene Carine B; Al-Dhabi, Naif Abdullah; Duraipandiyan, Veeramuthu; Xi, Qianyun; Yin, Yinlong

2017-01-01

Tryptophan, a nutritionally essential amino acid, is active in the regulation of immune responses in animals. The products of tryptophan metabolism, such as indoleamine 2,3-dioxygenase, kynurenine, quinolinic acid, and melatonin, may improve immunity in an organism and induce anti-inflammatory responses. The immune tolerance processes mediated by tryptophan metabolites are not well understood. Recent studies have reported that the enzymes that break down tryptophan through the kynurenine metabolic pathway are found in numerous cell types, including immunocytes. Moreover, some tryptophan metabolites have been shown to play a role in the inhibition of T lymphocyte proliferation, elevation of immunoglobulin levels in the blood, and promotion of antigen-presenting organization in tissues. This review summarizes the effects and mechanisms of tryptophan and metabolites in immune functions in livestock and poultry. It also highlights the areas in which our understanding of the role(s) of tryptophan is incomplete and suggests possible future research that might prove of benefit to livestock and poultry producers.

Neurons for hunger and thirst transmit a negative-valence teaching signal

PubMed Central

Gong, Rong; Magnus, Christopher J.; Yu, Yang; Sternson, Scott M.

2015-01-01

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics and dynamics of two separate neuron populations that regulate energy and fluid homeostasis by using cell type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis. PMID:25915020

Rules of engagement: incomplete and complete pronoun resolution.

PubMed

Love, Jessica; McKoon, Gail

2011-07-01

Research on shallow processing suggests that readers sometimes encode only a superficial representation of a text and fail to make use of all available information. Greene, McKoon, and Ratcliff (1992) extended this work to pronouns, finding evidence that readers sometimes fail to automatically identify referents even when these are unambiguous. In this paper we revisit those findings. In 11 recognition probe, priming, and self-report experiments, we manipulated Greene et al.'s stories to discover under what circumstances a pronoun's referent is automatically understood. We lengthened the stories from 4 to 8 lines. This simple manipulation led to automatic and correct resolution, which we attribute to readers' increased engagement with the stories. We found evidence of resolution even when the additional text did not mention the pronoun's referent. In addition, our results suggest that the pronoun temporarily boosts the referent's accessibility, an advantage that disappears by the end of the next sentence. Finally, we present evidence from memory experiments that supports complete pronoun resolution for the longer but not the shorter stories.

Dendritic cells and macrophages in the kidney: a spectrum of good and evil

PubMed Central

Rogers, NM; Ferenbach, DA; Isenberg, JS; Thomson, AW; Hughes, J

2015-01-01

Renal dendritic cells (DC) and macrophages (Mac) represent a constitutive, extensive and contiguous network of innate immune cells that provide sentinel and immune intelligence function. They induce and regulate inflammatory responses to freely-filtered antigenic material and protect the kidney from infection. Tissue–resident or infiltrating DC and Mac are key to the initiation and propagation of renal disease, as well as essential contributors to subsequent tissue regeneration regardless of its etiology and pathogenesis. Their identification, functional and phenotypic distinction, interplay and relationship with effector and regulatory adaptive immune cells is complex and incompletely understood. This review discusses both the common and distinct characteristics of these cells, as well as recent key advances in the field that have identified renal-specific functions of DC and Mac that enable these important, phagocytic, antigen-presenting, cells to mediate or mitigate intrinsic kidney disease. We also identify priority areas for further investigation and prospects for translational and therapeutic application of acquired knowledge. PMID:25266210

Redox-dependent substrate-cofactor interactions in the Michaelis-complex of a flavin-dependent oxidoreductase

NASA Astrophysics Data System (ADS)

Werther, Tobias; Wahlefeld, Stefan; Salewski, Johannes; Kuhlmann, Uwe; Zebger, Ingo; Hildebrandt, Peter; Dobbek, Holger

2017-07-01

How an enzyme activates its substrate for turnover is fundamental for catalysis but incompletely understood on a structural level. With redox enzymes one typically analyses structures of enzyme-substrate complexes in the unreactive oxidation state of the cofactor, assuming that the interaction between enzyme and substrate is independent of the cofactors oxidation state. Here, we investigate the Michaelis complex of the flavoenzyme xenobiotic reductase A with the reactive reduced cofactor bound to its substrates by X-ray crystallography and resonance Raman spectroscopy and compare it to the non-reactive oxidized Michaelis complex mimics. We find that substrates bind in different orientations to the oxidized and reduced flavin, in both cases flattening its structure. But only authentic Michaelis complexes display an unexpected rich vibrational band pattern uncovering a strong donor-acceptor complex between reduced flavin and substrate. This interaction likely activates the catalytic ground state of the reduced flavin, accelerating the reaction within a compressed cofactor-substrate complex.

Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline

DOE PAGES

Leal, Stephanie L.; Landau, Susan M.; Bell, Rachel K.; ...

2017-02-08

The amyloid hypothesis suggests that beta-amyloid (Aβ) deposition leads to alterations in neural function and ultimately to cognitive decline in Alzheimer’s disease. However, factors that underlie Aβ deposition are incompletely understood. One proposed model suggests that synaptic activity leads to increased Aβ deposition. More specifically, hyperactivity in the hippocampus may be detrimental and could be one factor that drives Aβ deposition. To test this model, we examined the relationship between hippocampal activity during a memory task using fMRI and subsequent longitudinal change in Aβ using PIB-PET imaging in cognitively normal older adults. We found that greater hippocampal activation at baselinemore » was associated with increased Aβ accumulation. Furthermore, increasing Aβ accumulation mediated the influence of hippocampal activation on declining memory performance, demonstrating a crucial role of Aβ in linking hippocampal activation and memory. These findings support a model linking increased hippocampal activation to subsequent Aβ deposition and cognitive decline.« less

Insights into GATA-1 Mediated Gene Activation versus Repression via Genome-wide Chromatin Occupancy Analysis

PubMed Central

Yu, Ming; Riva, Laura; Xie, Huafeng; Schindler, Yocheved; Moran, Tyler B.; Cheng, Yong; Yu, Duonan; Hardison, Ross; Weiss, Mitchell J; Orkin, Stuart H.; Bernstein, Bradley E.; Fraenkel, Ernest; Cantor, Alan B.

2009-01-01

Summary The transcription factor GATA-1 is required for terminal erythroid maturation and functions as an activator or repressor depending on gene context. Yet its in vivo site selectivity and ability to distinguish between activated versus repressed genes remain incompletely understood. In this study, we performed GATA-1 ChIP-seq in erythroid cells and compared it to GATA-1 induced gene expression changes. Bound and differentially expressed genes contain a greater number of GATA binding motifs, a higher frequency of palindromic GATA sites, and closer occupancy to the transcriptional start site versus non-differentially expressed genes. Moreover, we show that the transcription factor Zbtb7a occupies GATA-1 bound regions of some direct GATA-1 target genes, that the presence of SCL/TAL1 helps distinguish transcriptional activation versus repression, and that Polycomb Repressive Complex 2 (PRC2) is involved in epigenetic silencing of a subset of GATA-1 repressed genes. These data provide insights into GATA-1 mediated gene regulation in vivo. PMID:19941827

Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation

PubMed Central

Kinjyo, Ichiko; Qin, Jim; Tan, Sioh-Yang; Wellard, Cameron J.; Mrass, Paulus; Ritchie, William; Doi, Atsushi; Cavanagh, Lois L.; Tomura, Michio; Sakaue-Sawano, Asako; Kanagawa, Osami; Miyawaki, Atsushi; Hodgkin, Philip D.; Weninger, Wolfgang

2015-01-01

The precise pathways of memory T-cell differentiation are incompletely understood. Here we exploit transgenic mice expressing fluorescent cell cycle indicators to longitudinally track the division dynamics of individual CD8+ T cells. During influenza virus infection in vivo, naive T cells enter a CD62Lintermediate state of fast proliferation, which continues for at least nine generations. At the peak of the anti-viral immune response, a subpopulation of these cells markedly reduces their cycling speed and acquires a CD62Lhi central memory cell phenotype. Construction of T-cell family division trees in vitro reveals two patterns of proliferation dynamics. While cells initially divide rapidly with moderate stochastic variations of cycling times after each generation, a slow-cycling subpopulation displaying a CD62Lhi memory phenotype appears after eight divisions. Phenotype and cell cycle duration are inherited by the progeny of slow cyclers. We propose that memory precursors cell-intrinsically modulate their proliferative activity to diversify differentiation pathways. PMID:25709008

Inferring multi-scale neural mechanisms with brain network modelling

PubMed Central

Schirner, Michael; McIntosh, Anthony Randal; Jirsa, Viktor; Deco, Gustavo

2018-01-01

The neurophysiological processes underlying non-invasive brain activity measurements are incompletely understood. Here, we developed a connectome-based brain network model that integrates individual structural and functional data with neural population dynamics to support multi-scale neurophysiological inference. Simulated populations were linked by structural connectivity and, as a novelty, driven by electroencephalography (EEG) source activity. Simulations not only predicted subjects' individual resting-state functional magnetic resonance imaging (fMRI) time series and spatial network topologies over 20 minutes of activity, but more importantly, they also revealed precise neurophysiological mechanisms that underlie and link six empirical observations from different scales and modalities: (1) resting-state fMRI oscillations, (2) functional connectivity networks, (3) excitation-inhibition balance, (4, 5) inverse relationships between α-rhythms, spike-firing and fMRI on short and long time scales, and (6) fMRI power-law scaling. These findings underscore the potential of this new modelling framework for general inference and integration of neurophysiological knowledge to complement empirical studies. PMID:29308767