A COMPUTER-CONTROLLED SYSTEM FOR GENERATING UNIFORM SURFACE DEPOSITS TO STUDY THE TRANSPORT OF PARTICULATE MATTER

EPA Science Inventory

Improved methods for measuring and assessing microenvironmental exposure in individuals are needed. How human activities affect particulate matter in the personal cloud is poorly understood. A quality assurance tool to aid the study of particle transport mechanisms (e.g., re-en...

A 2.5-D Representation of the Human Hand

ERIC Educational Resources Information Center

Longo, Matthew R.; Haggard, Patrick

2012-01-01

Primary somatosensory maps in the brain represent the body as a discontinuous, fragmented set of two-dimensional (2-D) skin regions. We nevertheless experience our body as a coherent three-dimensional (3-D) volumetric object. The links between these different aspects of body representation, however, remain poorly understood. Perceiving the body's…

A Truth that's Told with Bad Intent: An ERP Study of Deception

ERIC Educational Resources Information Center

Carrion, Ricardo E.; Keenan, Julian P.; Sebanz, Natalie

2010-01-01

Human social cognition critically relies on the ability to deceive others. However, the cognitive and neural underpinnings of deception are still poorly understood. Why does lying place increased demands on cognitive control? The present study investigated whether cognitive control processes during deception are recruited due to the need to…

Improving ITS sequence data for identification of plant pathogenic fungi

Treesearch

R. Henrik Nilsson; Kevin D. Hyde; Julia Pawłowska; Martin Ryberg; Leho Tedersoo; Anders Bjørnsgard Aas; Siti A. Alias; Artur Alves; Cajsa Lisa Anderson; Alexandre Antonelli; A. Elizabeth Arnold; Barbara Bahnmann; Mohammad Bahram; Johan Bengtsson-Palme; Anna Berlin; Sara Branco; Putarak Chomnunti; Asha Dissanayake; Rein Drenkhan; Hanna Friberg; Tobias Guldberg Frøslev; Bettina Halwachs; Martin Hartmann; Beatrice Henricot; Ruvishika Jayawardena; Ari Jumpponen; Håvard Kauserud; Sonja Koskela; Tomasz Kulik; Kare Liimatainen; Björn D. Lindahl; Daniel Lindner; Jian-Kui Liu; Sajeewa Maharachchikumbura; Dimuthu Manamgoda; Svante Martinsson; Maria Alice Neves; Tuula Niskanen; Stephan Nylinder; Olinto Liparini Pereira; Danilo Batista Pinho; Teresita M. Porter; Valentin Queloz; Taavi Riit; Marisol Sánchez-García; Filipe de Sousa; Emil Stefańczyk; Mariusz Tadych; Susumu Takamatsu; Qing Tian; Dhanushka Udayanga; Martin Unterseher; Zheng Wang; Saowanee Wikee; Jiye Yan; Ellen Larsson; Karl-Henrik Larsson; Urmas Kõljalg; Kessy Abarenkov

2014-01-01

Plant pathogenic fungi are a large and diverse assemblage of eukaryotes with substantial impacts on natural ecosystems and human endeavours. These taxa often have complex and poorly understood life cycles, lack observable, discriminatory morphological characters, and may not be amenable to in vitro culturing. As a result, species identification is frequently difficult...

SYSTEMIC VASCULAR DISEASE IN MALE B6C3F1 MICE EXPOSED TO PARTICULATE MATTER BY INHALATION: STUDIES CONDUCTED BY THE NATIONAL TOXICOLOGY PROGRAM

EPA Science Inventory

Abstract

Epidemiological studies suggest an association between ambient particulate matter and cardiopulmonary diseases in humans. The mechanisms underlying these health effects are poorly understood. To better understand the potential relationship between particulate-ma...

Interactions of Salmonella enterica Serovar Typhimurium and Pectobacterium carotovorum within a tomato soft rot

USDA-ARS?s Scientific Manuscript database

The human pathogen Salmonella has shown a remarkable adaptability which allows these bacteria to thrive in a variety of environments and hosts. The manner in which these pathogens establish within a niche amidst the native microbiota remains poorly understood. Here, we aimed to uncover the mechanism...

SUBCHRONIC TOXICITY OF INHALED TOLUENE IN RATS: IMMUNOLOGY, CARDIAC GENE EXPRESSION AND MARKERS OF OXIDATIVE STRESS.

EPA Science Inventory

The health effects of long-term exposure to volatile organic compounds (VOCs) are poorly understood, due primarily to insufficient human exposure data and inconsistent animal models. To develop a rodent model of long-term exposure to VOCs, a sub-chronic inhalation study with mult...

Global Soil and Sediment transfer during the Anthropocene

NASA Astrophysics Data System (ADS)

Hoffmann, Thomas; Vanacker, Veerle; Stinchcombe, Gary; Penny, Dan; Xixi, Lu

2016-04-01

The vulnerability of soils to human-induced erosion and its downstream effects on fluvial and deltaic ecosystems is highly variable in space and time; dependent on climate, geology, the nature and duration of land use, and topography. Despite our knowledge of the mechanistic relationships between erosion, sediment storage, land-use and climate change, the global patterns of soil erosion, fluvial sediment flux and storage throughout the Holocene remain poorly understood. The newly launched PAGES working group GloSS aims to determine the sensitivity of soil resources and sediment routing systems to varying land use types during the period of agriculture, under contrasting climate regimes and socio-ecological settings. Successfully addressing these questions in relation to the sustainable use of soils, sediments and river systems requires an understanding of past human-landscape interactions. GloSS, therefore, aims to: Develop proxies for, or indices of, human impact on rates of soil erosion and fluvial sediment transfer that are applicable on a global scale and throughout the Holocene; Create a global database of long-term (102-104 years) human-accelerated soil erosion and sediment flux records; Identify hot spots of soil erosion and sediment deposition during the Anthropocene, and Locate data-poor regions where particular socio-ecological systems are not well understood, as strategic foci for future work. This paper will present the latest progress of the PAGES GloSS working group.

A missed Fe-S cluster handoff causes a metabolic shakeup.

PubMed

Berteau, Olivier

2018-05-25

The general framework of pathways by which iron-sulfur (Fe-S) clusters are assembled in cells is well-known, but the cellular consequences of disruptions to that framework are not fully understood. Crooks et al. report a novel cellular system that creates an acute Fe-S cluster deficiency, using mutants of ISCU, the main scaffold protein for Fe-S cluster assembly. Surprisingly, the resultant metabolic reprogramming leads to the accumulation of lipid droplets, a situation encountered in many poorly understood pathological conditions, highlighting unanticipated links between Fe-S assembly machinery and human disease. © 2018 Berteau.

Genetically modified Medicago truncatula lacking calcium oxalate has increased calcium bioavailability and partially rescues vitamin D receptor knockout mice phenotypes

USDA-ARS?s Scientific Manuscript database

How the distribution and sequestered form of plant macro/micro-nutrients influence their bioavailability, and ultimately impact human health, is poorly understood. The legume Medicago truncatula has a portion of its tissue calcium sequestered in the form of the calcium oxalate crystal, which reduces...

Role of Dentate Gyrus in Aligning Internal Spatial Map to External Landmark

ERIC Educational Resources Information Center

Lee, Jong Won; Kim, Woon Ryoung; Sun, Woong; Jung, Min Whan

2009-01-01

Humans and animals form internal representations of external space based on their own body movement (dead reckoning) as well as external landmarks. It is poorly understood, however, how different types of information are integrated to form a unified representation of external space. To examine the role of dentate gyrus (DG) in this process, we…

The semenogelins: proteins with functions beyond reproduction?

PubMed

Jonsson, M; Lundwall, A; Malm, J

2006-12-01

The coagulum proteins of human semen, semenogelins I and II, are secreted in abundance by the seminal vesicles. Their function in reproduction is poorly understood as they are rapidly degraded in ejaculated semen. However, more recent results indicate that it is time to put the semenogelins in a broader physiological perspective that goes beyond reproduction and fertility.

An InDel in the promoter of Al-activated malate transporter 9 selected during tomato domestication determines fruit malate content and aluminum tolerance

USDA-ARS?s Scientific Manuscript database

Deciphering the mechanism of malate accumulation in plants would contribute to a greater understanding of plant chemistry, which has implications for improving flavor quality in crop species and enhancing human health benefits. However, the regulation of malate metabolism is poorly understood in cro...

All in the Training: Techniques for Enhancing Karst Landscape Education through Show Cave Interpretation

ERIC Educational Resources Information Center

North, Leslie; van Beynen, Philip

2016-01-01

Despite the abundance of karst terrains and a universal lack of knowledge about the role they play in supplying freshwater resources, informal environmental education through guided show cave tours is poorly understood. This study evaluated techniques for educating cave guides on how to disseminate information about human-karst interactions to…

A Review of EEG, ERP, and Neuroimaging Studies of Creativity and Insight

ERIC Educational Resources Information Center

Dietrich, Arne; Kanso, Riam

2010-01-01

Creativity is a cornerstone of what makes us human, yet the neural mechanisms underlying creative thinking are poorly understood. A recent surge of interest into the neural underpinnings of creative behavior has produced a banquet of data that is tantalizing but, considered as a whole, deeply self-contradictory. We review the emerging literature…

Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses.

PubMed

Mahanty, Siddhartha; Hutchinson, Karen; Agarwal, Sudhanshu; McRae, Michael; Rollin, Pierre E; Pulendran, Bali

2003-03-15

Acute infection of humans with Ebola and Lassa viruses, two principal etiologic agents of hemorrhagic fevers, often results in a paradoxical pattern of immune responses: early infection, characterized by an outpouring of inflammatory mediators such as TNF-alpha, IL-1 beta, and IL-6, vs late stage infections, which are associated with poor immune responses. The mechanisms underlying these diverse outcomes are poorly understood. In particular, the role played by cells of the innate immune system, such as dendritic cells (DC), is not known. In this study, we show that Ebola and Lassa viruses infect human monocyte-derived DC and impair their function. Monocyte-derived DC exposed to either virus fail to secrete proinflammatory cytokines, do not up-regulate costimulatory molecules, and are poor stimulators of T cells. These data represent the first evidence for a mechanism by which Ebola and Lassa viruses target DC to impair adaptive immunity.

Repression of mammosphere formation of human breast cancer cells by soy isoflavone genistein and blueberry polyphenolic acids suggests diet-mediated targeting of cancer stem-like/progenitor cells

USDA-ARS?s Scientific Manuscript database

Mammary stem cells are undifferentiated epithelial cells which initiate mammary tumors and render them resistant to anticancer therapies, when deregulated. Diets rich in fruits and vegetables are implicated in breast cancer risk reduction, yet underlying mechanisms are poorly understood. Here, we ad...

Fire ecology and bird populations in eastern deciduous forests

Treesearch

Vanessa L. Artman; Todd F. Hutchinson; Jeffrey D. Brawn; Jeffrey D. Brawn

2005-01-01

Eastern deciduous forests are located across the central portion of eastern North America and provide habitat for a wide diversity of bird species. The occurrence of fi re in the region has been associated with the presence of humans for over 10,000 yr. While pre-European fire regimes are poorly understood, fire is widely thought to have promoted and maintained large...

The Handwriting Is on the Wall. A World Development Primer.

ERIC Educational Resources Information Center

World Neighbors, Inc., Oklahoma City, OK.

This anthology of writings on world development examines the widening gap between the rich and the poor of the world. Development is understood to mean the struggle to realize a just and humane life for everyone. The thoughts of third world economists and political leaders as well as those of European and North American observers are included. The…

Human Papilloma Viral DNA Replicates as a Stable Episome in Cultured Epidermal Keratinocytes

NASA Astrophysics Data System (ADS)

Laporta, Robert F.; Taichman, Lorne B.

1982-06-01

Human papilloma virus (HPV) is poorly understood because systems for its growth in tissue culture have not been developed. We report here that cultured human epidermal keratinocytes could be infected with HPV from plantar warts and that the viral DNA persisted and replicated as a stable episome. There were 50-200 copies of viral DNA per cell and there was no evidence to indicate integration of viral DNA into the cellular genome. There was also no evidence to suggest that viral DNA underwent productive replication. We conclude that cultured human epidermal keratinocytes may be a model for the study of certain aspects of HPV biology.

Human tears contain a chemosignal.

PubMed

Gelstein, Shani; Yeshurun, Yaara; Rozenkrantz, Liron; Shushan, Sagit; Frumin, Idan; Roth, Yehudah; Sobel, Noam

2011-01-14

Emotional tearing is a poorly understood behavior that is considered uniquely human. In mice, tears serve as a chemosignal. We therefore hypothesized that human tears may similarly serve a chemosignaling function. We found that merely sniffing negative-emotion-related odorless tears obtained from women donors induced reductions in sexual appeal attributed by men to pictures of women's faces. Moreover, after sniffing such tears, men experienced reduced self-rated sexual arousal, reduced physiological measures of arousal, and reduced levels of testosterone. Finally, functional magnetic resonance imaging revealed that sniffing women's tears selectively reduced activity in brain substrates of sexual arousal in men.

[Human coronavirus infections: importance and diagnosis].

PubMed

Vabret, A; Brouard, J; Petitjean, J; Eugene-Ruellan, G; Freymuth, F

1998-11-14

POORLY-KNOWN VIRUS: Coronaviruses, so named because of their sun-ray-like aspect, were discovered in the sixties. The biology of these RNA viruses is complex and poorly understood. KNOWN PATHOGENS: Coronaviruses are known pathogens in veterinary medicine, causing disease states in several domestic species. In human medicine, they can cause benign respiratory infections, but few laboratories include coronaviruses in their routine diagnostic tests. SUSPECTED PATHOGENS: There is some data in the literature suggesting coronaviruses might be implicated in more severe diseases including multiple sclerosis, necrotizing enterocolitis, and lower respiratory tract infections, particularly in infants. IMPROVING DIAGNOSTIC METHODS: Due to the lack of reliable and sensitive diagnostic techniques, it is impossible to date to correctly assess the medical impact of these ubiquitous and endemic viruses. Molecular biology techniques enabling detection of human coronavirus infections should be applied to verifying the suspected implication of these viruses in diverse disease states.

Skeletal muscle fatigue precedes the slow component of oxygen uptake kinetics during exercise in humans.

PubMed

Cannon, Daniel T; White, Ailish C; Andriano, Melina F; Kolkhorst, Fred W; Rossiter, Harry B

2011-02-01

The mechanisms determining exercise intolerance are poorly understood. A reduction in work efficiency in the form of an additional energy cost and oxygen requirement occurs during high-intensity exercise and contributes to exercise limitation. Muscle fatigue and subsequent recruitment of poorly efficient muscle fibres has been proposed to mediate this decline. These data demonstrate in humans, that muscle fatigue, generated in the initial minutes of exercise, is correlated with the increasing energy demands of high-intensity exercise. Surprisingly, however, while muscle fatigue reached a plateau, oxygen uptake continued to increase throughout 8 min of exercise. This suggests that additional recruitment of inefficient muscle fibres may not be the sole mechanism contributing to the decline in work efficiency during high-intensity exercise.

Waterborne disease-related risk perceptions in the Sonora River basin, Mexico.

PubMed

Morua, Agustin Robles; Halvorsen, Kathleen E; Mayer, Alex S

2011-05-01

Waterborne disease is estimated to cause about 10% of all diseases worldwide. However, related risk perceptions are not well understood, particularly in the developing world where waterborne disease is an enormous problem. We focus on understanding risk perceptions related to these issues in a region within northern Mexico. Our findings show how waterborne disease problems and solutions are understood in eight small communities along a highly contaminated river system. We found major differences in risk perceptions between health professionals, government officials, and lay citizens. Health professionals believed that a high level of human-waste-related risk existed within the region. Few officials and lay citizens shared this belief. In addition, few officials and lay citizens were aware of poor wastewater-management-related disease outbreaks and water contamination. Finally, aside from health professionals, a few interviewees understood the importance of basic hygiene and water treatment measures that could help to prevent disease. Our results add to the literature on environmentally-related risk perceptions in the developing world. We discuss recommendations for improving future human-wastewater-related risk communication within the region. © 2011 Society for Risk Analysis.

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.

Generalism: The Discipline of Family Medicine

PubMed Central

MacDonald, Peter J.

1981-01-01

The term ‘discipline’, as applied to family medicine, is widely used, yet poorly understood. The dictionary definitions of discipline as “a branch of knowledge or learning; training that develops self-control, character, or orderliness and efficiency” are related in this article to the personal discipline of family physicians. This discipline requires a commitment to whole person medicine, learning and growth; it is both efficient and humane. PMID:21289826

Human heart failure with preserved ejection versus feline cardiomyopathy: what can we learn from both veterinary and human medicine?

PubMed

Prat, Valentine; Rozec, Bertrand; Gauthier, Chantal; Lauzier, Benjamin

2017-11-01

Cardiovascular affections are a growing health burden in human populations. Recent advances in cardiology have improved treatments and outcomes for myocardial infarction and arrhythmias, but other conditions still remain poorly understood. To date, the classical approach to study cardiovascular diseases involves rodent models, despite their strong differences with human cardiac physiology. In this context, this review will focus on the common traits between human and feline cardiac diseases, namely heart failure with preserved ejection fraction and feline cardiomyopathies, respectively. These two affections share similar pathological patterns and epidemiological characteristics. An improved knowledge would be of interest for both human and feline patients and could lead to the establishment of a more accurate treatment and therapeutic strategy for medical doctors and veterinary practitioners.

Single-Dose Testosterone Administration Impairs Cognitive Reflection in Men.

PubMed

Nave, Gideon; Nadler, Amos; Zava, David; Camerer, Colin

2017-10-01

In nonhumans, the sex steroid testosterone regulates reproductive behaviors such as fighting between males and mating. In humans, correlational studies have linked testosterone with aggression and disorders associated with poor impulse control, but the neuropsychological processes at work are poorly understood. Building on a dual-process framework, we propose a mechanism underlying testosterone's behavioral effects in humans: reduction in cognitive reflection. In the largest study of behavioral effects of testosterone administration to date, 243 men received either testosterone or placebo and took the Cognitive Reflection Test (CRT), which estimates the capacity to override incorrect intuitive judgments with deliberate correct responses. Testosterone administration reduced CRT scores. The effect remained after we controlled for age, mood, math skills, whether participants believed they had received the placebo or testosterone, and the effects of 14 additional hormones, and it held for each of the CRT questions in isolation. Our findings suggest a mechanism underlying testosterone's diverse effects on humans' judgments and decision making and provide novel, clear, and testable predictions.

Characterization of human cervical remodeling throughout pregnancy using in vivo Raman spectroscopy

NASA Astrophysics Data System (ADS)

O'Brien, Christine M.; Vargis, Elizabeth; Slaughter, Chris; Rudin, Amy P.; Herington, Jennifer L.; Bennett, Kelly A.; Reese, Jeff; Mahadevan-Jansen, Anita

2015-02-01

Globally, fifteen million babies are born preterm each year, affecting 1 in 8 pregnancies in the US alone. Cervical remodeling includes a biochemical cascade of changes that ultimately result in the thinning and dilation of the cervix for passage of a fetus. This process is poorly understood and is the focus of this study. Our group is utilizing Raman spectroscopy to evaluate biochemical changes occurring in the human cervix throughout pregnancy. This technique has high molecular specificity and can be performed in vivo, with the potential to unveil new molecular dynamics essential for cervical remodeling.

Heterogeneity of Clonal Expansion and Maturation-Linked Mutation Acquisition in Hematopoietic Progenitors in Human Acute Myeloid Leukemia

PubMed Central

Walter, Roland B.; Laszlo, George S.; Lionberger, Jack M.; Pollard, Jessica A.; Harrington, Kimberly H.; Gudgeon, Chelsea J.; Othus, Megan; Rafii, Shahin; Meshinchi, Soheil; Appelbaum, Frederick R.; Bernstein, Irwin D.

2014-01-01

Recent technological advances led to an appreciation of the genetic complexity of human acute myeloid leukemia (AML) but underlying progenitor cells remain poorly understood because their rarity precludes direct study. We developed a co-culture method integrating hypoxia, aryl hydrocarbon receptor inhibition, and micro-environmental support via human endothelial cells to isolate these cells. X-chromosome inactivation studies of the least mature precursors derived following prolonged culture of CD34+/CD33− cells revealed polyclonal growth in highly curable AMLs, suggesting mutations necessary for clonal expansion were acquired in more mature progenitors. Consistently, in core-binding factor (CBF) leukemias with known complementing mutations, immature precursors derived following prolonged culture of CD34+/CD33− cells harbored neither mutation or the CBF mutation alone, whereas more mature precursors often carried both mutations. These results were in contrast to those with leukemias with poor prognosis that showed clonal dominance in the least mature precursors. These data indicate heterogeneity among progenitors in human AML that may have prognostic and therapeutic implications. PMID:24721792

Cancer Risk from Exposure to Galactic Cosmic Rays - Implications for Human Space Exploration

NASA Technical Reports Server (NTRS)

Cucinotta, Francis A.; Durant, marco

2006-01-01

Current space programs are shifting toward planetary exploration, and in particular towards human missions to the moon and Mars. However, space radiation is a major barrier to human exploration of the solar system because the biological effects of high-energy and charge (HZE) ions, which are the main contributors to radiation risks in deep space, are poorly understood. Predictions of the nature and magnitude of the risks posed by space radiation are subject to very large uncertainties. Great efforts have been dedicated worldwide in recent years toward a better understanding of the oncogenic potential of galactic cosmic rays. A review of the new results in this field will be presented here.

Structure of Ljungan virus provides insight into genome packaging of this picornavirus

NASA Astrophysics Data System (ADS)

Zhu, Ling; Wang, Xiangxi; Ren, Jingshan; Porta, Claudine; Wenham, Hannah; Ekström, Jens-Ola; Panjwani, Anusha; Knowles, Nick J.; Kotecha, Abhay; Siebert, C. Alistair; Lindberg, A. Michael; Fry, Elizabeth E.; Rao, Zihe; Tuthill, Tobias J.; Stuart, David I.

2015-10-01

Picornaviruses are responsible for a range of human and animal diseases, but how their RNA genome is packaged remains poorly understood. A particularly poorly studied group within this family are those that lack the internal coat protein, VP4. Here we report the atomic structure of one such virus, Ljungan virus, the type member of the genus Parechovirus B, which has been linked to diabetes and myocarditis in humans. The 3.78-Å resolution cryo-electron microscopy structure shows remarkable features, including an extended VP1 C terminus, forming a major protuberance on the outer surface of the virus, and a basic motif at the N terminus of VP3, binding to which orders some 12% of the viral genome. This apparently charge-driven RNA attachment suggests that this branch of the picornaviruses uses a different mechanism of genome encapsidation, perhaps explored early in the evolution of picornaviruses.

Structure of Ljungan virus provides insight into genome packaging of this picornavirus.

PubMed

Zhu, Ling; Wang, Xiangxi; Ren, Jingshan; Porta, Claudine; Wenham, Hannah; Ekström, Jens-Ola; Panjwani, Anusha; Knowles, Nick J; Kotecha, Abhay; Siebert, C Alistair; Lindberg, A Michael; Fry, Elizabeth E; Rao, Zihe; Tuthill, Tobias J; Stuart, David I

2015-10-08

Picornaviruses are responsible for a range of human and animal diseases, but how their RNA genome is packaged remains poorly understood. A particularly poorly studied group within this family are those that lack the internal coat protein, VP4. Here we report the atomic structure of one such virus, Ljungan virus, the type member of the genus Parechovirus B, which has been linked to diabetes and myocarditis in humans. The 3.78-Å resolution cryo-electron microscopy structure shows remarkable features, including an extended VP1 C terminus, forming a major protuberance on the outer surface of the virus, and a basic motif at the N terminus of VP3, binding to which orders some 12% of the viral genome. This apparently charge-driven RNA attachment suggests that this branch of the picornaviruses uses a different mechanism of genome encapsidation, perhaps explored early in the evolution of picornaviruses.

Potential Sources and Transmission of Salmonella and Antimicrobial Resistance in Kampala, Uganda

PubMed Central

Afema, Josephine A.; Byarugaba, Denis K.; Shah, Devendra H.; Atukwase, Esther; Nambi, Maria; Sischo, William M.

2016-01-01

In sub‒Saharan Africa, non‒typhoidal Salmonellae (NTS) cause invasive disease particularly in children and HIV infected adults, but the disease epidemiology is poorly understood. Between 2012 and 2013, we investigated NTS sources and transmission in Kampala. We detected Salmonella in 60% of the influent and 60% of the effluent samples from a wastewater treatment plant and 53.3% of the influent and 10% of the effluent samples from waste stabilization ponds that serve the human population; 40.9% of flush‒water samples from ruminant slaughterhouses, 6.6% of the poultry fecal samples from live bird markets and 4% of the fecal samples from swine at slaughter; and in 54.2% of the water samples from a channel that drains storm–water and effluents from the city. We obtained 775 Salmonella isolates, identified 32 serovars, and determined resistance to 15 antimicrobials. We genotyped common serovars using multiple‒locus variable number tandem repeats analysis or pulsed‒field gel electrophoresis. In addition, we analyzed 49 archived NTS isolates from asymptomatic livestock and human clinical cases. Salmonella from ruminant and swine sources were mostly pan‒susceptible (95%) while poultry isolates were generally more resistant. Salmonella Kentucky isolated from poultry exhibited extensive drug resistance characterized by resistance to 10 antimicrobials. Interestingly, similar genotypes of S. Kentucky but with less antimicrobial resistance (AMR) were found in poultry, human and environmental sources. The observed AMR patterns could be attributed to host or management factors associated with production. Alternatively, S. Kentucky may be prone to acquiring AMR. The factors driving AMR remain poorly understood and should be elucidated. Overall, shared genotypes and AMR phenotypes were found in NTS from human, livestock and environmental sources, suggesting zoonotic and environmental transmissions most likely occur. Information from this study could be used to control NTS transmission. PMID:26999788

Identification and characterization of poorly differentiated invasive carcinomas in a mouse model of pancreatic neuroendocrine tumorigenesis.

PubMed

Hunter, Karen E; Quick, Marsha L; Sadanandam, Anguraj; Hanahan, Douglas; Joyce, Johanna A

2013-01-01

Pancreatic neuroendocrine tumors (PanNETs) are a relatively rare but clinically challenging tumor type. In particular, high grade, poorly-differentiated PanNETs have the worst patient prognosis, and the underlying mechanisms of disease are poorly understood. In this study we have identified and characterized a previously undescribed class of poorly differentiated PanNETs in the RIP1-Tag2 mouse model. We found that while the majority of tumors in the RIP1-Tag2 model are well-differentiated insulinomas, a subset of tumors had lost multiple markers of beta-cell differentiation and were highly invasive, leading us to term them poorly differentiated invasive carcinomas (PDICs). In addition, we found that these tumors exhibited a high mitotic index, resembling poorly differentiated (PD)-PanNETs in human patients. Interestingly, we identified expression of Id1, an inhibitor of DNA binding gene, and a regulator of differentiation, specifically in PDIC tumor cells by histological analysis. The identification of PDICs in this mouse model provides a unique opportunity to study the pathology and molecular characteristics of PD-PanNETs.

Ecology. Three-Gorges Dam--experiment in habitat fragmentation?

PubMed

Wu, Jianguo; Huang, Jianhui; Han, Xingguo; Xie, Zongqiang; Gao, Xianming

2003-05-23

Habitat fragmentation is the primary cause of the loss of biodiversity and ecosystem services, but its underlying processes and mechanisms remain poorly understood. Studies of islands and insular terrestrial habitats are essential for improving our understanding of habitat fragmentation. We argue that the Three-Gorges Dam, the largest that humans have ever created, presents a unique grand-scale natural experiment that allows ecologists to address a range of critical questions concerning the theory and practice of biodiversity conservation.

Therapeutic Remyelination Strategies in a Novel Model of Multiple Sclerosis: Japanese Macaque Encephalomyelitis

DTIC Science & Technology

2013-05-01

Although the etiology of MS is still poorly understood, particular viruses, especially gama- herpesviruses , may act as triggers of MS (Levin et al., 2010...than others, suggesting a genetic pre-disposition to JME. Furthermore, we have cloned a gamma- herpesvirus (called Japanese macaque rhadovirus; JMRV...than other EAE and viral models in non-human primates and rodents. Our major aim was to use this model to better understand how gamma- herpesviruses

Induction of Inhibitory Receptors on T Cells During Plasmodium vivax Malaria Impairs Cytokine Production

PubMed Central

Costa, Pedro A. C.; Leoratti, Fabiana M. S.; Figueiredo, Maria M.; Tada, Mauro S.; Pereira, Dhelio B.; Junqueira, Caroline; Soares, Irene S.; Barber, Daniel L.; Gazzinelli, Ricardo T.; Antonelli, Lis R. V.

2015-01-01

The function and regulation of the immune response triggered during malaria is complex and poorly understood, and there is a particular paucity of studies conducted in humans infected with Plasmodium vivax. While it has been proposed that T-cell-effector responses are crucial for protection against blood-stage malaria in mice, the mechanisms behind this in humans remain poorly understood. Experimental models of malaria have shown that the regulatory molecules, cytotoxic T-lymphocyte attenuator-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), and programmed death-1 (PD-1) are involved in the functional impairment of T cells during infection. Our goal was to define the role of these molecules during P. vivax malaria. We demonstrate that infection triggers the expression of regulatory molecules on T cells. The pattern of expression differs in CD4+ and CD8+ T cells. Higher frequencies of CD4+ express more than 1 regulatory molecule compared to CD8+ T cells. Moreover, lower proportions of CD4+ T cells coexpress regulatory molecules, but are still able to proliferate. Importantly, simultaneously blockade of the CLTA-4, PD-1, and T-cell immunoglobulin and mucin–3 signaling restores the cytokine production by antigen-specific cells. These data support the hypothesis that upregulation of inhibitory receptors on T cells during P. vivax malaria impairs parasite-specific T-cell effector function. PMID:26019284

Genome-Wide Screen Reveals Valosin-Containing Protein Requirement for Coronavirus Exit from Endosomes

PubMed Central

Wong, Hui Hui; Kumar, Pankaj; Tay, Felicia Pei Ling; Moreau, Dimitri

2015-01-01

ABSTRACT Coronaviruses are RNA viruses with a large zoonotic reservoir and propensity for host switching, representing a real threat for public health, as evidenced by severe acute respiratory syndrome (SARS) and the emerging Middle East respiratory syndrome (MERS). Cellular factors required for their replication are poorly understood. Using genome-wide small interfering RNA (siRNA) screening, we identified 83 novel genes supporting infectious bronchitis virus (IBV) replication in human cells. Thirty of these hits can be placed in a network of interactions with viral proteins and are involved in RNA splicing, membrane trafficking, and ubiquitin conjugation. In addition, our screen reveals an unexpected role for valosin-containing protein (VCP/p97) in early steps of infection. Loss of VCP inhibits a previously uncharacterized degradation of the nucleocapsid N protein. This inhibition derives from virus accumulation in early endosomes, suggesting a role for VCP in the maturation of virus-loaded endosomes. The several host factors identified in this study may provide avenues for targeted therapeutics. IMPORTANCE Coronaviruses are RNA viruses representing a real threat for public health, as evidenced by SARS and the emerging MERS. However, cellular factors required for their replication are poorly understood. Using genome-wide siRNA screening, we identified novel genes supporting infectious bronchitis virus (IBV) replication in human cells. The several host factors identified in this study may provide directions for future research on targeted therapeutics. PMID:26311884

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

Connecting marine ecosystem services to human well-being: insights from participatory well-being assessment in Kenya.

PubMed

Abunge, Caroline; Coulthard, Sarah; Daw, Tim M

2013-12-01

The linkage between ecosystems and human well-being is a focus of the conceptualization of "ecosystem services" as promoted by the Millennium Ecosystem Assessment. However, the actual nature of connections between ecosystems and the well-being of individuals remains complex and poorly understood. We conducted a series of qualitative focus groups with five different stakeholder groups connected to a small-scale Kenyan coastal fishery to understand (1) how well-being is understood within the community, and what is important for well-being, (2) how people's well-being has been affected by changes over the recent past, and (3) people's hopes and aspirations for their future fishery. Our results show that people conceive well-being in a diversity of ways, but that these can clearly map onto the MA framework. In particular, our research unpacks the "freedoms and choices" element of the framework and argues for greater recognition of these aspects of well-being in fisheries management in Kenya through, for example, more participatory governance processes.

Meta-Analysis of DNA Tumor-Viral Integration Site Selection Indicates a Role for Repeats, Gene Expression and Epigenetics

PubMed Central

Doolittle-Hall, Janet M.; Cunningham Glasspoole, Danielle L.; Seaman, William T.; Webster-Cyriaque, Jennifer

2015-01-01

Oncoviruses cause tremendous global cancer burden. For several DNA tumor viruses, human genome integration is consistently associated with cancer development. However, genomic features associated with tumor viral integration are poorly understood. We sought to define genomic determinants for 1897 loci prone to hosting human papillomavirus (HPV), hepatitis B virus (HBV) or Merkel cell polyomavirus (MCPyV). These were compared to HIV, whose enzyme-mediated integration is well understood. A comprehensive catalog of integration sites was constructed from the literature and experimentally-determined HPV integration sites. Features were scored in eight categories (genes, expression, open chromatin, histone modifications, methylation, protein binding, chromatin segmentation and repeats) and compared to random loci. Random forest models determined loci classification and feature selection. HPV and HBV integrants were not fragile site associated. MCPyV preferred integration near sensory perception genes. Unique signatures of integration-associated predictive genomic features were detected. Importantly, repeats, actively-transcribed regions and histone modifications were common tumor viral integration signatures. PMID:26569308

The effects of HIV/AIDS on economic growth and human capitals: a panel study evidence from Asian countries.

PubMed

Roy, Shongkour

2014-01-01

Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) affects economic growths by reducing the human capitals are among the most poorly understood aspect of the AIDS epidemic. This article analyzes the effects of the prevalence of HIV and full-blown AIDS on a country's human capitals and economic growths. Using a fixed effect model for panel data 1990-2010 from the Asia, I explored the dynamic relationships among HIV/AIDS, economic growths, and human capitals within countries over time. The econometric effects concerned that HIV/AIDS plays an important role in the field of economic growths and it is measured as a change in real gross domestic product (GDP) per capita and human capitals. The modeling results for the Asian countries indicates HIV/AIDS prevalence that has a hurtful effect on GDP per capita by reducing human capitals within countries over time.

Brain and Cognitive Reserve: Translation via Network Control Theory

PubMed Central

Medaglia, John Dominic; Pasqualetti, Fabio; Hamilton, Roy H.; Thompson-Schill, Sharon L.; Bassett, Danielle S.

2017-01-01

Traditional approaches to understanding the brain’s resilience to neuropathology have identified neurophysiological variables, often described as brain or cognitive “reserve,” associated with better outcomes. However, mechanisms of function and resilience in large-scale brain networks remain poorly understood. Dynamic network theory may provide a basis for substantive advances in understanding functional resilience in the human brain. In this perspective, we describe recent theoretical approaches from network control theory as a framework for investigating network level mechanisms underlying cognitive function and the dynamics of neuroplasticity in the human brain. We describe the theoretical opportunities offered by the application of network control theory at the level of the human connectome to understand cognitive resilience and inform translational intervention. PMID:28104411

Normative brain size variation and brain shape diversity in humans.

PubMed

Reardon, P K; Seidlitz, Jakob; Vandekar, Simon; Liu, Siyuan; Patel, Raihaan; Park, Min Tae M; Alexander-Bloch, Aaron; Clasen, Liv S; Blumenthal, Jonathan D; Lalonde, Francois M; Giedd, Jay N; Gur, Ruben C; Gur, Raquel E; Lerch, Jason P; Chakravarty, M Mallar; Satterthwaite, Theodore D; Shinohara, Russell T; Raznahan, Armin

2018-06-15

Brain size variation over primate evolution and human development is associated with shifts in the proportions of different brain regions. Individual brain size can vary almost twofold among typically developing humans, but the consequences of this for brain organization remain poorly understood. Using in vivo neuroimaging data from more than 3000 individuals, we find that larger human brains show greater areal expansion in distributed frontoparietal cortical networks and related subcortical regions than in limbic, sensory, and motor systems. This areal redistribution recapitulates cortical remodeling across evolution, manifests by early childhood in humans, and is linked to multiple markers of heightened metabolic cost and neuronal connectivity. Thus, human brain shape is systematically coupled to naturally occurring variations in brain size through a scaling map that integrates spatiotemporally diverse aspects of neurobiology. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Other-regarding preferences in a non-human primate: Common marmosets provision food altruistically

PubMed Central

Burkart, Judith M.; Fehr, Ernst; Efferson, Charles; van Schaik, Carel P.

2007-01-01

Human cooperation is unparalleled in the animal world and rests on an altruistic concern for the welfare of genetically unrelated strangers. The evolutionary roots of human altruism, however, remain poorly understood. Recent evidence suggests a discontinuity between humans and other primates because individual chimpanzees do not spontaneously provide food to other group members, indicating a lack of concern for their welfare. Here, we demonstrate that common marmoset monkeys (Callithrix jacchus) do spontaneously provide food to nonreciprocating and genetically unrelated individuals, indicating that other-regarding preferences are not unique to humans and that their evolution did not require advanced cognitive abilities such as theory of mind. Because humans and marmosets are cooperative breeders and the only two primate taxa in which such unsolicited prosociality has been found, we conclude that these prosocial predispositions may emanate from cooperative breeding. PMID:18077409

Humanized Mouse Models for the Study of Human Malaria Parasite Biology, Pathogenesis, and Immunity.

PubMed

Minkah, Nana K; Schafer, Carola; Kappe, Stefan H I

2018-01-01

Malaria parasite infection continues to inflict extensive morbidity and mortality in resource-poor countries. The insufficiently understood parasite biology, continuously evolving drug resistance and the lack of an effective vaccine necessitate intensive research on human malaria parasites that can inform the development of new intervention tools. Humanized mouse models have been greatly improved over the last decade and enable the direct study of human malaria parasites in vivo in the laboratory. Nevertheless, no small animal model developed so far is capable of maintaining the complete life cycle of Plasmodium parasites that infect humans. The ultimate goal is to develop humanized mouse systems in which a Plasmodium infection closely reproduces all stages of a parasite infection in humans, including pre-erythrocytic infection, blood stage infection and its associated pathology, transmission as well as the human immune response to infection. Here, we discuss current humanized mouse models and the future directions that should be taken to develop next-generation models for human malaria parasite research.

Laboratory tests for mumps vaccines.

PubMed

Minor, P D

1997-03-01

The action of live attenuated vaccines against mumps is poorly understood although their clinical efficacy is beyond doubt. The attenuated character of the vaccine is assured by consistency of production related to clinical trials, and limited studies of vaccine seeds in primates. Potency is assessed by infectivity in vitro and is subject to poorly understood sources of variation. Molecular biological studies are at an early stage.

LincRNA-p21: Implications in Human Diseases.

PubMed

Tang, Sai-Sai; Zheng, Bi-Ying; Xiong, Xing-Dong

2015-08-11

Long noncoding RNAs (lncRNAs), which lack significant protein-coding capacity, regulate various biological processes through diverse and as yet poorly understood molecular mechanisms. However, a number of studies in the past few years have documented important functions for lncRNAs in human diseases. Among these lncRNAs, lincRNA-p21 has been proposed to be a novel regulator of cell proliferation, apoptosis and DNA damage response, and involved in the initiation and progression of human diseases. In this review, we summarize the current knowledge of lincRNA-p21, mainly focus on the known biological functions and its underlying mechanisms. Moreover, we highlight the growing body of evidences for the importance of lincRNA-p21 in diverse human diseases, which indicate lincRNA-p21 as a potential diagnostic marker and/or a valuable therapeutic target for these diseases.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

PubMed

Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J; Tropf, Felix C; Shen, Xia; Wilson, James F; Chasman, Daniel I; Nolte, Ilja M; Tragante, Vinicius; van der Laan, Sander W; Perry, John R B; Kong, Augustine; Ahluwalia, Tarunveer S; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J; Gieger, Christian; Gunderson, Erica P; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F; McMahon, George; Meddens, S Fleur W; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A; Monnereau, Claire; van der Most, Peter J; Myhre, Ronny; Nalls, Mike A; Nutile, Teresa; Kalafati, Ioanna Panagiota; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B; Rich-Edwards, Janet; Rietveld, Cornelius A; Robino, Antonietta; Rose, Lynda M; Rueedi, Rico; Ryan, Kathleen A; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A; Stolk, Lisette; Streeten, Elizabeth; Tönjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I; Buring, Julie E; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R; Cucca, Francesco; Toniolo, Daniela; Davey-Smith, George; Deary, Ian J; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M; de Geus, Eco J C; Eriksson, Johan G; Evans, Denis A; Faul, Jessica D; Sala, Cinzia Felicita; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J F; de Haan, Hugoline G; Haerting, Johannes; Harris, Tamara B; Heath, Andrew C; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hyppönen, Elina; Jacobsson, Bo; Jaddoe, Vincent W V; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L R; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William G; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia M; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McQuillan, Ruth; Medland, Sarah E; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Traglia, Michela; Milani, Lili; Mitchell, Paul; Montgomery, Grant W; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda W J H; Perola, Markus; Peyser, Patricia A; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M; Ring, Susan M; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D; Starr, John M; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tung, Joyce Y; Uitterlinden, André G; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G; Wang, Jie Jin; Wareham, Nicholas J; Weir, David R; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F; Zondervan, Krina T; Stefansson, Kari; Krueger, Robert F; Lee, James J; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C

2016-12-01

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

DNA replication-timing analysis of human chromosome 22 at high resolution and different developmental states.

PubMed

White, Eric J; Emanuelsson, Olof; Scalzo, David; Royce, Thomas; Kosak, Steven; Oakeley, Edward J; Weissman, Sherman; Gerstein, Mark; Groudine, Mark; Snyder, Michael; Schübeler, Dirk

2004-12-21

Duplication of the genome during the S phase of the cell cycle does not occur simultaneously; rather, different sequences are replicated at different times. The replication timing of specific sequences can change during development; however, the determinants of this dynamic process are poorly understood. To gain insights into the contribution of developmental state, genomic sequence, and transcriptional activity to replication timing, we investigated the timing of DNA replication at high resolution along an entire human chromosome (chromosome 22) in two different cell types. The pattern of replication timing was correlated with respect to annotated genes, gene expression, novel transcribed regions of unknown function, sequence composition, and cytological features. We observed that chromosome 22 contains regions of early- and late-replicating domains of 100 kb to 2 Mb, many (but not all) of which are associated with previously described chromosomal bands. In both cell types, expressed sequences are replicated earlier than nontranscribed regions. However, several highly transcribed regions replicate late. Overall, the DNA replication-timing profiles of the two different cell types are remarkably similar, with only nine regions of difference observed. In one case, this difference reflects the differential expression of an annotated gene that resides in this region. Novel transcribed regions with low coding potential exhibit a strong propensity for early DNA replication. Although the cellular function of such transcripts is poorly understood, our results suggest that their activity is linked to the replication-timing program.

On the Communicative Function of Body Odors.

PubMed

de Groot, Jasper H B; Semin, Gün R; Smeets, Monique A M

2017-03-01

Humans use multiple senses to navigate the social world, and the sense of smell is arguably the most underestimated one. An intriguing aspect of the sense of smell is its social communicative function. Research has shown that human odors convey information about a range of states (e.g., emotions, sickness) and traits (e.g., individuality, gender). Yet, what underlies the communicability of these states and traits via smell? We fill this explanatory gap with a framework that highlights the dynamic and flexible aspects of human olfactory communication. In particular, we explain how chemical profiles, associative learning (i.e., the systematic co-occurrence of chemical profiles with state- or trait-related information), and top-down contextual influences could interact to shape human odor perception. Our model not only helps to integrate past research on human olfactory communication but it also opens new avenues for future research on this fascinating, yet to date poorly understood, field.

Comprehensive transcriptional map of primate brain development

PubMed Central

Bakken, Trygve E.; Miller, Jeremy A.; Ding, Song-Lin; Sunkin, Susan M.; Smith, Kimberly A.; Ng, Lydia; Szafer, Aaron; Dalley, Rachel A.; Royall, Joshua J.; Lemon, Tracy; Shapouri, Sheila; Aiona, Kaylynn; Arnold, James; Bennett, Jeffrey L.; Bertagnolli, Darren; Bickley, Kristopher; Boe, Andrew; Brouner, Krissy; Butler, Stephanie; Byrnes, Emi; Caldejon, Shiella; Carey, Anita; Cate, Shelby; Chapin, Mike; Chen, Jefferey; Dee, Nick; Desta, Tsega; Dolbeare, Tim A.; Dotson, Nadia; Ebbert, Amanda; Fulfs, Erich; Gee, Garrett; Gilbert, Terri L.; Goldy, Jeff; Gourley, Lindsey; Gregor, Ben; Gu, Guangyu; Hall, Jon; Haradon, Zeb; Haynor, David R.; Hejazinia, Nika; Hoerder-Suabedissen, Anna; Howard, Robert; Jochim, Jay; Kinnunen, Marty; Kriedberg, Ali; Kuan, Chihchau L.; Lau, Christopher; Lee, Chang-Kyu; Lee, Felix; Luong, Lon; Mastan, Naveed; May, Ryan; Melchor, Jose; Mosqueda, Nerick; Mott, Erika; Ngo, Kiet; Nyhus, Julie; Oldre, Aaron; Olson, Eric; Parente, Jody; Parker, Patrick D.; Parry, Sheana; Pendergraft, Julie; Potekhina, Lydia; Reding, Melissa; Riley, Zackery L.; Roberts, Tyson; Rogers, Brandon; Roll, Kate; Rosen, David; Sandman, David; Sarreal, Melaine; Shapovalova, Nadiya; Shi, Shu; Sjoquist, Nathan; Sodt, Andy J.; Townsend, Robbie; Velasquez, Lissette; Wagley, Udi; Wakeman, Wayne B.; White, Cassandra; Bennett, Crissa; Wu, Jennifer; Young, Rob; Youngstrom, Brian L.; Wohnoutka, Paul; Gibbs, Richard A.; Rogers, Jeffrey; Hohmann, John G.; Hawrylycz, Michael J.; Hevner, Robert F.; Molnár, Zoltán; Phillips, John W.; Dang, Chinh; Jones, Allan R.; Amaral, David G.; Bernard, Amy; Lein, Ed S.

2017-01-01

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high resolution transcriptional atlas of rhesus monkey brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical parcellation of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons, and cortical layers and areas acquire adult-like molecular profiles surprisingly late postnatally. Disparate cell populations exhibit distinct developmental timing but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, and approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny. PMID:27409810

Integrative analyses of human reprogramming reveal dynamic nature of induced pluripotency

PubMed Central

Cacchiarelli, Davide; Trapnell, Cole; Ziller, Michael J.; Soumillon, Magali; Cesana, Marcella; Karnik, Rahul; Donaghey, Julie; Smith, Zachary D.; Ratanasirintrawoot, Sutheera; Zhang, Xiaolan; Ho Sui, Shannan J.; Wu, Zhaoting; Akopian, Veronika; Gifford, Casey A.; Doench, John; Rinn, John L.; Daley, George Q.; Meissner, Alexander; Lander, Eric S.; Mikkelsen, Tarjei S.

2015-01-01

Summary Induced pluripotency is a promising avenue for disease modeling and therapy, but the molecular principles underlying this process, particularly in human cells, remain poorly understood due to donor-to-donor variability and intercellular heterogeneity. Here we constructed and characterized a clonal, inducible human reprogramming system that provides a reliable source of cells at any stage of the process. This system enabled integrative transcriptional and epigenomic analysis across the human reprogramming timeline at high resolution. We observed distinct waves of gene network activation, including the ordered reactivation of broad developmental regulators followed by early embryonic patterning genes and culminating in the emergence of a signature reminiscent of pre-implantation stages. Moreover, complementary functional analyses allowed us to identify and validate novel regulators of the reprogramming process. Altogether, this study sheds light on the molecular underpinnings of induced pluripotency in human cells and provides a robust cell platform for further studies. PMID:26186193

Low calorie sweeteners: Evidence remains lacking for effects on human gut function.

PubMed

Bryant, Charlotte; Mclaughlin, John

2016-10-01

The importance of nutrient induced gut-brain signalling in the regulation of human food intake has become an increasing focus of research. Much of the caloric excess consumed comes from dietary sugars, but our knowledge about the mechanisms mediating the physiological and appetitive effects of sweet tastants in the human gut and gut-brain axis is far from complete. The comparative effects of natural sugars vs low calorie sweeteners are also poorly understood. Research in animal and cellular models has suggested a key functional role in gut endocrine cells for the sweet taste receptors previously well described in oral taste. However human studies to date have very consistently failed to show that activation of the sweet taste receptor by low calorie sweeteners placed in the human gut fails to replicate any of the effects on gastric motility, gut hormones or appetitive responses evoked by caloric sugars. Copyright © 2016. Published by Elsevier Inc.

Exercising arrhythmias and sudden cardiac death in horses: Review of the literature and comparative aspects.

PubMed

Navas de Solis, C

2016-07-01

Arrhythmias are common in equine athletes during and immediately after exercise. Many of these rhythm variations are not clinically relevant. In horses, a link between different exercising arrhythmias and poor performance or between exercising arrhythmias and sudden cardiac death (SCD) is strongly suspected but not fully understood or proven. SCD during races or competitions is rare, but has catastrophic consequences for the safety of the human partner and public perceptions of welfare during equestrian sports. This review summarises current knowledge of equine exercise arrhythmias and their implications in SCD and compares existing principles and recommendations for equine subjects with those for human athletes. © 2016 EVJ Ltd.

Myeloid-derived suppressor cells modulate B-cell responses.

PubMed

Lelis, Felipe J N; Jaufmann, Jennifer; Singh, Anurag; Fromm, Katja; Teschner, Annkathrin Chiara; Pöschel, Simone; Schäfer, Iris; Beer-Hammer, Sandra; Rieber, Nikolaus; Hartl, Dominik

2017-08-01

Myeloid-derived suppressor cells (MDSCs) are key regulators of adaptive immunity by suppressing T-cell functions. However, their potential action on or interaction with B cells remained poorly understood. Here we demonstrate that human polymorphonuclear MDSCs differentially modulate B-cell function by suppressing B-cell proliferation and antibody production. We further demonstrate that this MDSC-mediated effect is cell contact dependent and involves established mediators such as arginase-1, nitric oxide (NO), reactive oxygen species (ROS) as well as B-cell death. Collectively, our studies provide novel evidence that human MDSCs modulate B cells, which could have future implications for immunotherapy approaches. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Perturbation of nucleo-cytoplasmic transport affects size of nucleus and nucleolus in human cells.

PubMed

Ganguly, Abira; Bhattacharjee, Chumki; Bhave, Madhura; Kailaje, Vaishali; Jain, Bhawik K; Sengupta, Isha; Rangarajan, Annapoorni; Bhattacharyya, Dibyendu

2016-03-01

Size regulation of human cell nucleus and nucleolus are poorly understood subjects. 3D reconstruction of live image shows that the karyoplasmic ratio (KR) increases by 30-80% in transformed cell lines compared to their immortalized counterpart. The attenuation of nucleo-cytoplasmic transport causes the KR value to increase by 30-50% in immortalized cell lines. Nucleolus volumes are significantly increased in transformed cell lines and the attenuation of nucleo-cytoplasmic transport causes a significant increase in the nucleolus volume of immortalized cell lines. A cytosol and nuclear fraction swapping experiment emphasizes the potential role of unknown cytosolic factors in nuclear and nucleolar size regulation. © 2016 Federation of European Biochemical Societies.

Self-organized amniogenesis by human pluripotent stem cells in a biomimetic implantation-like niche

NASA Astrophysics Data System (ADS)

Shao, Yue; Taniguchi, Kenichiro; Gurdziel, Katherine; Townshend, Ryan F.; Xue, Xufeng; Yong, Koh Meng Aw; Sang, Jianming; Spence, Jason R.; Gumucio, Deborah L.; Fu, Jianping

2017-04-01

Amniogenesis--the development of amnion--is a critical developmental milestone for early human embryogenesis and successful pregnancy. However, human amniogenesis is poorly understood due to limited accessibility to peri-implantation embryos and a lack of in vitro models. Here we report an efficient biomaterial system to generate human amnion-like tissue in vitro through self-organized development of human pluripotent stem cells (hPSCs) in a bioengineered niche mimicking the in vivo implantation environment. We show that biophysical niche factors act as a switch to toggle hPSC self-renewal versus amniogenesis under self-renewal-permissive biochemical conditions. We identify a unique molecular signature of hPSC-derived amnion-like cells and show that endogenously activated BMP-SMAD signalling is required for the amnion-like tissue development by hPSCs. This study unveils the self-organizing and mechanosensitive nature of human amniogenesis and establishes the first hPSC-based model for investigating peri-implantation human amnion development, thereby helping advance human embryology and reproductive medicine.

Viral hemorrhagic fever in the tropics: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine.

PubMed

Hidalgo, Jorge; Richards, Guy A; Jiménez, Juan Ignacio Silesky; Baker, Tim; Amin, Pravin

2017-12-01

Viral hemorrhagic fevers (VHFs) are a group of illnesses caused by four families of viruses namely Arenaviruses, Filoviruses, Bunyaviruses, and Flaviviruses. Humans are not the natural reservoir for any of these organisms and acquire the disease through vectors from animal reservoirs. In some conditions human to human transmission is possible increasing the risk to healthy individuals in the vicinity, more so to Health Care Workers (HCW). The pathogenesis of VHF, though poorly understood, varies according to the viruses involved. The resultant microvascular damage leads to increased vascular permeability, organ dysfunction and even death. The management is generally supportive but antiviral agents are of benefit in certain circumstances. Copyright © 2017 Elsevier Inc. All rights reserved.

Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements

PubMed Central

Levitt, David G; Levitt, Michael D

2016-01-01

Serum albumin concentration (CP) is a remarkably strong prognostic indicator of morbidity and mortality in both sick and seemingly healthy subjects. Surprisingly, the specifics of the pathophysiology underlying the relationship between CP and ill-health are poorly understood. This review provides a summary that is not previously available in the literature, concerning how synthesis, catabolism, and renal and gastrointestinal clearance of albumin interact to bring about albumin homeostasis, with a focus on the clinical factors that influence this homeostasis. In normal humans, the albumin turnover time of about 25 days reflects a liver albumin synthesis rate of about 10.5 g/day balanced by renal (≈6%), gastrointestinal (≈10%), and catabolic (≈84%) clearances. The acute development of hypoalbuminemia with sepsis or trauma results from increased albumin capillary permeability leading to redistribution of albumin from the vascular to interstitial space. The best understood mechanism of chronic hypoalbuminemia is the decreased albumin synthesis observed in liver disease. Decreased albumin production also accounts for hypoalbuminemia observed with a low-protein and normal caloric diet. However, a calorie- and protein-deficient diet does not reduce albumin synthesis and is not associated with hypoalbuminemia, and CP is not a useful marker of malnutrition. In most disease states other than liver disease, albumin synthesis is normal or increased, and hypoalbuminemia reflects an enhanced rate of albumin turnover resulting either from an increased rate of catabolism (a poorly understood phenomenon) or enhanced loss of albumin into the urine (nephrosis) or intestine (protein-losing enteropathy). The latter may occur with subtle intestinal pathology and hence may be more prevalent than commonly appreciated. Clinically, reduced CP appears to be a result rather than a cause of ill-health, and therapy designed to increase CP has limited benefit. The ubiquitous occurrence of hypoalbuminemia in disease states limits the diagnostic utility of the CP measurement. PMID:27486341

Lymphocyte-specific protein tyrosine kinase (LCK) is involved in the aryl hydrocarbon receptor (AHR)-mediated impairment of immunoglobulin secretion in human primary B cells.

PubMed

Zhou, Jiajun; Zhang, Qiang; Henriquez, Joseph E; Crawford, Robert B; Kaminski, Norbert E

2018-05-31

The aryl hydrocarbon receptor (AHR) is a cytosolic ligand-activated transcription factor involved in xenobiotic sensing, cell cycle regulation and cell development. In humans, the activation of AHR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high affinity AHR-ligand, impairs the secretion of immunoglobulin M (IgM) to suppress humoral immunity. However, the mechanisms bridging the activation of AHR and the impairment of IgM secretion by human primary B cells remain poorly understood. Recent transcriptomic analysis revealed upregulation of lymphocyte-specific protein tyrosine kinase (LCK) in AHR activated human primary B cells. LCK is a well-characterized tyrosine kinase that phosphorylates critical signaling proteins involved in activation and cytokine production in T cells. Conversely, the role of LCK in human primary B cells is not well understood. In the current studies, we have verified the transcriptomic finding by detecting AHR-mediated upregulation of LCK protein in human primary B cells. We also confirmed the role of AHR in the upregulation of LCK by using a specific AHR antagonist, which abolished the AHR-mediated increase of LCK. Furthermore, we have confirmed the role of LCK in the AHR-mediated suppression of IgM by using LCK specific inhibitors, which restored IgM secretion by human B cells in the presence of TCDD. Collectively, the current studies demonstrate a novel role of LCK in IgM secretion and provide new insights into the mechanism for AHR-mediated impairment of immunoglobulin secretion by human primary B cells.

Silicon as Versatile Player in Plant and Human Biology: Overlooked and Poorly Understood

PubMed Central

Farooq, Muhammad Ansar; Dietz, Karl-Josef

2015-01-01

Silicon (Si) serves as bioactive beneficial element. Si is highly abundant in soil, and occurs ubiquitously in all organisms including plants and humans. During the last three decades, nutritional significance of Si for plant and human health has received increasing attention. Plant Si plays a pivotal role in growth and development, and this beneficial effect depends usually on accumulation in plant tissues, which are then protected from various forms of biotic and abiotic stresses. Likewise, human exposure to Si imparts health benefits and essentially occurs through plant-derived food products. Si bioavailability in human diet, e.g., strengthens bones and improves immune response, as well as neuronal and connective tissue health. Despite this empiric knowledge, the essentiality of Si still remains enigmatic. Thus the link between Si availability for plant development and its profound implication for human welfare should receive attention. This review aims to provide a broad perspective on Si as important element for plant and human nutrition and to define research fields for interdisciplinary research. PMID:26617630

Germ cell tumors: Insights from the Drosophila ovary and the mouse testis

PubMed Central

Salz, Helen K.; Dawson, Emily P.; Heaney, Jason D.

2017-01-01

SUMMARY Ovarian and testicular germ cell tumors of young adults are thought to arise from defects in germ cell development, but the molecular mechanisms underlying malignant transformation are poorly understood. In this review, we focus on the biology of germ cell tumor formation in the Drosophila ovary and the mouse testis, for which the evidence supports common underlying mechanisms such as blocking initiation into the differentiation pathway, impaired lineage progression, and sexual identity instability. We then discuss how these concepts inform our understanding of the disease in humans. PMID:28079292

Missing focus on Human Factors – organizational and cognitive ergonomics – in the safety management for the petroleum industry

PubMed Central

Johnsen, Stig O; Kilskar, Stine Skaufel; Fossum, Knut Robert

2017-01-01

More attention has recently been given to Human Factors in petroleum accident investigations. The Human Factors areas examined in this article are organizational, cognitive and physical ergonomics. A key question to be explored is as follows: To what degree are the petroleum industry and safety authorities in Norway focusing on these Human Factors areas from the design phase? To investigate this, we conducted an innovative exploratory study of the development of four control centres in Norwegian oil and gas industry in collaboration between users, management and Human Factors experts. We also performed a literature survey and discussion with the professional Human Factors network in Norway. We investigated the Human Factors focus, reasons for not considering Human Factors and consequences of missing Human Factors in safety management. The results revealed an immature focus and organization of Human Factors. Expertise on organizational ergonomics and cognitive ergonomics are missing from companies and safety authorities and are poorly prioritized during the development. The easy observable part of Human Factors (i.e. physical ergonomics) is often in focus. Poor focus on Human Factors in the design process creates demanding conditions for human operators and impact safety and resilience. There is lack of non-technical skills such as communication and decision-making. New technical equipment such as Closed Circuit Television is implemented without appropriate use of Human Factors standards. Human Factors expertise should be involved as early as possible in the responsible organizations. Verification and validation of Human Factors should be improved and performed from the start, by certified Human Factors experts in collaboration with the workforce. The authorities should check-back that the regulatory framework of Human Factors is communicated, understood and followed. PMID:29278242

TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.

PubMed

Cebola, Inês; Rodríguez-Seguí, Santiago A; Cho, Candy H-H; Bessa, José; Rovira, Meritxell; Luengo, Mario; Chhatriwala, Mariya; Berry, Andrew; Ponsa-Cobas, Joan; Maestro, Miguel Angel; Jennings, Rachel E; Pasquali, Lorenzo; Morán, Ignasi; Castro, Natalia; Hanley, Neil A; Gomez-Skarmeta, Jose Luis; Vallier, Ludovic; Ferrer, Jorge

2015-05-01

The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas.

LincRNA-p21: Implications in Human Diseases

PubMed Central

Tang, Sai-Sai; Zheng, Bi-Ying; Xiong, Xing-Dong

2015-01-01

Long noncoding RNAs (lncRNAs), which lack significant protein-coding capacity, regulate various biological processes through diverse and as yet poorly understood molecular mechanisms. However, a number of studies in the past few years have documented important functions for lncRNAs in human diseases. Among these lncRNAs, lincRNA-p21 has been proposed to be a novel regulator of cell proliferation, apoptosis and DNA damage response, and involved in the initiation and progression of human diseases. In this review, we summarize the current knowledge of lincRNA-p21, mainly focus on the known biological functions and its underlying mechanisms. Moreover, we highlight the growing body of evidences for the importance of lincRNA-p21 in diverse human diseases, which indicate lincRNA-p21 as a potential diagnostic marker and/or a valuable therapeutic target for these diseases. PMID:26270659

Selective sweep on human amylase genes postdates the split with Neanderthals

PubMed Central

Inchley, Charlotte E.; Larbey, Cynthia D. A.; Shwan, Nzar A. A.; Pagani, Luca; Saag, Lauri; Antão, Tiago; Jacobs, Guy; Hudjashov, Georgi; Metspalu, Ene; Mitt, Mario; Eichstaedt, Christina A.; Malyarchuk, Boris; Derenko, Miroslava; Wee, Joseph; Abdullah, Syafiq; Ricaut, François-Xavier; Mormina, Maru; Mägi, Reedik; Villems, Richard; Metspalu, Mait; Jones, Martin K.; Armour, John A. L.; Kivisild, Toomas

2016-01-01

Humans have more copies of amylase genes than other primates. It is still poorly understood, however, when the copy number expansion occurred and whether its spread was enhanced by selection. Here we assess amylase copy numbers in a global sample of 480 high coverage genomes and find that regions flanking the amylase locus show notable depression of genetic diversity both in African and non-African populations. Analysis of genetic variation in these regions supports the model of an early selective sweep in the human lineage after the split of humans from Neanderthals which led to the fixation of multiple copies of AMY1 in place of a single copy. We find evidence of multiple secondary losses of copy number with the highest frequency (52%) of a deletion of AMY2A and associated low copy number of AMY1 in Northeast Siberian populations whose diet has been low in starch content. PMID:27853181

Selective sweep on human amylase genes postdates the split with Neanderthals.

PubMed

Inchley, Charlotte E; Larbey, Cynthia D A; Shwan, Nzar A A; Pagani, Luca; Saag, Lauri; Antão, Tiago; Jacobs, Guy; Hudjashov, Georgi; Metspalu, Ene; Mitt, Mario; Eichstaedt, Christina A; Malyarchuk, Boris; Derenko, Miroslava; Wee, Joseph; Abdullah, Syafiq; Ricaut, François-Xavier; Mormina, Maru; Mägi, Reedik; Villems, Richard; Metspalu, Mait; Jones, Martin K; Armour, John A L; Kivisild, Toomas

2016-11-17

Humans have more copies of amylase genes than other primates. It is still poorly understood, however, when the copy number expansion occurred and whether its spread was enhanced by selection. Here we assess amylase copy numbers in a global sample of 480 high coverage genomes and find that regions flanking the amylase locus show notable depression of genetic diversity both in African and non-African populations. Analysis of genetic variation in these regions supports the model of an early selective sweep in the human lineage after the split of humans from Neanderthals which led to the fixation of multiple copies of AMY1 in place of a single copy. We find evidence of multiple secondary losses of copy number with the highest frequency (52%) of a deletion of AMY2A and associated low copy number of AMY1 in Northeast Siberian populations whose diet has been low in starch content.

Time-specific ecological niche modeling predicts spatial dynamics of vector insects and human dengue cases.

PubMed

Peterson, A Townsend; Martínez-Campos, Carmen; Nakazawa, Yoshinori; Martínez-Meyer, Enrique

2005-09-01

Numerous human diseases-malaria, dengue, yellow fever and leishmaniasis, to name a few-are transmitted by insect vectors with brief life cycles and biting activity that varies in both space and time. Although the general geographic distributions of these epidemiologically important species are known, the spatiotemporal variation in their emergence and activity remains poorly understood. We used ecological niche modeling via a genetic algorithm to produce time-specific predictive models of monthly distributions of Aedes aegypti in Mexico in 1995. Significant predictions of monthly mosquito activity and distributions indicate that predicting spatiotemporal dynamics of disease vector species is feasible; significant coincidence with human cases of dengue indicate that these dynamics probably translate directly into transmission of dengue virus to humans. This approach provides new potential for optimizing use of resources for disease prevention and remediation via automated forecasting of disease transmission risk.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

PubMed Central

Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; van der Laan, Sander W.; Perry, John R. B.; Kong, Augustine; Ahluwalia, Tarunveer; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; van der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Panagiota, Kalafati Ioanna; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathy; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tonjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Daniela, Toniolo; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M.; de Geus, Eco JC.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Felicita, Sala Cinzia; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J.F.; de Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hypponen, Elina; Jacobsson, Bo; Jaddoe, Vincent W. V.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L.R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Michela, Traglia; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda WJH; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tönjes, Anke; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefansson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.

2017-01-01

The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits. PMID:27798627

The Chemical Nature of Mercury in Human Brain Following Poisoning or Environmental Exposure

PubMed Central

2010-01-01

Methylmercury is among the most potentially toxic species to which human populations are exposed, both at high levels through poisonings and at lower levels through consumption of fish and other seafood. However, the molecular mechanisms of methylmercury toxicity in humans remain poorly understood. We used synchrotron X-ray absorption spectroscopy (XAS) to study mercury chemical forms in human brain tissue. Individuals poisoned with high levels of methylmercury species showed elevated cortical selenium with significant proportions of nanoparticulate mercuric selenide plus some inorganic mercury and methylmercury bound to organic sulfur. Individuals with a lifetime of high fish consumption showed much lower levels of mercuric selenide and methylmercury cysteineate. Mercury exposure did not perturb organic selenium levels. These results elucidate a key detoxification pathway in the central nervous system and provide new insights into the appropriate methods for biological monitoring. PMID:22826746

Comparison of deep neural networks to spatio-temporal cortical dynamics of human visual object recognition reveals hierarchical correspondence

PubMed Central

Cichy, Radoslaw Martin; Khosla, Aditya; Pantazis, Dimitrios; Torralba, Antonio; Oliva, Aude

2016-01-01

The complex multi-stage architecture of cortical visual pathways provides the neural basis for efficient visual object recognition in humans. However, the stage-wise computations therein remain poorly understood. Here, we compared temporal (magnetoencephalography) and spatial (functional MRI) visual brain representations with representations in an artificial deep neural network (DNN) tuned to the statistics of real-world visual recognition. We showed that the DNN captured the stages of human visual processing in both time and space from early visual areas towards the dorsal and ventral streams. Further investigation of crucial DNN parameters revealed that while model architecture was important, training on real-world categorization was necessary to enforce spatio-temporal hierarchical relationships with the brain. Together our results provide an algorithmically informed view on the spatio-temporal dynamics of visual object recognition in the human visual brain. PMID:27282108

Comparison of deep neural networks to spatio-temporal cortical dynamics of human visual object recognition reveals hierarchical correspondence.

PubMed

Cichy, Radoslaw Martin; Khosla, Aditya; Pantazis, Dimitrios; Torralba, Antonio; Oliva, Aude

2016-06-10

The complex multi-stage architecture of cortical visual pathways provides the neural basis for efficient visual object recognition in humans. However, the stage-wise computations therein remain poorly understood. Here, we compared temporal (magnetoencephalography) and spatial (functional MRI) visual brain representations with representations in an artificial deep neural network (DNN) tuned to the statistics of real-world visual recognition. We showed that the DNN captured the stages of human visual processing in both time and space from early visual areas towards the dorsal and ventral streams. Further investigation of crucial DNN parameters revealed that while model architecture was important, training on real-world categorization was necessary to enforce spatio-temporal hierarchical relationships with the brain. Together our results provide an algorithmically informed view on the spatio-temporal dynamics of visual object recognition in the human visual brain.

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

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

Zoonotic Transmission of Waterborne Disease: A Mathematical Model.

PubMed

Waters, Edward K; Hamilton, Andrew J; Sidhu, Harvinder S; Sidhu, Leesa A; Dunbar, Michelle

2016-01-01

Waterborne parasites that infect both humans and animals are common causes of diarrhoeal illness, but the relative importance of transmission between humans and animals and vice versa remains poorly understood. Transmission of infection from animals to humans via environmental reservoirs, such as water sources, has attracted attention as a potential source of endemic and epidemic infections, but existing mathematical models of waterborne disease transmission have limitations for studying this phenomenon, as they only consider contamination of environmental reservoirs by humans. This paper develops a mathematical model that represents the transmission of waterborne parasites within and between both animal and human populations. It also improves upon existing models by including animal contamination of water sources explicitly. Linear stability analysis and simulation results, using realistic parameter values to describe Giardia transmission in rural Australia, show that endemic infection of an animal host with zoonotic protozoa can result in endemic infection in human hosts, even in the absence of person-to-person transmission. These results imply that zoonotic transmission via environmental reservoirs is important.

Clinical and tree hollow populations of human pathogenic yeast in Hamilton, Ontario, Canada are different.

PubMed

Carvalho, Chris; Yang, Jiaqi; Vogan, Aaron; Maganti, Harinad; Yamamura, Deborah; Xu, Jianping

2014-05-01

Yeast are among the most frequent pathogens in humans. The dominant yeast causing human infections belong to the genus Candida and Candida albicans is the most frequently isolated species. However, several non-C. albicans species are becoming increasingly common in patients worldwide. The relationships between yeast in humans and the natural environments remain poorly understood. Furthermore, it is often difficult to identify or exclude the origins of disease-causing yeast from specific environmental reservoirs. In this study, we compared the yeast isolates from tree hollows and from clinics in Hamilton, Ontario, Canada. Our surveys and analyses showed significant differences in yeast species composition, in their temporal dynamics, and in yeast genotypes between isolates from tree hollows and hospitals. Our results are inconsistent with the hypothesis that yeast from trees constitute a significant source of pathogenic yeast in humans in this region. Similarly, the yeast in humans and clinics do not appear to contribute to yeast in tree hollows. © 2013 Blackwell Verlag GmbH.

MAVS-dependent host species range and pathogenicity of human hepatitis A virus.

PubMed

Hirai-Yuki, Asuka; Hensley, Lucinda; McGivern, David R; González-López, Olga; Das, Anshuman; Feng, Hui; Sun, Lu; Wilson, Justin E; Hu, Fengyu; Feng, Zongdi; Lovell, William; Misumi, Ichiro; Ting, Jenny P-Y; Montgomery, Stephanie; Cullen, John; Whitmire, Jason K; Lemon, Stanley M

2016-09-30

Hepatotropic viruses are important causes of human disease, but the intrahepatic immune response to hepatitis viruses is poorly understood because of a lack of tractable small- animal models. We describe a murine model of hepatitis A virus (HAV) infection that recapitulates critical features of type A hepatitis in humans. We demonstrate that the capacity of HAV to evade MAVS-mediated type I interferon responses defines its host species range. HAV-induced liver injury was associated with interferon-independent intrinsic hepatocellular apoptosis and hepatic inflammation that unexpectedly resulted from MAVS and IRF3/7 signaling. This murine model thus reveals a previously undefined link between innate immune responses to virus infection and acute liver injury, providing a new paradigm for viral pathogenesis in the liver. Copyright © 2016, American Association for the Advancement of Science.

Expected utility violations evolve under status-based selection mechanisms.

PubMed

Dickson, Eric S

2008-10-07

The expected utility theory of decision making under uncertainty, a cornerstone of modern economics, assumes that humans linearly weight "utilities" for different possible outcomes by the probabilities with which these outcomes occur. Despite the theory's intuitive appeal, both from normative and from evolutionary perspectives, many experiments demonstrate systematic, though poorly understood, patterns of deviation from EU predictions. This paper offers a novel theoretical account of such patterns of deviation by demonstrating that EU violations can emerge from evolutionary selection when individual "status" affects inclusive fitness. In humans, battles for resources and social standing involve high-stakes decision making, and assortative mating ensures that status matters for fitness outcomes. The paper therefore proposes grounding the study of decision making under uncertainty in an evolutionary game-theoretic framework.

Transmission of the gut microbiota: spreading of health

PubMed Central

Browne, Hilary P.; Neville, B. Anne; Forster, Samuel C.; Lawley, Trevor D.

2018-01-01

Transmission of commensal intestinal bacteria between humans could promote health by establishing, maintaining and replenishing microbial diversity in the microbiota of an individual. Unlike pathogens, the routes of transmission for commensal bacteria remain unappreciated and poorly understood, despite the likely commonalities between both. Consequently, broad infection control measures that are designed to prevent pathogen transmission and infection, such as oversanitation and the overuse of antibiotics, may inadvertently affect human health by altering normal commensal transmission. In this Review, we discuss the mechanisms and factors that influence host-to-host transmission of the intestinal microbiota and examine how a better understanding of these processes will identify new approaches to nurture and restore transmission routes that are used by beneficial bacteria. PMID:28603278

Identification of the Upward Movement of Human CSF In Vivo and its Relation to the Brain Venous System.

PubMed

Dreha-Kulaczewski, Steffi; Joseph, Arun A; Merboldt, Klaus-Dietmar; Ludwig, Hans-Christoph; Gärtner, Jutta; Frahm, Jens

2017-03-01

CSF flux is involved in the pathophysiology of neurodegenerative diseases and cognitive impairment after traumatic brain injury, all hallmarked by the accumulation of cellular metabolic waste. Its effective disposal via various CSF routes has been demonstrated in animal models. In contrast, the CSF dynamics in humans are still poorly understood. Using novel real-time MRI, forced inspiration has been identified recently as a main driving force of CSF flow in the human brain. Exploiting technical advances toward real-time phase-contrast MRI, the current work analyzed directions, velocities, and volumes of human CSF flow within the brain aqueduct as part of the internal ventricular system and in the spinal canal during respiratory cycles. A consistent upward CSF movement toward the brain in response to forced inspiration was seen in all subjects at the aqueduct, in 11/12 subjects at thoracic level 2, and in 4/12 subjects at thoracic level 5. Concomitant analyses of CSF dynamics and cerebral venous blood flow, that is, in epidural veins at cervical level 3, uniquely demonstrated CSF and venous flow to be closely communicating cerebral fluid systems in which inspiration-induced downward flow of venous blood due to reduced intrathoracic pressure is counterbalanced by an upward movement of CSF. The results extend our understanding of human CSF flux and open important clinical implications, including concepts for drug delivery and new classifications and therapeutic options for various forms of hydrocephalus and idiopathic intracranial hypertension. SIGNIFICANCE STATEMENT Effective disposal of brain cellular waste products via CSF has been demonstrated repeatedly in animal models. However, CSF dynamics in humans are still poorly understood. A novel quantitative real-time MRI technique yielded in vivo CSF flow directions, velocities, and volumes in the human brain and upper spinal canal. CSF moved upward toward the head in response to forced inspiration. Concomitant analysis of brain venous blood flow indicated that CSF and venous flux act as closely communicating systems. The finding of a human CSF-venous network with upward CSF net movement opens new clinical concepts for drug delivery and new classifications and therapeutic options for various forms of hydrocephalus and ideopathic intracranial hypertension. Copyright © 2017 the authors 0270-6474/17/372395-08$15.00/0.

Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression

PubMed Central

Karp, Cristina M.; Tan, Ting Ting; Mathew, Robin; Nelson, Deidre; Mukherjee, Chandreyee; Degenhardt, Kurt; Karantza-Wadsworth, Vassiliki; White, Eileen

2009-01-01

Most tumors are epithelial-derived, and although disruption of polarity and aberrant cellular junction formation is a poor prognosticator in human cancer, the role of polarity determinants in oncogenesis is poorly understood. Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial (iBMK) cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity and contact inhibition, while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila. PMID:18519669

Chronic Rhinosinusitis and the Evolving Understanding of Microbial Ecology in Chronic Inflammatory Mucosal Disease.

PubMed

Hoggard, Michael; Wagner Mackenzie, Brett; Jain, Ravi; Taylor, Michael W; Biswas, Kristi; Douglas, Richard G

2017-01-01

Chronic rhinosinusitis (CRS) encompasses a heterogeneous group of debilitating chronic inflammatory sinonasal diseases. Despite considerable research, the etiology of CRS remains poorly understood, and debate on potential roles of microbial communities is unresolved. Modern culture-independent (molecular) techniques have vastly improved our understanding of the microbiology of the human body. Recent studies that better capture the full complexity of the microbial communities associated with CRS reintroduce the possible importance of the microbiota either as a direct driver of disease or as being potentially involved in its exacerbation. This review presents a comprehensive discussion of the current understanding of bacterial, fungal, and viral associations with CRS, with a specific focus on the transition to the new perspective offered in recent years by modern technology in microbiological research. Clinical implications of this new perspective, including the role of antimicrobials, are discussed in depth. While principally framed within the context of CRS, this discussion also provides an analogue for reframing our understanding of many similarly complex and poorly understood chronic inflammatory diseases for which roles of microbes have been suggested but specific mechanisms of disease remain unclear. Finally, further technological advancements on the horizon, and current pressing questions for CRS microbiological research, are considered. Copyright © 2016 American Society for Microbiology.

Contact variables for exposure to avian influenza H5N1 virus at the human-animal interface.

PubMed

Rabinowitz, P; Perdue, M; Mumford, E

2010-06-01

Although the highly pathogenic avian influenza H5N1 virus continues to cause infections in both avian and human populations, the specific zoonotic risk factors remain poorly understood. This review summarizes available evidence regarding types of contact associated with transmission of H5N1 virus at the human-animal interface. A systematic search of the published literature revealed five analytical studies and 15 case reports describing avian influenza transmission from animals to humans for further review. Risk factors identified in analytical studies were compared, and World Health Organization-confirmed cases, identified in case reports, were classified according to type of contact reported using a standardized algorithm. Although cases were primarily associated with direct contact with sick/unexpectedly dead birds, some cases reported only indirect contact with birds or contaminated environments or contact with apparently healthy birds. Specific types of contacts or activities leading to exposure could not be determined from data available in the publications reviewed. These results support previous reports that direct contact with sick birds is not the only means of human exposure to avian influenza H5N1 virus. To target public health measures and disease awareness messaging for reducing the risk of zoonotic infection with avian influenza H5N1 virus, the specific types of contacts and activities leading to transmission need to be further understood. The role of environmental virus persistence, shedding of virus by asymptomatic poultry and disease pathophysiology in different avian species relative to human zoonotic risk, as well as specific modes of zoonotic transmission, should be determined.

Viruses and neurodegeneration

PubMed Central

2013-01-01

Neurodegenerative diseases (NDs) are chronic degenerative diseases of the central nervous system (CNS), which affect 37 million people worldwide. As the lifespan increases, the NDs are the fourth leading cause of death in the developed countries and becoming increasingly prevalent in developing countries. Despite considerable research, the underlying mechanisms remain poorly understood. Although the large majority of studies do not show support for the involvement of pathogenic aetiology in classical NDs, a number of emerging studies show support for possible association of viruses with classical neurodegenerative diseases in humans. Space does not permit for extensive details to be discussed here on non-viral-induced neurodegenerative diseases in humans, as they are well described in literature. Viruses induce alterations and degenerations of neurons both directly and indirectly. Their ability to attack the host immune system, regions of nervous tissue implies that they can interfere with the same pathways involved in classical NDs in humans. Supporting this, many similarities between classical NDs and virus-mediated neurodegeneration (non-classical) have been shown at the anatomic, sub-cellular, genomic and proteomic levels suggesting that viruses can explain neurodegenerative disorders mechanistically. The main objective of this review is to provide readers a detailed snapshot of similarities viral and non-viral neurodegenerative diseases share, so that mechanistic pathways of neurodegeneration in human NDs can be clearly understood. Viruses can guide us to unveil these pathways in human NDs. This will further stimulate the birth of new concepts in the biological research, which is needed for gaining deeper insights into the treatment of human NDs and delineate mechanisms underlying neurodegeneration. PMID:23724961

Commensal bacteria produce GPCR ligands that mimic human signaling molecules

PubMed Central

Cohen, Louis J.; Esterhazy, Daria; Kim, Seong-Hwan; Lemetre, Christophe; Aguilar, Rhiannon R.; Gordon, Emma A.; Pickard, Amanda J.; Cross, Justin R.; Emiliano, Ana B.; Han, Sun M.; Chu, John; Vila-Farres, Xavier; Kaplitt, Jeremy; Rogoz, Aneta; Calle, Paula Y.; Hunter, Craig; Bitok, J. Kipchirchir; Brady, Sean F.

2017-01-01

Summary Statement Commensal bacteria are believed to play important roles in human health. The mechanisms by which they affect mammalian physiology are poorly understood; however, bacterial metabolites are likely to be key components of host interactions. Here, we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands although future studies are needed to define their potential physiologic role in humans. This work suggests that chemical mimicry of eukaryotic signaling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a new small molecule therapeutic modality (microbiome-biosynthetic-gene-therapy). PMID:28854168

Recent Advances in the Genetics of Vocal Learning

PubMed Central

Condro, Michael C.; White, Stephanie A.

2015-01-01

Language is a complex communicative behavior unique to humans, and its genetic basis is poorly understood. Genes associated with human speech and language disorders provide some insights, originating with the FOXP2 transcription factor, a mutation in which is the source of an inherited form of developmental verbal dyspraxia. Subsequently, targets of FOXP2 regulation have been associated with speech and language disorders, along with other genes. Here, we review these recent findings that implicate genetic factors in human speech. Due to the exclusivity of language to humans, no single animal model is sufficient to study the complete behavioral effects of these genes. Fortunately, some animals possess subcomponents of language. One such subcomponent is vocal learning, which though rare in the animal kingdom, is shared with songbirds. We therefore discuss how songbird studies have contributed to the current understanding of genetic factors that impact human speech, and support the continued use of this animal model for such studies in the future. PMID:26052371

Persistent RNA virus infections: do PAMPS drive chronic disease?

PubMed Central

McCarthy, Mary K.; Morrison, Thomas E.

2017-01-01

Chronic disease associated with persistent RNA virus infections represents a key public health concern. While human immunodeficiency virus-1 and hepatitis C virus are perhaps the most well-known examples of persistent RNA viruses that cause chronic disease, evidence suggests that many other RNA viruses, including re-emerging viruses such as chikungunya virus, Ebola virus and Zika virus, establish persistent infections. The mechanisms by which RNA viruses drive chronic disease are poorly understood. Here, we discuss how the persistence of viral RNA may drive chronic disease manifestations via the activation of RNA sensing pathways. PMID:28214732

Immunological mechanisms behind the cystic fibrosis-ABPA link.

PubMed

Hartl, Dominik

2009-01-01

Allergic bronchopulmonary aspergillosis (ABPA), a pulmonary hypersensitivity disease mediated by an allergic response to Aspergillus fumigatus (A. fumigatus), occurs preferentially in disease conditions with an impaired pulmonary immunity, especially in cystic fibrosis (CF) and allergic asthma. The pathophysiological mechanisms underlying the link between CF and ABPA are poorly understood. Animal and human data support a critical role for chemokines, especially CCL17 and its receptor CCR4, in ABPA. A summary and discussion of the immunological mechanism involved in the pathogenesis of ABPA with a focus on CF lung disease and the role of chemokines is presented here.

The Ufm1 Cascade

PubMed Central

Daniel, Jens; Liebau, Eva

2014-01-01

The ubiquitin-fold modifier 1 (Ufm1) is a posttranslational modifier that belongs to the ubiquitin-like protein (UBL) family. Ufm1 is present in nearly all eukaryotic organisms, with the exception of fungi. It resembles ubiquitin in its ability to be ligated to other proteins, as well as in the mechanism of ligation. While the Ufm1 cascade has been implicated in endoplasmic reticulum functions and cell cycle control, its biological role still remains poorly understood. In this short review, we summarize the current state of Ufm1 research and its potential role in human diseases, like diabetes, ischemic heart disease and cancer. PMID:24921187

Flagellar generated flow mediates attachment of Giardia Lamblia

NASA Astrophysics Data System (ADS)

Picou, Theodore; Polackwich, Jamie; Burrola Gabilondo, Beatriz; McAllister, Ryan; Powers, Tom; Elmendorf, Heidi; Urbach, Jeff

2011-11-01

Giardia lamblia is a protozoan parasite responsible for widespread diarrheal disease in humans and animals worldwide. Attachment to the host intestinal mucosa and resistance to peristalsis is necessary for establishing infection, but the physical basis for this attachment is poorly understood. We report results from confocal fluorescence microscopy that demonstrate that the regular beating of the posterior flagella generate a flow through the ventral disk, a suction-cup shaped structure that is against the substrate during attachment. Finite element simulations show that the negative pressure generated by the flow is consistent with the measured force of attachement between the parasite and its substrate.

Atmospheric Research at BNL

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

Peter Daum

2008-10-06

Brookhaven researcher Peter Daum discusses an international field experiment designed to make observations of critical components of the climate system of the southeastern Pacific. Because elements of this system are poorly understood and poorly represent

Atmospheric Research at BNL

ScienceCinema

Peter Daum

2017-12-09

Brookhaven researcher Peter Daum discusses an international field experiment designed to make observations of critical components of the climate system of the southeastern Pacific. Because elements of this system are poorly understood and poorly represent

HIV-1 infection depletes human CD34+CD38- hematopoietic progenitor cells via pDC-dependent mechanisms.

PubMed

Li, Guangming; Zhao, Juanjuan; Cheng, Liang; Jiang, Qi; Kan, Sheng; Qin, Enqiang; Tu, Bo; Zhang, Xin; Zhang, Liguo; Su, Lishan; Zhang, Zheng

2017-07-01

Chronic human immunodeficiency virus-1 (HIV-1) infection in patients leads to multi-lineage hematopoietic abnormalities or pancytopenia. The deficiency in hematopoietic progenitor cells (HPCs) induced by HIV-1 infection has been proposed, but the relevant mechanisms are poorly understood. We report here that both human CD34+CD38- early and CD34+CD38+ intermediate HPCs were maintained in the bone marrow (BM) of humanized mice. Chronic HIV-1 infection preferentially depleted CD34+CD38- early HPCs in the BM and reduced their proliferation potential in vivo in both HIV-1-infected patients and humanized mice, while CD34+CD38+ intermediate HSCs were relatively unaffected. Strikingly, depletion of plasmacytoid dendritic cells (pDCs) prevented human CD34+CD38- early HPCs from HIV-1 infection-induced depletion and functional impairment and restored the gene expression profile of purified CD34+ HPCs in humanized mice. These findings suggest that pDCs contribute to the early hematopoietic suppression induced by chronic HIV-1 infection and provide a novel therapeutic target for the hematopoiesis suppression in HIV-1 patients.

Generous economic investments after basolateral amygdala damage.

PubMed

van Honk, Jack; Eisenegger, Christoph; Terburg, David; Stein, Dan J; Morgan, Barak

2013-02-12

Contemporary economic models hold that instrumental and impulsive behaviors underlie human social decision making. The amygdala is assumed to be involved in social-economic behavior, but its role in human behavior is poorly understood. Rodent research suggests that the basolateral amygdala (BLA) subserves instrumental behaviors and regulates the central-medial amygdala, which subserves impulsive behaviors. The human amygdala, however, typically is investigated as a single unit. If these rodent data could be translated to humans, selective dysfunction of the human BLA might constrain instrumental social-economic decisions and result in more impulsive social-economic choice behavior. Here we show that humans with selective BLA damage and a functional central-medial amygdala invest nearly 100% more money in unfamiliar others in a trust game than do healthy controls. We furthermore show that this generosity is not caused by risk-taking deviations in nonsocial contexts. Moreover, these BLA-damaged subjects do not expect higher returns or perceive people as more trustworthy, implying that their generous investments are not instrumental in nature. These findings suggest that the human BLA is essential for instrumental behaviors in social-economic interactions.

Pathogen-mediated manipulation of arthropod microbiota to promote infection

PubMed Central

Abraham, Nabil M.; Liu, Lei; Jutras, Brandon Lyon; Yadav, Akhilesh K.; Narasimhan, Sukanya; Gopalakrishnan, Vissagan; Ansari, Juliana M.; Jefferson, Kimberly K.; Cava, Felipe; Jacobs-Wagner, Christine; Fikrig, Erol

2017-01-01

Arthropods transmit diverse infectious agents; however, the ways microbes influence their vector to enhance colonization are poorly understood. Ixodes scapularis ticks harbor numerous human pathogens, including Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis. We now demonstrate that A. phagocytophilum modifies the I. scapularis microbiota to more efficiently infect the tick. A. phagocytophilum induces ticks to express Ixodes scapularis antifreeze glycoprotein (iafgp), which encodes a protein with several properties, including the ability to alter bacterial biofilm formation. IAFGP thereby perturbs the tick gut microbiota, which influences the integrity of the peritrophic matrix and gut barrier—critical obstacles for Anaplasma colonization. Mechanistically, IAFGP binds the terminal d-alanine residue of the pentapeptide chain of bacterial peptidoglycan, resulting in altered permeability and the capacity of bacteria to form biofilms. These data elucidate the molecular mechanisms by which a human pathogen appropriates an arthropod antibacterial protein to alter the gut microbiota and more effectively colonize the vector. PMID:28096373

Discovery of a proteinaceous cellular receptor for a norovirus

PubMed Central

Orchard, Robert C.; Wilen, Craig B.; Doench, John G.; Baldridge, Megan T.; McCune, Broc T.; Lee, Ying-Chiang J.; Lee, Sanghyun; Pruett-Miller, Shondra M.; Nelson, Christopher A.; Fremont, Daved H.; Virgin, Herbert W.

2017-01-01

Human noroviruses (NoV) are a leading cause of gastroenteritis globally, yet host factors required for NoV infection are poorly understood. We identified host molecules essential for murine NoV (MNoV) induced cell death including CD300lf as a proteinaceous receptor. CD300lf is essential for MNoV binding and replication in cell lines and primary cells. Additionally, Cd300lf−/− mice are resistant to MNoV infection. Expression of CD300lf in human cells breaks the species barrier restricting MNoV replication. The crystal structure of the CD300lf ectodomain revealed a potential ligand binding cleft composed of residues critical for MNoV infection. Therefore, the presence of a proteinaceous receptor is the primary determinant of MNoV species tropism while other components of cellular machinery required for NoV replication are conserved between humans and mice. PMID:27540007

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

Thai,V.; Renesto, P.; Fowler, C.

Although multiple viruses utilize host cell cyclophilins, including severe acute respiratory syndrome (SARS) and human immunodeficiency virus type-1(HIV-1), their role in infection is poorly understood. To help elucidate these roles, we have characterized the first virally encoded cyclophilin (mimicyp) derived from the largest virus discovered to date (the Mimivirus) that is also a causative agent of pneumonia in humans. Mimicyp adopts a typical cyclophilin-fold, yet it also forms trimers unlike any previously characterized homologue. Strikingly, immunofluorescence assays reveal that mimicyp localizes to the surface of the mature virion, as recently proposed for several viruses that recruit host cell cyclophilins suchmore » as SARS and HIV-1. Additionally mimicyp lacks peptidyl-prolyl isomerase activity in contrast to human cyclophilins. Thus, this study suggests that cyclophilins, whether recruited from host cells (ie HIV-1 and SARS) or virally encoded (ie Mimivirus), are localized on viral surfaces for at least a subset of viruses.« less

A novel enzyme with antioxidant capacity produced by the ubiquitous skin colonizer Propionibacterium acnes.

PubMed

Allhorn, Maria; Arve, Sabine; Brüggemann, Holger; Lood, Rolf

2016-11-02

The role of the skin microbiota in human health is poorly understood. Here, we identified and characterized a novel antioxidant enzyme produced by the skin microbiota, designated RoxP for radical oxygenase of Propionibacterium acnes. RoxP is uniquely produced by the predominant skin bacterium P. acnes, with no homologs in other bacteria; it is highly expressed and strongly secreted into culture supernatants. We show that RoxP binds heme, reduces free radicals, and can protect molecules from oxidation. Strikingly, RoxP is crucial for the survival of P. acnes in oxic conditions and for skin colonization of P. acnes ex vivo. Taken together, our study strongly suggests that RoxP facilitates P. acnes' survival on human skin, and is an important beneficial factor for the host-commensal interaction. Thus, RoxP is the first described skin microbiota-derived mutualistic factor that potentially can be exploited for human skin protection.

New Insights into Human Cryptosporidiosis

PubMed Central

Clark, Douglas P.

1999-01-01

Cryptosporidium parvum is an important cause of diarrhea worldwide. Cryptosporidium causes a potentially life-threatening disease in people with AIDS and contributes significantly to morbidity among children in developing countries. In immunocompetent adults, Cryptosporidium is often associated with waterborne outbreaks of acute diarrheal illness. Recent studies with human volunteers have indicated that Cryptosporidium is highly infectious. Diagnosis of infection with this parasite has relied on identification of acid-fast oocysts in stool; however, new immunoassays or PCR-based assays may increase the sensitivity of detection. Although the mechanism by which Cryptosporidium causes diarrhea is still poorly understood, the parasite and the immune response to it probably combine to impair absorption and enhance secretion within the intestinal tract. Important genetic studies suggest that humans can be infected by at least two genetically distinct types of Cryptosporidium, which may vary in virulence. This may, in part, explain the clinical variability seen in patients with cryptosporidiosis. PMID:10515902

A Quaternary Mechanism Enables the Complex Biological Functions of Octameric Human UDP-glucose Pyrophosphorylase, a Key Enzyme in Cell Metabolism

PubMed Central

Führing, Jana Indra; Cramer, Johannes Thomas; Schneider, Julia; Baruch, Petra; Gerardy-Schahn, Rita; Fedorov, Roman

2015-01-01

In mammals, UDP-glucose pyrophosphorylase (UGP) is the only enzyme capable of activating glucose-1-phosphate (Glc-1-P) to UDP-glucose (UDP-Glc), a metabolite located at the intersection of virtually all metabolic pathways in the mammalian cell. Despite the essential role of its product, the molecular basis of UGP function is poorly understood. Here we report the crystal structure of human UGP in complex with its product UDP-Glc. Beyond providing first insight into the active site architecture, we describe the substrate binding mode and intermolecular interactions in the octameric enzyme that are crucial to its activity. Importantly, the quaternary mechanism identified for human UGP in this study may be common for oligomeric sugar-activating nucleotidyltransferases. Elucidating such mechanisms is essential for understanding nucleotide sugar metabolism and opens the perspective for the development of drugs that specifically inhibit simpler organized nucleotidyltransferases in pathogens. PMID:25860585

Recombinant human dihydroxyacetonephosphate acyl-transferase characterization as an integral monotopic membrane protein.

PubMed

Piano, Valentina; Nenci, Simone; Magnani, Francesca; Aliverti, Alessandro; Mattevi, Andrea

2016-12-02

Although the precise functions of ether phospholipids are still poorly understood, significant alterations in their physiological levels are associated either to inherited disorders or to aggressive metastatic cancer. The essential precursor, alkyl-dihydroxyacetone phosphate (DHAP), for all ether phospholipids species is synthetized in two consecutive reactions performed by two enzymes sitting on the inner side of the peroxisomal membrane. Here, we report the characterization of the recombinant human DHAP acyl-transferase, which performs the first step in alkyl-DHAP synthesis. By exploring several expression systems and designing a number of constructs, we were able to purify the enzyme in its active form and we found that it is tightly bound to the membrane through the N-terminal residues. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Purification, crystallization and preliminary X-ray diffraction of the C-terminal bromodomain from human BRD2

PubMed Central

Umehara, Takashi; Wakamori, Masatoshi; Tanaka, Akiko; Padmanabhan, Balasundaram; Yokoyama, Shigeyuki

2007-01-01

BRD2 is a bromodomain-containing BET-family protein that associates with acetylated histones throughout the cell cycle. Although the tertiary structures of the bromodomains involved in histone acetyl transfer are already known, the structures of the BET-type bromodomains, which are required for tight association with acetylated chromatin, are poorly understood. Here, the expression, purification and crystallization of the C-terminal bromodomain of human BRD2 are reported. The protein was crystallized by the sitting-drop vapour-diffusion method in the orthorhombic space group P21212, with unit-cell parameters a = 71.78, b = 52.60, c = 32.06 Å and one molecule per asymmetric unit. The crystal diffracted beyond 1.80 Å resolution using synchrotron radiation. PMID:17620725

Mapping the evolutionary trajectories of morbilliviruses: what, where and whither.

PubMed

Nambulli, Sham; Sharp, Claire R; Acciardo, Andrew S; Drexler, J Felix; Duprex, W Paul

2016-02-01

Morbilliviruses are pathogens of humans and other animals. Live attenuated morbillivirus vaccines have been used to end endemic transmission of measles virus (MV) in many parts of the developed world and to eradicate rinderpest virus. Entry is mediated by two different receptors which govern virus lymphotropism and epitheliotropism. Morbillivirus transmissibility is unparalleled and MV represents the most infectious human pathogen on earth. Their evolutionary origins remain obscure and their potential for adaption to new hosts is poorly understood. It has been suggested that MV could be eradicated. Therefore it is imperative to dissect barriers which restrict cross species infections. This is important as ecological studies identify novel morbilliviruses in a vast number of small mammals and carnivorous predators. Copyright © 2016 Elsevier B.V. All rights reserved.

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications

PubMed Central

Pohl, Calvin S.; Medland, Julia E.

2015-01-01

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. PMID:26451004

Antimicrobial activity of extracts from macroalgae Ulva lactuca against clinically important Staphylococci is impacted by lunar phase of macroalgae harvest.

PubMed

Deveau, A M; Miller-Hope, Z; Lloyd, E; Williams, B S; Bolduc, C; Meader, J M; Weiss, F; Burkholder, K M

2016-05-01

Staphylococcus aureus is a common human bacterial pathogen that causes skin and soft tissue infections. Methicillin-resistant Staph. aureus (MRSA) are increasingly drug-resistant, and thus there is great need for new therapeutics to treat Staph. aureus infections. Attention has focused on potential utility of natural products, such as extracts of marine macroalgae, as a source of novel antimicrobial compounds. The green macroalgae Ulva lactuca produces compounds inhibitory to human pathogens, although the effectiveness of U. lactuca extracts against clinically relevant strains of Staph. aureus is poorly understood. In addition, macroalgae produce secondary metabolites that may be influenced by exogenous factors including lunar phase, but whether lunar phase affects U. lactuca antimicrobial capacity is unknown. We sought to evaluate the antibacterial properties of U. lactuca extracts against medically important Staphylococci, and to determine the effect of lunar phase on antimicrobial activity. We report that U. lactuca methanolic extracts inhibit a range of Staphylococci, and that lunar phase of macrolagae harvest significantly impacts antimicrobial activity, suggesting that antimicrobial properties can be maximized by manipulating time of algal harvest. These findings provide useful parameters for future studies aimed at isolating and characterizing U. lactuca anti-Staphylococcal agents. The growing prevalence of antibiotic-resistant human pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) has intensified efforts towards discovery and development of novel therapeutics. Marine macroalgae like Ulva lactuca are increasingly recognized as potential sources of antimicrobials, but the efficacy of U. lactuca extracts against common, virulent strains of Staph. aureus is poorly understood. We demonstrate that U. lactuca methanolic extracts inhibit a variety of clinically relevant Staphylococcus strains, and that the antimicrobial activity can be maximized by optimizing time of algal harvest. These findings provide potentially useful parameters for future work of isolating and identifying novel antimicrobial agents from macroalgae. © 2016 The Society for Applied Microbiology.

The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism

PubMed Central

Bermingham, Daniel P.; Snider, Sam L.; Miller, David M.

2017-01-01

The neurotransmitter dopamine (DA) regulates multiple behaviors across phylogeny, with disrupted DA signaling in humans associated with addiction, attention-deficit/ hyperactivity disorder, schizophrenia, and Parkinson's disease. The DA transporter (DAT) imposes spatial and temporal limits on DA action, and provides for presynaptic DA recycling to replenish neurotransmitter pools. Molecular mechanisms that regulate DAT expression, trafficking, and function, particularly in vivo, remain poorly understood, though recent studies have implicated rho-linked pathways in psychostimulant action. To identify genes that dictate the ability of DAT to sustain normal levels of DA clearance, we pursued a forward genetic screen in Caenorhabditis elegans based on the phenotype swimming-induced paralysis (Swip), a paralytic behavior observed in hermaphrodite worms with loss-of-function dat-1 mutations. Here, we report the identity of swip-13, which encodes a highly conserved ortholog of the human atypical MAP kinase ERK8. We present evidence that SWIP-13 acts presynaptically to insure adequate levels of surface DAT expression and DA clearance. Moreover, we provide in vitro and in vivo evidence supporting a conserved pathway involving SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and function. SIGNIFICANCE STATEMENT Signaling by the neurotransmitter dopamine (DA) is tightly regulated by the DA transporter (DAT), insuring efficient DA clearance after release. Molecular networks that regulate DAT are poorly understood, particularly in vivo. Using a forward genetic screen in the nematode Caenorhabditis elegans, we implicate the atypical mitogen activated protein kinase, SWIP-13, in DAT regulation. Moreover, we provide in vitro and in vivo evidence that SWIP-13, as well as its human counterpart ERK8, regulate DAT surface availability via the activation of Rho proteins. Our findings implicate a novel pathway that regulates DA synaptic availability and that may contribute to risk for disorders linked to perturbed DA signaling. Targeting this pathway may be of value in the development of therapeutics in such disorders. PMID:28842414

Ancient DNA Investigation of a Medieval German Cemetery Confirms Long-Term Stability of CCR5-Δ32 Allele Frequencies in Central Europe.

PubMed

Bouwman, Abigail; Shved, Natallia; Akgül, Gülfirde; Rühli, Frank; Warinner, Christina

2017-04-01

The CCR5-Δ32 mutation present in European populations is among the most prominently debated cases of recent positive selection in humans. This allele, a 32-bp deletion that renders the T-cell CCR5 receptor nonfunctional, has important epidemiological and public health significance, as homozygous carriers are resistant to several HIV strains. However, although the function of this allele in preventing HIV infection is now well described, its human evolutionary origin is poorly understood. Initial attempts to determine the emergence of the CCR5-Δ32 allele pointed to selection during the 14th-century Black Death pandemic; however, subsequent analyses suggest that the allele rose in frequency more than 5,000 years ago, possibly through drift. Recently, three studies have identified populations predating the 14th century CE that are positive for the CCR5-Δ32 allele, supporting the claim for a more ancient origin. However, these studies also suggest poorly understood regional differences in the recent evolutionary history of the CCR5-Δ32 allele. Here a new hydrolysis-probe-based real-time PCR assay was designed to ascertain CCR5 allele frequency in 53 individuals from a 10th- to 12th-century CE church and convent complex in central Germany that predates outbreaks of the Black Death pandemic. High-confidence genotypes were obtained for 32 individuals, and results show that CCR5-Δ32 allele frequency has remained unchanged in this region of Central Europe over the last millennium, suggesting that there has been no strong positive selective pressure over this time period and confirming a more ancient origin for the allele.

Functional Imaging of Audio-Visual Selective Attention in Monkeys and Humans: How do Lapses in Monkey Performance Affect Cross-Species Correspondences?

PubMed

Rinne, Teemu; Muers, Ross S; Salo, Emma; Slater, Heather; Petkov, Christopher I

2017-06-01

The cross-species correspondences and differences in how attention modulates brain responses in humans and animal models are poorly understood. We trained 2 monkeys to perform an audio-visual selective attention task during functional magnetic resonance imaging (fMRI), rewarding them to attend to stimuli in one modality while ignoring those in the other. Monkey fMRI identified regions strongly modulated by auditory or visual attention. Surprisingly, auditory attention-related modulations were much more restricted in monkeys than humans performing the same tasks during fMRI. Further analyses ruled out trivial explanations, suggesting that labile selective-attention performance was associated with inhomogeneous modulations in wide cortical regions in the monkeys. The findings provide initial insights into how audio-visual selective attention modulates the primate brain, identify sources for "lost" attention effects in monkeys, and carry implications for modeling the neurobiology of human cognition with nonhuman animals. © The Author 2017. Published by Oxford University Press.

Functional Imaging of Audio–Visual Selective Attention in Monkeys and Humans: How do Lapses in Monkey Performance Affect Cross-Species Correspondences?

PubMed Central

Muers, Ross S.; Salo, Emma; Slater, Heather; Petkov, Christopher I.

2017-01-01

Abstract The cross-species correspondences and differences in how attention modulates brain responses in humans and animal models are poorly understood. We trained 2 monkeys to perform an audio–visual selective attention task during functional magnetic resonance imaging (fMRI), rewarding them to attend to stimuli in one modality while ignoring those in the other. Monkey fMRI identified regions strongly modulated by auditory or visual attention. Surprisingly, auditory attention-related modulations were much more restricted in monkeys than humans performing the same tasks during fMRI. Further analyses ruled out trivial explanations, suggesting that labile selective-attention performance was associated with inhomogeneous modulations in wide cortical regions in the monkeys. The findings provide initial insights into how audio–visual selective attention modulates the primate brain, identify sources for “lost” attention effects in monkeys, and carry implications for modeling the neurobiology of human cognition with nonhuman animals. PMID:28419201

Computational Precision of Mental Inference as Critical Source of Human Choice Suboptimality.

PubMed

Drugowitsch, Jan; Wyart, Valentin; Devauchelle, Anne-Dominique; Koechlin, Etienne

2016-12-21

Making decisions in uncertain environments often requires combining multiple pieces of ambiguous information from external cues. In such conditions, human choices resemble optimal Bayesian inference, but typically show a large suboptimal variability whose origin remains poorly understood. In particular, this choice suboptimality might arise from imperfections in mental inference rather than in peripheral stages, such as sensory processing and response selection. Here, we dissociate these three sources of suboptimality in human choices based on combining multiple ambiguous cues. Using a novel quantitative approach for identifying the origin and structure of choice variability, we show that imperfections in inference alone cause a dominant fraction of suboptimal choices. Furthermore, two-thirds of this suboptimality appear to derive from the limited precision of neural computations implementing inference rather than from systematic deviations from Bayes-optimal inference. These findings set an upper bound on the accuracy and ultimate predictability of human choices in uncertain environments. Copyright © 2016 Elsevier Inc. All rights reserved.

Behavioral economics.

PubMed

Chambers, David W

2009-01-01

It is human nature to overestimate how rational we are, both in general and even when we are trying to be. Such irrationality is not random, and the search for and explanation of patterns of fuzzy thinking is the basis for a new academic discipline known as behavioral economics. Examples are given of some of the best understood of our foibles, including prospect theory, framing, anchoring, salience, confirmation bias, superstition, and ownership. Humans have two cognitive systems: one conscious, deliberate, slow, and rational; the other fast, pattern-based, emotionally tinged, and intuitive. Each is subject to its own kind of error. In the case of rational thought, we tend to exaggerate our capacity; for intuition, we fail to train it or recognize contexts where it is inappropriate. Humans are especially poor at estimating probabilities, or even understanding what they are. It is a common human failing to reason backwards from random outcomes that are favorable to beliefs about our power to predict the future. Five suggestions are offered for thinking within our means.

Will Culling White-Tailed Deer Prevent Lyme Disease?

PubMed

Kugeler, K J; Jordan, R A; Schulze, T L; Griffith, K S; Mead, P S

2016-08-01

White-tailed deer play an important role in the ecology of Lyme disease. In the United States, where the incidence and geographic range of Lyme disease continue to increase, reduction of white-tailed deer populations has been proposed as a means of preventing human illness. The effectiveness of this politically sensitive prevention method is poorly understood. We summarize and evaluate available evidence regarding the effect of deer reduction on vector tick abundance and human disease incidence. Elimination of deer from islands and other isolated settings can have a substantial impact on the reproduction of blacklegged ticks, while reduction short of complete elimination has yielded mixed results. To date, most studies have been conducted in ecologic situations that are not representative to the vast majority of areas with high human Lyme disease risk. Robust evidence linking deer control to reduced human Lyme disease risk is lacking. Currently, there is insufficient evidence to recommend deer population reduction as a Lyme disease prevention measure, except in specific ecologic circumstances. © 2015 Blackwell Verlag GmbH.

Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.

PubMed

Petrie, Emma J; Sandow, Jarrod J; Jacobsen, Annette V; Smith, Brian J; Griffin, Michael D W; Lucet, Isabelle S; Dai, Weiwen; Young, Samuel N; Tanzer, Maria C; Wardak, Ahmad; Liang, Lung-Yu; Cowan, Angus D; Hildebrand, Joanne M; Kersten, Wilhelmus J A; Lessene, Guillaume; Silke, John; Czabotar, Peter E; Webb, Andrew I; Murphy, James M

2018-06-21

Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.

KRAS Mouse Models

PubMed Central

O’Hagan, Rónán C.; Heyer, Joerg

2011-01-01

KRAS is a potent oncogene and is mutated in about 30% of all human cancers. However, the biological context of KRAS-dependent oncogenesis is poorly understood. Genetically engineered mouse models of cancer provide invaluable tools to study the oncogenic process, and insights from KRAS-driven models have significantly increased our understanding of the genetic, cellular, and tissue contexts in which KRAS is competent for oncogenesis. Moreover, variation among tumors arising in mouse models can provide insight into the mechanisms underlying response or resistance to therapy in KRAS-dependent cancers. Hence, it is essential that models of KRAS-driven cancers accurately reflect the genetics of human tumors and recapitulate the complex tumor-stromal intercommunication that is manifest in human cancers. Here, we highlight the progress made in modeling KRAS-dependent cancers and the impact that these models have had on our understanding of cancer biology. In particular, the development of models that recapitulate the complex biology of human cancers enables translational insights into mechanisms of therapeutic intervention in KRAS-dependent cancers. PMID:21779503

Active role of a human genomic insert in replication of a yeast artificial chromosome.

PubMed

van Brabant, A J; Fangman, W L; Brewer, B J

1999-06-01

Yeast artificial chromosomes (YACs) are a common tool for cloning eukaryotic DNA. The manner by which large pieces of foreign DNA are assimilated by yeast cells into a functional chromosome is poorly understood, as is the reason why some of them are stably maintained and some are not. We examined the replication of a stable YAC containing a 240-kb insert of DNA from the human T-cell receptor beta locus. The human insert contains multiple sites that serve as origins of replication. The activity of these origins appears to require the yeast ARS consensus sequence and, as with yeast origins, additional flanking sequences. In addition, the origins in the human insert exhibit a spacing, a range of activation efficiencies, and a variation in times of activation during S phase similar to those found for normal yeast chromosomes. We propose that an appropriate combination of replication origin density, activation times, and initiation efficiencies is necessary for the successful maintenance of YAC inserts.

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

PubMed Central

Kim, Ju-Hyun; Choi, Won-Gu; Lee, Sangkyu; Lee, Hye Suk

2017-01-01

Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography–mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and N-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as “flags” to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach. PMID:28335386

Will Culling White-Tailed Deer Prevent Lyme Disease?

PubMed Central

Kugeler, K. J.; Jordan, R. A.; Schulze, T. L.; Griffith, K. S.; Mead, P. S.

2015-01-01

Summary White-tailed deer play an important role in the ecology of Lyme disease. In the United States, where the incidence and geographic range of Lyme disease continue to increase, reduction of white-tailed deer populations has been proposed as a means of preventing human illness. The effectiveness of this politically sensitive prevention method is poorly understood. We summarize and evaluate available evidence regarding the effect of deer reduction on vector tick abundance and human disease incidence. Elimination of deer from islands and other isolated settings can have a substantial impact on the reproduction of blacklegged ticks, while reduction short of complete elimination has yielded mixed results. To date, most studies have been conducted in ecologic situations that are not representative to the vast majority of areas with high human Lyme disease risk. Robust evidence linking deer control to reduced human Lyme disease risk is lacking. Currently, there is insufficient evidence to recommend deer population reduction as a Lyme disease prevention measure, except in specific ecologic circumstances. PMID:26684932

Human Impacts and Climate Change Influence Nestedness and Modularity in Food-Web and Mutualistic Networks.

PubMed

Takemoto, Kazuhiro; Kajihara, Kosuke

2016-01-01

Theoretical studies have indicated that nestedness and modularity-non-random structural patterns of ecological networks-influence the stability of ecosystems against perturbations; as such, climate change and human activity, as well as other sources of environmental perturbations, affect the nestedness and modularity of ecological networks. However, the effects of climate change and human activities on ecological networks are poorly understood. Here, we used a spatial analysis approach to examine the effects of climate change and human activities on the structural patterns of food webs and mutualistic networks, and found that ecological network structure is globally affected by climate change and human impacts, in addition to current climate. In pollination networks, for instance, nestedness increased and modularity decreased in response to increased human impacts. Modularity in seed-dispersal networks decreased with temperature change (i.e., warming), whereas food web nestedness increased and modularity declined in response to global warming. Although our findings are preliminary owing to data-analysis limitations, they enhance our understanding of the effects of environmental change on ecological communities.

Tumor-line specific causes of intertumor heterogeneity in blood supply in human melanoma xenografts.

PubMed

Simonsen, Trude G; Gaustad, Jon-Vidar; Leinaas, Marit N; Rofstad, Einar K

2013-01-01

The efficacy of most cancer treatments is strongly influenced by the tumor blood supply. The results of experimental studies using xenografted tumors to evaluate novel cancer treatments may therefore vary considerably depending on the blood supply of the specific tumor model being used. Mechanisms underlying intertumor heterogeneity in the blood supply of xenografted tumors derived from same tumor line are poorly understood, and were investigated here by using intravital microscopy to assess tumor blood supply and vascular morphology in human melanomas growing in dorsal window chambers in BALB/c nu/nu mice. Two melanoma lines, A-07 and R-18, were included in the study. These lines differed substantially in angiogenic profiles. Thus, when the expression of 84 angiogenesis-related genes was investigated with a quantitative PCR array, 25% of these genes showed more than a 10-fold difference in expression. Furthermore, A-07 tumors showed higher vascular density, higher vessel tortuosity, higher vessel diameters, shorter vessel segments, and more chaotic vascular architecture than R-18 tumors. Both lines showed large intertumor heterogeneity in blood supply. In the A-07 line, tumors with low microvascular density, long vessel segment, and high vessel tortuosity showed poor blood supply, whereas in the R-18 line, poor tumor blood supply was associated with low tumor arteriolar diameters. Thus, tumor-line specific causes of intertumor heterogeneity in blood supply were identified in human melanoma xenografts, and these tumor-line specific mechanisms were possibly a result of tumor-line specific angiogenic profiles. Copyright © 2012 Elsevier Inc. All rights reserved.

Filament formation associated with spirochetal infection: a comparative approach to Morgellons disease

PubMed Central

Middelveen, Marianne J; Stricker, Raphael B

2011-01-01

Bovine digital dermatitis is an emerging infectious disease that causes lameness, decreased milk production, and weight loss in livestock. Proliferative stages of bovine digital dermatitis demonstrate keratin filament formation in skin above the hooves in affected animals. The multifactorial etiology of digital dermatitis is not well understood, but spirochetes and other coinfecting microorganisms have been implicated in the pathogenesis of this veterinary illness. Morgellons disease is an emerging human dermopathy characterized by the presence of filamentous fibers of undetermined composition, both in lesions and subdermally. While the etiology of Morgellons disease is unknown, there is serological and clinical evidence linking this phenomenon to Lyme borreliosis and coinfecting tick-borne agents. Although the microscopy of Morgellons filaments has been described in the medical literature, the structure and pathogenesis of these fibers is poorly understood. In contrast, most microscopy of digital dermatitis has focused on associated pathogens and histology rather than the morphology of late-stage filamentous fibers. Clinical, laboratory, and microscopic characteristics of these two diseases are compared. PMID:22253541

Filament formation associated with spirochetal infection: a comparative approach to Morgellons disease.

PubMed

Middelveen, Marianne J; Stricker, Raphael B

2011-01-01

Bovine digital dermatitis is an emerging infectious disease that causes lameness, decreased milk production, and weight loss in livestock. Proliferative stages of bovine digital dermatitis demonstrate keratin filament formation in skin above the hooves in affected animals. The multifactorial etiology of digital dermatitis is not well understood, but spirochetes and other coinfecting microorganisms have been implicated in the pathogenesis of this veterinary illness. Morgellons disease is an emerging human dermopathy characterized by the presence of filamentous fibers of undetermined composition, both in lesions and subdermally. While the etiology of Morgellons disease is unknown, there is serological and clinical evidence linking this phenomenon to Lyme borreliosis and coinfecting tick-borne agents. Although the microscopy of Morgellons filaments has been described in the medical literature, the structure and pathogenesis of these fibers is poorly understood. In contrast, most microscopy of digital dermatitis has focused on associated pathogens and histology rather than the morphology of late-stage filamentous fibers. Clinical, laboratory, and microscopic characteristics of these two diseases are compared.

Consumer perception of beneficial effects of probiotics for human health.

PubMed

Rijkers, G T; Bimmel, D; Grevers, D; den Haan, N; Hristova, Y

2013-03-01

The purpose of this study was to evaluate the knowledge, perception and buying behaviour of probiotics. 72 participants in Middelburg, the Netherlands, filled out a detailed questionnaire regarding probiotics and their customer and consumer behaviour. It can be concluded from this study that the concept of probiotics is generally poorly understood. Health-conscious consumers seem to be the group most aware of the correct meaning of the term probiotics. Almost 50% of the participants did not believe that probiotics had any health effect. Independent organisations and/or government agencies appeared to be the preferred source of information on the functionality of probiotics.

Germ cell tumors: Insights from the Drosophila ovary and the mouse testis.

PubMed

Salz, Helen K; Dawson, Emily P; Heaney, Jason D

2017-03-01

Ovarian and testicular germ cell tumors of young adults are thought to arise from defects in germ cell development, but the molecular mechanisms underlying malignant transformation are poorly understood. In this review, we focus on the biology of germ cell tumor formation in the Drosophila ovary and the mouse testis, for which evidence supports common underlying mechanisms, such as blocking initiation into the differentiation pathway, impaired lineage progression, and sexual identity instability. We then discuss how these concepts inform our understanding of the disease in humans. Mol. Reprod. Dev. 84: 200-211, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

European network using fish as osteoporosis research models (ENFORM)

NASA Astrophysics Data System (ADS)

Goerlich, R.; Renn, J.; Alestrom, P.; Nouizadeh-Lillabadi, R.; Schartl, M.; Winkler, C.; Muller, M.; Midtyng, P. J.; Eberius, M.; Slenzka, K.

2005-08-01

Osteoporosis, characterised by loss of bone density, is one of the most important bone diseases of humans worldwide. It causes problems in post-menopausal women, in astronauts during long-term spaceflights and in industrial animal production. Bone alterations leading to osteoporosis are well-documented at the cellular level, but the underlying molecular events are still poorly understood and most of our knowledge is derived from in vitro studies using cell culture systems. Recent findings indicate a remarkable conservation of the key regulators of bone development and homeostasis between mammals and fish. Medaka (Oryzias latipes) and zebrafish (Danio rerio) offer experimental advantages that can be exploited for bone research.

Comparative transcriptional profiling of human Merkel cells and Merkel cell carcinoma.

PubMed

Mouchet, Nicolas; Coquart, Nolwenn; Lebonvallet, Nicolas; Le Gall-Ianotto, Christelle; Mogha, Ariane; Fautrel, Alain; Boulais, Nicholas; Dréno, Brigitte; Martin, Ludovic; Hu, Weiguo; Galibert, Marie-Dominique; Misery, Laurent

2014-12-01

Merkel cell carcinoma is believed to be derived from Merkel cells after infection by Merkel cell polyomavirus (MCPyV) and other poorly understood events. Transcriptional profiling using cDNA microarrays was performed on cells from MCPy-negative and MCPy-positive Merkel cell carcinomas and isolated normal Merkel cells. This microarray revealed numerous significantly upregulated genes and some downregulated genes. The extensive list of genes that were identified in these experiments provides a large body of potentially valuable information of Merkel cell carcinoma carcinogenesis and could represent a source of potential targets for cancer therapy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Organophosphorus Flame Retardants Inhibit Specific Liver Carboxylesterases and Cause Serum Hypertriglyceridemia

PubMed Central

2015-01-01

Humans are prevalently exposed to organophosphorus flame retardants (OPFRs) contained in consumer products and electronics, though their toxicological effects and mechanisms remain poorly understood. We show here that OPFRs inhibit specific liver carboxylesterases (Ces) and cause altered hepatic lipid metabolism. Ablation of the OPFR target Ces1g has been previously linked to dyslipidemia in mice. Consistent with OPFR inhibition of Ces1g, we also observe OPFR-induced serum hypertriglyceridemia in mice. Our findings suggest novel toxicities that may arise from OPFR exposure and highlight the utility of chemoproteomic and metabolomic platforms in the toxicological characterization of environmental chemicals. PMID:24597639

[Fanconi anemia: cellular and molecular features].

PubMed

Macé, G; Briot, D; Guervilly, J-H; Rosselli, F

2007-02-01

Fanconi anemia (FA) is a recessive human cancer prone syndrome featuring bone marrow failure, developmental abnormalities and hypersensitivity to DNA crosslinking agents exposure. 11 among 12 FA gene have been isolated. The biochemical functions of the FANC proteins remain poorly understood. Anyhow, to cope with DNA crosslinks a cell needs a functional FANC pathway. Moreover, the FANC proteins appear to be involved in cell protection against oxidative damage and in the control of TNF-alpha activity. In this review, we describe the current understanding of the FANC pathway and we present how it may be integrated in the complex networks of proteins involved in maintaining the cellular homeostasis.

Genocide in Bosnia: the case of Dr. Radovan Karadzic.

PubMed

Dekleva, K B; Post, J M

1997-01-01

From 1992 to 1995 the Republic of Bosnia-Herzegovina experienced a war of genocidal proportions between the Bosnian Serbs, the Bosnian Croats, and the Bosnian Muslims. The international Criminal Tribunal for the Former Yugoslavia has indicted Dr. Radovan Karadzic--former President of the Bosnian Serb Republic, psychiatrist, and poet--as a suspected war criminal for his role in war crimes, crimes against humanity, and genocide. Karadzic remains enigmatic and poorly understood. Psychological profiling highlights in Karadzic's case the complex coalescence of the psychology of a genocide perpetrator with that of a charismatic narcissistic political leader. Such a profile may possess usefulness in forensic psychiatric investigations and legal proceedings.

Neural mechanisms of genetic risk for impulsivity and violence in humans.

PubMed

Meyer-Lindenberg, Andreas; Buckholtz, Joshua W; Kolachana, Bhaskar; R Hariri, Ahmad; Pezawas, Lukas; Blasi, Giuseppe; Wabnitz, Ashley; Honea, Robyn; Verchinski, Beth; Callicott, Joseph H; Egan, Michael; Mattay, Venkata; Weinberger, Daniel R

2006-04-18

Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.

Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options.

PubMed

Bock, Karl Walter

2017-04-01

Metabolism of aryl hydrocarbons and toxicity of dioxins led to the discovery of the aryl hydrocarbon receptor (AHR). Tremendous advances have been made on multiplicity of AHR signaling and identification of endogenous ligands including the tryptophan metabolites FICZ and kynurenine. However, human AHR functions are still poorly understood due to marked species differences as well as cell-type- and cell context-dependent AHR functions. Observations in dioxin-poisoned individuals may provide hints to physiologic AHR functions in humans. Based on these observations three human AHR functions are discussed: (1) Chemical defence and homeostasis of endobiotics. The AHR variant Val381 in modern humans leads to reduced AHR affinity to aryl hydrocarbons in comparison with Neanderthals and primates expressing the Ala381 variant while affinity to indoles remains unimpaired. (2) Homeostasis of stem/progenitor cells. Dioxins dysregulate homeostasis in sebocyte stem cells. (3) Modulation of immunity. In addition to microbial defence, AHR may be involved in a 'disease tolerance defence pathway'. Further characterization of physiologic AHR functions may lead to therapeutic options.

Human Genomic Signatures of Brain Oscillations During Memory Encoding.

PubMed

Berto, Stefano; Wang, Guang-Zhong; Germi, James; Lega, Bradley C; Konopka, Genevieve

2018-05-01

Memory encoding is an essential step for all learning. However, the genetic and molecular mechanisms underlying human memory encoding remain poorly understood, and how this molecular framework permits the emergence of specific patterns of brain oscillations observed during mnemonic processing is unknown. Here, we directly compare intracranial electroencephalography recordings from the neocortex in individuals performing an episodic memory task with human gene expression from the same areas. We identify genes correlated with oscillatory memory effects across 6 frequency bands. These genes are enriched for autism-related genes and have preferential expression in neurons, in particular genes encoding synaptic proteins and ion channels, supporting the idea that the genes regulating voltage gradients are involved in the modulation of oscillatory patterns during successful memory encoding across brain areas. Memory-related genes are distinct from those correlated with other forms of cognitive processing and resting state fMRI. These data are the first to identify correlations between gene expression and active human brain states as well as provide a molecular window into memory encoding oscillations in the human brain.

On the Growth of Scientific Knowledge: Yeast Biology as a Case Study

PubMed Central

He, Xionglei; Zhang, Jianzhi

2009-01-01

The tempo and mode of human knowledge expansion is an enduring yet poorly understood topic. Through a temporal network analysis of three decades of discoveries of protein interactions and genetic interactions in baker's yeast, we show that the growth of scientific knowledge is exponential over time and that important subjects tend to be studied earlier. However, expansions of different domains of knowledge are highly heterogeneous and episodic such that the temporal turnover of knowledge hubs is much greater than expected by chance. Familiar subjects are preferentially studied over new subjects, leading to a reduced pace of innovation. While research is increasingly done in teams, the number of discoveries per researcher is greater in smaller teams. These findings reveal collective human behaviors in scientific research and help design better strategies in future knowledge exploration. PMID:19300476

On the growth of scientific knowledge: yeast biology as a case study.

PubMed

He, Xionglei; Zhang, Jianzhi

2009-03-01

The tempo and mode of human knowledge expansion is an enduring yet poorly understood topic. Through a temporal network analysis of three decades of discoveries of protein interactions and genetic interactions in baker's yeast, we show that the growth of scientific knowledge is exponential over time and that important subjects tend to be studied earlier. However, expansions of different domains of knowledge are highly heterogeneous and episodic such that the temporal turnover of knowledge hubs is much greater than expected by chance. Familiar subjects are preferentially studied over new subjects, leading to a reduced pace of innovation. While research is increasingly done in teams, the number of discoveries per researcher is greater in smaller teams. These findings reveal collective human behaviors in scientific research and help design better strategies in future knowledge exploration.

New experimental models of skin homeostasis and diseases.

PubMed

Larcher, F; Espada, J; Díaz-Ley, B; Jaén, P; Juarranz, A; Quintanilla, M

2015-01-01

Homeostasis, whose regulation at the molecular level is still poorly understood, is intimately related to the functions of epidermal stem cells. Five research groups have been brought together to work on new in vitro and in vivo skin models through the SkinModel-CM program, under the auspices of the Spanish Autonomous Community of Madrid. This project aims to analyze the functions of DNA methyltransferase 1, endoglin, and podoplanin in epidermal stem cell activity, homeostasis, and skin cancer. These new models include 3-dimensional organotypic cultures, immunodeficient skin-humanized mice, and genetically modified mice. Another aim of the program is to use skin-humanized mice to model dermatoses such as Gorlin syndrome and xeroderma pigmentosum in order to optimize new protocols for photodynamic therapy. Copyright © 2013 Elsevier España, S.L.U. and AEDV. All rights reserved.

Stimulation of IKK-gamma oligomerization by the human T-cell leukemia virus oncoprotein Tax.

PubMed

Huang, Guo Jin; Zhang, Zhi Qing; Jin, Dong Yan

2002-11-20

Human T-cell leukemia virus type 1 oncoprotein Tax activates NF-kappaB through direct binding to IKK-gamma, the regulatory component of the IkappaB kinase complex. Mechanisms by which IKK-gamma adapts the Tax signal to the IkappaB kinase are poorly understood. Here we demonstrate that IKK-gamma forms homodimer and homotrimer both in vitro and in yeast or mammalian cells through a C-terminal domain comprising amino acids 251-419. In contrast, Tax protein targets a central region of IKK-gamma, which consists of amino acids 201-250. Interestingly, Tax stimulates the oligomerization of IKK-gamma, likely through direct binding. Taken together, our findings suggest a new model of Tax activation of NF-kappaB, in which Tax interacts with IKK-gamma to stimulate its oligomerization.

Inheritance Patterns in Citation Networks Reveal Scientific Memes

NASA Astrophysics Data System (ADS)

Kuhn, Tobias; Perc, Matjaž; Helbing, Dirk

2014-10-01

Memes are the cultural equivalent of genes that spread across human culture by means of imitation. What makes a meme and what distinguishes it from other forms of information, however, is still poorly understood. Our analysis of memes in the scientific literature reveals that they are governed by a surprisingly simple relationship between frequency of occurrence and the degree to which they propagate along the citation graph. We propose a simple formalization of this pattern and validate it with data from close to 50 million publication records from the Web of Science, PubMed Central, and the American Physical Society. Evaluations relying on human annotators, citation network randomizations, and comparisons with several alternative approaches confirm that our formula is accurate and effective, without a dependence on linguistic or ontological knowledge and without the application of arbitrary thresholds or filters.

Genes Related to Oxytocin and Arginine-Vasopressin Pathways: Associations with Autism Spectrum Disorders.

PubMed

Zhang, Rong; Zhang, Hong-Feng; Han, Ji-Sheng; Han, Song-Ping

2017-04-01

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorders characterized by impaired social interactions, communication deficits, and repetitive behavior. Although the mechanisms underlying its etiology and manifestations are poorly understood, several lines of evidence from rodent and human studies suggest involvement of the evolutionarily highly-conserved oxytocin (OXT) and arginine-vasopressin (AVP), as these neuropeptides modulate various aspects of mammalian social behavior. As far as we know, there is no comprehensive review of the roles of the OXT and AVP systems in the development of ASD from the genetic aspect. In this review, we summarize the current knowledge regarding associations between ASD and single-nucleotide variants of the human OXT-AVP pathway genes OXT, AVP, AVP receptor 1a (AVPR1a), OXT receptor (OXTR), the oxytocinase/vasopressinase (LNPEP), and ADP-ribosyl cyclase (CD38).

The intestine is a blender

NASA Astrophysics Data System (ADS)

Yang, Patricia; Lamarca, Morgan; Kravets, Victoria; Hu, David

According to the U.S. Department of Health and Human Services, digestive disease affects 60 to 70 million people and costs over 140 billion annually. Despite the significance of the gastrointestinal tract to human health, the physics of digestion remains poorly understood. In this study, we ask a simple question: what sets the frequency of intestinal contractions? We measure the frequency of intestinal contractions in rats, as a function of distance down the intestine. We find that intestines Contract radially ten times faster than longitudinally. This motion promotes mixing and, in turn, absorption of food products by the intestinal wall. We calculate viscous dissipation in the intestinal fluid to rationalize the relationship between frequency of intestinal contraction and the viscosity of the intestinal contents. Our findings may help to understand the evolution of the intestine as an ideal mixer.

The intestine is a blender

NASA Astrophysics Data System (ADS)

Yang, Patricia; Lamarca, Morgan; Hu, David

2015-11-01

According to the U.S. Department of Health and Human Services, digestive disease affects 60 to 70 million people and costs over 140 billion annually. Despite the significance of the gastrointestinal tract to human health, the physics of digestion remains poorly understood. In this study, we ask a simple question: what sets the frequency of intestinal contractions? We measure the frequency of intestinal contractions in rats, as a function of distance down the intestine. We find that intestines contract radially ten times faster than longitudinally. This motion promotes mixing and, in turn, absorption of food products by the intestinal wall. We calculate viscous dissipation in the intestinal fluid to rationalize the relationship between frequency of intestinal contraction and the viscosity of the intestinal contents. Our findings may help to understand the evolution of the intestine as an ideal mixer.

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications.

PubMed

Pohl, Calvin S; Medland, Julia E; Moeser, Adam J

2015-12-15

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. Copyright © 2015 the American Physiological Society.

Exploring the Buruli Ulcer Incidence across a socio-ecological landscape in Ghana

NASA Astrophysics Data System (ADS)

Naithani, K. J.; Konzelman, C.; Tschakert, P.; Smithwick, E. A. H.

2016-12-01

The Buruli Ulcer (BU) disease is one of the most prevalent, but poorly understood mycobacterial infections in the world. Fundamental ecological aspects of the disease causing bacteria (Mycobacterium ulcerans) are not understood completely, but its emergence is attributed to unidentified thresholds in human and natural systems. We explored the network of these interactions across socio-ecological landscapes of Ghana to understand the movement of bacteria and the emergence of BU in response to climate, disturbance, social and economic factors. We chose five communities, three endemic and two control, and explored the correlations of disease incidence with climate, landscape disturbance, water quality and social factors using path analysis. Our results show that water quality is strongly linked to disease emergence with high alkalinity, PO43-, NH4+, F, Mn, S, Cd, Fe, Pb, and Se were associated with higher disease incidents and high Cu concentration was associated with low or healthy communities. Contrary to previous studies, arsenic concentration in water was not linked to higher disease incidence. Water quality was linked to climate, type of mining, and agricultural practices. Higher annual precipitation and lower air temperature were found linked to higher disease incidence across communities. Our exploratory work provides insight into how human land use, social practices, demographics, and climatic factors influence the BU disease spread.

Context processing in adolescents with autism spectrum disorder: How complex could it be?

PubMed

Ben-Yosef, Dekel; Anaki, David; Golan, Ofer

2017-03-01

The ability of individuals with Autism Spectrum Disorder (ASD) to process context has long been debated: According to the Weak Central Coherence theory, ASD is characterized by poor global processing, and consequently-poor context processing. In contrast, the Social Cognition theory argues individuals with ASD will present difficulties only in social context processing. The complexity theory of autism suggests context processing in ASD will depend on task complexity. The current study examined this controversy through two priming tasks, one presenting human stimuli (facial expressions) and the other presenting non-human stimuli (animal faces). Both tasks presented visual targets, preceded by congruent, incongruent, or neutral auditory primes. Local and global processing were examined by presenting the visual targets in three spatial frequency conditions: High frequency, low frequency, and broadband. Tasks were administered to 16 adolescents with high functioning ASD and 16 matched typically developing adolescents. Reaction time and accuracy were measured for each task in each condition. Results indicated that individuals with ASD processed context for both human and non-human stimuli, except in one condition, in which human stimuli had to be processed globally (i.e., target presented in low frequency). The task demands presented in this condition, and the performance deficit shown in the ASD group as a result, could be understood in terms of cognitive overload. These findings provide support for the complexity theory of autism and extend it. Our results also demonstrate how associative priming could support intact context processing of human and non-human stimuli in individuals with ASD. Autism Res 2017, 10: 520-530. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Galectins are human milk glycan receptors

PubMed Central

Noll, Alexander J; Gourdine, Jean-Philippe; Yu, Ying; Lasanajak, Yi; Smith, David F; Cummings, Richard D

2016-01-01

The biological recognition of human milk glycans (HMGs) is poorly understood. Because HMGs are rich in galactose we explored whether they might interact with human galectins, which bind galactose-containing glycans and are highly expressed in epithelial cells and other cell types. We screened a number of human galectins for their binding to HMGs on a shotgun glycan microarray consisting of 247 HMGs derived from human milk, as well as to a defined HMG microarray. Recombinant human galectins (hGal)-1, -3, -4, -7, -8 and -9 bound selectively to glycans, with each galectin recognizing a relatively unique binding motif; by contrast hGal-2 did not recognize HMGs, but did bind to the human blood group A Type 2 determinants on other microarrays. Unlike other galectins, hGal-7 preferentially bound to glycans expressing a terminal Type 1 (Galβ1-3GlcNAc) sequence, a motif that had eluded detection on non-HMG glycan microarrays. Interactions with HMGs were confirmed in a solution setting by isothermal titration microcalorimetry and hapten inhibition experiments. These results demonstrate that galectins selectively bind to HMGs and suggest the possibility that galectin–HMG interactions may play a role in infant immunity. PMID:26747425

Zebrafish Axenic Larvae Colonization with Human Intestinal Microbiota.

PubMed

Arias-Jayo, Nerea; Alonso-Saez, Laura; Ramirez-Garcia, Andoni; Pardo, Miguel A

2018-04-01

The human intestine hosts a vast and complex microbial community that is vital for maintaining several functions related with host health. The processes that determine the gut microbiome composition are poorly understood, being the interaction between species, the external environment, and the relationship with the host the most feasible. Animal models offer the opportunity to understand the interactions between the host and the microbiota. There are different gnotobiotic mice or rat models colonized with the human microbiota, however, to our knowledge, there are no reports on the colonization of germ-free zebrafish with a complex human intestinal microbiota. In the present study, we have successfully colonized 5 days postfertilization germ-free zebrafish larvae with the human intestinal microbiota previously extracted from a donor and analyzed by high-throughput sequencing the composition of the transferred microbial communities that established inside the zebrafish gut. Thus, we describe for first time which human bacteria phylotypes are able to colonize the zebrafish digestive tract. Species with relevant interest because of their linkage to dysbiosis in different human diseases, such as Akkermansia muciniphila, Eubacterium rectale, Faecalibacterium prausnitzii, Prevotella spp., or Roseburia spp. have been successfully transferred inside the zebrafish digestive tract.

The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome.

PubMed

Hannigan, Geoffrey D; Meisel, Jacquelyn S; Tyldsley, Amanda S; Zheng, Qi; Hodkinson, Brendan P; SanMiguel, Adam J; Minot, Samuel; Bushman, Frederic D; Grice, Elizabeth A

2015-10-20

Viruses make up a major component of the human microbiota but are poorly understood in the skin, our primary barrier to the external environment. Viral communities have the potential to modulate states of cutaneous health and disease. Bacteriophages are known to influence the structure and function of microbial communities through predation and genetic exchange. Human viruses are associated with skin cancers and a multitude of cutaneous manifestations. Despite these important roles, little is known regarding the human skin virome and its interactions with the host microbiome. Here we evaluated the human cutaneous double-stranded DNA virome by metagenomic sequencing of DNA from purified virus-like particles (VLPs). In parallel, we employed metagenomic sequencing of the total skin microbiome to assess covariation and infer interactions with the virome. Samples were collected from 16 subjects at eight body sites over 1 month. In addition to the microenviroment, which is known to partition the bacterial and fungal microbiota, natural skin occlusion was strongly associated with skin virome community composition. Viral contigs were enriched for genes indicative of a temperate phage replication style and also maintained genes encoding potential antibiotic resistance and virulence factors. CRISPR spacers identified in the bacterial DNA sequences provided a record of phage predation and suggest a mechanism to explain spatial partitioning of skin phage communities. Finally, we modeled the structure of bacterial and phage communities together to reveal a complex microbial environment with a Corynebacterium hub. These results reveal the previously underappreciated diversity, encoded functions, and viral-microbial dynamic unique to the human skin virome. To date, most cutaneous microbiome studies have focused on bacterial and fungal communities. Skin viral communities and their relationships with their hosts remain poorly understood despite their potential to modulate states of cutaneous health and disease. Previous studies employing whole-metagenome sequencing without purification for virus-like particles (VLPs) have provided some insight into the viral component of the skin microbiome but have not completely characterized these communities or analyzed interactions with the host microbiome. Here we present an optimized virus purification technique and corresponding analysis tools for gaining novel insights into the skin virome, including viral "dark matter," and its potential interactions with the host microbiome. The work presented here establishes a baseline of the healthy human skin virome and is a necessary foundation for future studies examining viral perturbations in skin health and disease. Copyright © 2015 Hannigan et al.

A First: NASA Spots Single Methane Leak from Space

NASA Image and Video Library

2016-06-14

Atmospheric methane is a potent greenhouse gas, but the percentage of it produced through human activities is still poorly understood. Future instruments on orbiting satellites can help address this issue by surveying human-produced methane emissions. Recent data from the Aliso Canyon event, a large accidental methane release near Porter Ranch, California, demonstrates this capability. The Hyperion imaging spectrometer onboard NASA's EO-1 satellite successfully detected this release event on three different overpasses during the winter of 2015-2016. This is the first time the methane plume from a single facility has been observed from space. The orbital observations were consistent with airborne measurements. This image pair shows a comparison of detected methane plumes over Aliso Canyon, California, acquired 11 days apart in Jan. 2016 by: (left) NASA's AVIRIS instrument on a NASA ER-2 aircraft at 4.1 miles (6.6 kilometers) altitude and (right) by the Hyperion instrument on NASA's Earth Observing-1 satellite in low-Earth orbit. The additional red streaks visible in the EO-1 Hyperion image result from measurement noise -- Hyperion was not specifically designed for methane sensing and is not as sensitive as AVIRIS-NG. Additionally, the EO-1 satellite's current orbit provided poor illumination conditions. Future instruments with much greater sensitivity on orbiting satellites can survey the biggest sources of human-produced methane around the world. http://photojournal.jpl.nasa.gov/catalog/PIA20716

Midbrain adaptation may set the stage for the perception of musical beat

PubMed Central

2017-01-01

The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat-specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat. PMID:29118141

Displacement effects of heavy human use on coral reef predators within the Molokini Marine Life Conservation District.

PubMed

Filous, Alexander; Friedlander, Alan M; Koike, Haruko; Lammers, Marc; Wong, Adam; Stone, Kristy; Sparks, Russell T

2017-08-15

The impact of marine ecotourism on reef predators is poorly understood and there is growing concern that overcrowding in Marine Protected Areas (MPAs) may disturb the species that these areas were established to protect. To improve our understanding of this issue, we used acoustic telemetry to examine the relationship between human activity at the Molokini Marine Life Conservation District (MLCD) and the habitat use of five reef-associated predators (Caranx melampygus, Caranx ignobilis, Triaenodon obesus, Carcharhinus amblyrhynchos, and Aprion virscens). During peak hours of human use, there was a negative relationship (R 2 =0.77, P<0.001) between the presence of bluefin trevally (Caranx melampygus) and vessels in subzone A. No other species showed strong evidence of this relationship. However, our results suggest that during this time, the natural ecosystem function that the reserve was established to protect may be compromised and overcrowding should be considered when managing MPAs. Copyright © 2017 Elsevier Ltd. All rights reserved.

T Cells Are Not Required for Pathogenesis in the Syrian Hamster Model of Hantavirus Pulmonary Syndrome ▿

PubMed Central

Hammerbeck, Christopher D.; Hooper, Jay W.

2011-01-01

Andes virus (ANDV) is associated with a lethal vascular leak syndrome in humans termed hantavirus pulmonary syndrome (HPS). In hamsters, ANDV causes a respiratory distress syndrome closely resembling human HPS. The mechanism for the massive vascular leakage associated with HPS is poorly understood; however, T cell immunopathology has been implicated on the basis of circumstantial and corollary evidence. Here, we show that following ANDV challenge, hamster T cell activation corresponds with the onset of disease. However, treatment with cyclophosphamide or specific T cell depletion does not impact the course of disease or alter the number of surviving animals, despite significant reductions in T cell number. These data demonstrate, for the first time, that T cells are not required for hantavirus pathogenesis in the hamster model of human HPS. Depletion of T cells from Syrian hamsters did not significantly influence early events in disease progression. Moreover, these data argue for a mechanism of hantavirus-induced vascular permeability that does not involve T cell immunopathology. PMID:21775442

T cells are not required for pathogenesis in the Syrian hamster model of hantavirus pulmonary syndrome.

PubMed

Hammerbeck, Christopher D; Hooper, Jay W

2011-10-01

Andes virus (ANDV) is associated with a lethal vascular leak syndrome in humans termed hantavirus pulmonary syndrome (HPS). In hamsters, ANDV causes a respiratory distress syndrome closely resembling human HPS. The mechanism for the massive vascular leakage associated with HPS is poorly understood; however, T cell immunopathology has been implicated on the basis of circumstantial and corollary evidence. Here, we show that following ANDV challenge, hamster T cell activation corresponds with the onset of disease. However, treatment with cyclophosphamide or specific T cell depletion does not impact the course of disease or alter the number of surviving animals, despite significant reductions in T cell number. These data demonstrate, for the first time, that T cells are not required for hantavirus pathogenesis in the hamster model of human HPS. Depletion of T cells from Syrian hamsters did not significantly influence early events in disease progression. Moreover, these data argue for a mechanism of hantavirus-induced vascular permeability that does not involve T cell immunopathology.

ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling

PubMed Central

Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S.; Costa, Magdaline; Ghahremani, Morvarid Farhang; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J. Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S.; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W.; Janzen, Viktor; McCormack, Matthew P.; Lock, Richard B.; Curtis, David J.; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P. P.; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J.

2015-01-01

Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model. PMID:25565005

Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation.

PubMed

Oh, Jung Hwa; Lee, Tae-Jin; Kim, Sang Hyun; Choi, Yung Hyun; Lee, Sang Han; Lee, Jin Man; Kim, Young-Ho; Park, Jong-Wook; Kwon, Taeg Kyu

2008-12-01

Withaferin A, a major chemical constituent of Withania somnifera, has been reported for its tumor cell growth inhibitory activity, antitumor effects, and impairing metastasis and angiogenesis. The mechanism by which withaferin A initiates apoptosis remains poorly understood. In the present report, we investigated the effect of withaferin A on the apoptotic pathway in U937 human promonocytic cells. We show that withaferin A induces apoptosis in association with the activation of caspase-3. JNK and Akt signal pathways play crucial roles in withaferin A-induced apoptosis in U937 cells. Furthermore, we have shown that overexpression of Bcl-2 and active Akt (myr-Akt) in U937 cells inhibited the induction of apoptosis, activation of caspase-3, and PLC-gamma1 cleavage by withaferin A. Taken together, our results indicated that the JNK and Akt pathways and inhibition of NF-kappaB activity were key regulators of apoptosis in response to withaferin A in human leukemia U937 cells.

Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging.

PubMed

Soreq, Lilach; Rose, Jamie; Soreq, Eyal; Hardy, John; Trabzuni, Daniah; Cookson, Mark R; Smith, Colin; Ryten, Mina; Patani, Rickie; Ule, Jernej

2017-01-10

Gene expression studies suggest that aging of the human brain is determined by a complex interplay of molecular events, although both its region- and cell-type-specific consequences remain poorly understood. Here, we extensively characterized aging-altered gene expression changes across ten human brain regions from 480 individuals ranging in age from 16 to 106 years. We show that astrocyte- and oligodendrocyte-specific genes, but not neuron-specific genes, shift their regional expression patterns upon aging, particularly in the hippocampus and substantia nigra, while the expression of microglia- and endothelial-specific genes increase in all brain regions. In line with these changes, high-resolution immunohistochemistry demonstrated decreased numbers of oligodendrocytes and of neuronal subpopulations in the aging brain cortex. Finally, glial-specific genes predict age with greater precision than neuron-specific genes, thus highlighting the need for greater mechanistic understanding of neuron-glia interactions in aging and late-life diseases. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Neutrophils kill the parasite Trichomonas vaginalis using trogocytosis

PubMed Central

Mercer, Frances; Ng, Shek Hang; Brown, Taylor M.; Boatman, Grace; Johnson, Patricia J.

2018-01-01

T. vaginalis, a human-infective parasite, causes the most common nonviral sexually transmitted infection (STI) worldwide and contributes to adverse inflammatory disorders. The immune response to T. vaginalis is poorly understood. Neutrophils (polymorphonuclear cells [PMNs]) are the major immune cell present at the T. vaginalis–host interface and are thought to clear T. vaginalis. However, the mechanism of PMN clearance of T. vaginalis has not been characterized. We demonstrate that human PMNs rapidly kill T. vaginalis in a dose-dependent, contact-dependent, and neutrophil extracellular trap (NET)-independent manner. In contrast to phagocytosis, we observed that PMN killing of T. vaginalis involves taking “bites” of T. vaginalis prior to parasite death, using trogocytosis to achieve pathogen killing. Both trogocytosis and parasite killing are dependent on the presence of PMN serine proteases and human serum factors. Our analyses provide the first demonstration, to our knowledge, of a mammalian phagocyte using trogocytosis for pathogen clearance and reveal a novel mechanism used by PMNs to kill a large, highly motile target. PMID:29408891

Inflammatory signaling in human Tuberculosis granulomas is spatially organized

PubMed Central

Marakalala, Mohlopheni J.; Raju, Ravikiran M.; Sharma, Kirti; Zhang, Yanjia J.; Eugenin, Eliseo A.; Prideaux, Brendan; Daudelin, Isaac B.; Chen, Pei-Yu; Booty, Matthew G.; Kim, Jin Hee; Eum, Seok Yong; Via, Laura E.; Behar, Samuel M.; Barry, Clifton E.; Mann, Matthias; Dartois, Véronique; Rubin, Eric J.

2016-01-01

Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased fashion. Using laser capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas possess a pro-inflammatory environment characterized by anti-microbial peptides, ROS and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum possesses a comparatively anti-inflammatory signature. These findings are consistent across a set of six subjects and in rabbits. While the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. The protein and lipid snapshots of human and rabbit lesions analysed here suggest that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma. PMID:27043495

Midbrain adaptation may set the stage for the perception of musical beat.

PubMed

Rajendran, Vani G; Harper, Nicol S; Garcia-Lazaro, Jose A; Lesica, Nicholas A; Schnupp, Jan W H

2017-11-15

The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat-specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat. © 2017 The Authors.

Essential role of microfibrillar-associated protein 4 in human cutaneous homeostasis and in its photoprotection

PubMed Central

Kasamatsu, Shinya; Hachiya, Akira; Fujimura, Tsutomu; Sriwiriyanont, Penkanok; Haketa, Keiichi; Visscher, Marty O.; Kitzmiller, William J.; Bello, Alexander; Kitahara, Takashi; Kobinger, Gary P.; Takema, Yoshinori

2011-01-01

UVB-induced cutaneous photodamage/photoaging is characterized by qualitative and quantitative deterioration in dermal extracellular matrix (ECM) components such as collagen and elastic fibers. Disappearance of microfibrillar-associated protein 4 (MFAP-4), a possible limiting factor for cutaneous elasticity, was documented in photoaged dermis, but its function is poorly understood. To characterize its possible contribution to photoprotection, MFAP-4 expression was either augmented or inhibited in a human skin xenograft photodamage murine model and human fibroblasts. Xenografted skin with enhanced MFAP-4 expression was protected from UVB-induced photodamage/photoaging accompanied by the prevention of ECM degradation and aggravated elasticity. Additionally, remarkably increased or decreased fibrillin-1-based microfibril development was observed when fibroblasts were treated with recombinant MFAP-4 or with MFAP-4-specific siRNA, respectively. Immunoprecipitation analysis confirmed direct interaction between MFAP-4 and fibrillin-1. Taken together, our findings reveal the essential role of MFAP-4 in photoprotection and offer new therapeutic opportunities to prevent skin-associated pathologies. PMID:22355679

The Human SepSecS-tRNASec Complex Reveals the Mechanism of Selenocysteine Formation

PubMed Central

Palioura, Sotiria; Sherrer, R. Lynn; Steitz, Thomas A.; Söll, Dieter; Simonović, Miljan

2010-01-01

Selenocysteine is the only genetically encoded amino acid in humans whose biosynthesis occurs on its cognate transfer RNA (tRNA). O-Phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS) catalyzes the final step of selenocysteine formation by a poorly understood tRNA-dependent mechanism. The crystal structure of human tRNASec in complex with SepSecS, phosphoserine, and thiophosphate, together with in vivo and in vitro enzyme assays, supports a pyridoxal phosphate–dependent mechanism of Sec-tRNASec formation. Two tRNASec molecules, with a fold distinct from other canonical tRNAs, bind to each SepSecS tetramer through their 13–base pair acceptor-TΨC arm (where Ψ indicates pseudouridine). The tRNA binding is likely to induce a conformational change in the enzyme’s active site that allows a phosphoserine covalently attached to tRNASec, but not free phosphoserine, to be oriented properly for the reaction to occur. PMID:19608919

The global antigenic diversity of swine influenza A viruses

PubMed Central

Lewis, Nicola S; Russell, Colin A; Langat, Pinky; Anderson, Tavis K; Berger, Kathryn; Bielejec, Filip; Burke, David F; Dudas, Gytis; Fonville, Judith M; Fouchier, Ron AM; Kellam, Paul; Koel, Bjorn F; Lemey, Philippe; Nguyen, Tung; Nuansrichy, Bundit; Peiris, JS Malik; Saito, Takehiko; Simon, Gaelle; Skepner, Eugene; Takemae, Nobuhiro; Webby, Richard J; Van Reeth, Kristien; Brookes, Sharon M; Larsen, Lars; Watson, Simon J; Brown, Ian H; Vincent, Amy L

2016-01-01

Swine influenza presents a substantial disease burden for pig populations worldwide and poses a potential pandemic threat to humans. There is considerable diversity in both H1 and H3 influenza viruses circulating in swine due to the frequent introductions of viruses from humans and birds coupled with geographic segregation of global swine populations. Much of this diversity is characterized genetically but the antigenic diversity of these viruses is poorly understood. Critically, the antigenic diversity shapes the risk profile of swine influenza viruses in terms of their epizootic and pandemic potential. Here, using the most comprehensive set of swine influenza virus antigenic data compiled to date, we quantify the antigenic diversity of swine influenza viruses on a multi-continental scale. The substantial antigenic diversity of recently circulating viruses in different parts of the world adds complexity to the risk profiles for the movement of swine and the potential for swine-derived infections in humans. DOI: http://dx.doi.org/10.7554/eLife.12217.001 PMID:27113719

Research Review: The Neurobiology and Genetics of Maltreatment and Adversity

ERIC Educational Resources Information Center

McCrory, Eamon; De Brito, Stephane A.; Viding, Essi

2010-01-01

The neurobiological mechanisms by which childhood maltreatment heightens vulnerability to psychopathology remain poorly understood. It is likely that a complex interaction between environmental experiences (including poor caregiving) and an individual's genetic make-up influence neurobiological development across infancy and childhood, which in…

Potential impact of acid precipitation on arsenic and selenium.

PubMed Central

Mushak, P

1985-01-01

The potential impact of acidic precipitation on the environmental mobility of the metalloids arsenic (As) and selenium (Se) has not been given much attention and is poorly understood. As with other elements, the interest here is the potential effect of environmental acidification on environmental behavior in ways that are relevant to human exposure to these metalloids. Available information on acid precipitation and the environmental behavior of these metalloids do, however, permit some preliminary conclusions to be drawn. Both As and Se appear to be mobilized from household plumbing into tap water by the corrosive action of soft, mildly acidic water, while surface water catchment systems in areas impacted by acidic deposition may contain elevated soluble As levels. Acidification of aquatic ecosystems that are drinking water sources may pose the prospect of enhanced release of As from sediment to water as well as reduction in water levels of Se. Acidification of ground waters, where As appears to be especially mobile, is of particular concern in this regard. The potential impact of acidic deposition on As and Se in soils cannot readily be assessed with respect to human exposure, but it would appear that the behavior of these metalloids in poorly buffered, poorly immobilizing soils, e.g., sandy soils of low metal hydrous oxide content, would be most affected. The effect is opposite for the two elements; lowered pH would appear to enhance As mobility and to reduce Se availability. Altered acidity of both soil and aquatic systems poses a risk for altered biotransformation processes involving both As and Se, thereby affecting the relative amounts of different chemical forms varying in their toxicity to humans as well as influencing biogeochemical cycling. PMID:4076075

Potential impact of acid precipitation on arsenic and selenium.

PubMed

Mushak, P

1985-11-01

The potential impact of acidic precipitation on the environmental mobility of the metalloids arsenic (As) and selenium (Se) has not been given much attention and is poorly understood. As with other elements, the interest here is the potential effect of environmental acidification on environmental behavior in ways that are relevant to human exposure to these metalloids. Available information on acid precipitation and the environmental behavior of these metalloids do, however, permit some preliminary conclusions to be drawn. Both As and Se appear to be mobilized from household plumbing into tap water by the corrosive action of soft, mildly acidic water, while surface water catchment systems in areas impacted by acidic deposition may contain elevated soluble As levels. Acidification of aquatic ecosystems that are drinking water sources may pose the prospect of enhanced release of As from sediment to water as well as reduction in water levels of Se. Acidification of ground waters, where As appears to be especially mobile, is of particular concern in this regard. The potential impact of acidic deposition on As and Se in soils cannot readily be assessed with respect to human exposure, but it would appear that the behavior of these metalloids in poorly buffered, poorly immobilizing soils, e.g., sandy soils of low metal hydrous oxide content, would be most affected. The effect is opposite for the two elements; lowered pH would appear to enhance As mobility and to reduce Se availability. Altered acidity of both soil and aquatic systems poses a risk for altered biotransformation processes involving both As and Se, thereby affecting the relative amounts of different chemical forms varying in their toxicity to humans as well as influencing biogeochemical cycling.

Human activity spaces and plague risks in three contrasting landscapes in Lushoto District, Tanzania.

PubMed

Hieronimo, Proches; Gulinck, Hubert; Kimaro, Didas N; Mulungu, Loth S; Kihupi, Nganga I; Msanya, Balthazar M; Leirs, Herwig; Deckers, Jozef A

2014-07-01

Since 1980 plague has been a human threat in the Western Usambara Mountains in Tanzania. However, the spatial-temporal pattern of plague occurrence remains poorly understood. The main objective of this study was to gain understanding of human activity patterns in relation to spatial distribution of fleas in Lushoto District. Data were collected in three landscapes differing in plague incidence. Field survey coupled with Geographic Information System (GIS) and physical sample collections were used to collect data in wet (April to June 2012) and dry (August to October 2012) seasons. Data analysis was done using GIS, one-way ANOVA and nonparametric statistical tools. The degree of spatial co-occurrence of potential disease vectors (fleas) and humans in Lushoto focus differs significantly (p ≤ 0.05) among the selected landscapes, and in both seasons. This trend gives a coarse indication of the possible association of the plague outbreaks and the human frequencies of contacting environments with fleas. The study suggests that plague surveillance and control programmes at landscape scale should consider the existence of plague vector contagion risk gradient from high to low incidence landscapes due to human presence and intensity of activities.

A Method for Whole Protein Isolation from Human Cranial Bone

PubMed Central

Lyon, Sarah M.; Mayampurath, Anoop; Rogers, M. Rose; Wolfgeher, Donald J.; Fisher, Sean M.; Volchenboum, Samuel L.; He, Tong-Chuan; Reid, Russell R.

2016-01-01

The presence of the dense hydroxyapatite matrix within human bone limits the applicability of conventional protocols for protein extraction. This has hindered the complete and accurate characterization of the human bone proteome thus far, leaving many bone-related disorders poorly understood. We sought to refine an existing method of protein extraction from mouse bone to extract whole proteins of varying molecular weights from human cranial bone. Whole protein was extracted from human cranial suture by mechanically processing samples using a method that limits protein degradation by minimizing heat introduction to proteins. The presence of whole protein was confirmed by western blotting. Mass spectrometry was used to sequence peptides and identify isolated proteins. The data have been deposited to the ProteomeXchange with identifier PXD003215. Extracted proteins were characterized as both intra- and extracellular and had molecular weights ranging from 9.4-629 kDa. High correlation scores among suture protein spectral counts support the reproducibility of the method. Ontology analytics revealed proteins of myriad functions including mediators of metabolic processes and cell organelles. These results demonstrate a reproducible method for isolation of whole protein from human cranial bone, representing a large range of molecular weights, origins and functions. PMID:27677936

Pentatrichomonas hominis: prevalence and molecular characterization in humans, dogs, and monkeys in Northern China.

PubMed

Li, Wen-Chao; Ying, Meng; Gong, Peng-Tao; Li, Jian-Hua; Yang, Ju; Li, He; Zhang, Xi-Chen

2016-02-01

Pentatrichomonas hominis is an anaerobic amitochondrial flagellated protist that primarily colonizes the large intestines of a number of species, including cats, dogs, nonhuman primates, and humans. The prevalence of this parasite in dogs, monkeys, and humans is, however, poorly understood. In this study, a total of 362 fecal samples including 252 dogs, 60 monkeys, and 50 humans from northern China were collected for an epidemiological survey of P. hominis infection.The average prevalence of P. hominis infection determined by nested PCR was 27.38% (69/252), 4.00% (2/50), and 46.67% (28/60) in dogs, humans, and monkeys, respectively. The prevalence was significantly higher in 6-month-old dogs (41.53%) and children (7.69%) than in older dogs (14.39%) and adults (0%) (P < 0.05). Sequencing of amplicons revealed that four variable positions separated sequences into three types, called CC1-3. CC1 was the most prevalent in the study population. This study determined that P. hominis infection is common in dogs, monkeys, and humans, especially in children and young dogs. Given the infection prevalence, P. hominis may pose a risk of zoonotic and anthroponotic transmission.

Can Earth Sciences Help Alleviate Global Poverty?

NASA Astrophysics Data System (ADS)

Mutter, J. C.

2004-12-01

Poverty is not properly described solely in terms of economics. Certainly the billion people living on less than a dollar a day are the extreme poor and the two billion people who are living today on two dollars a day or less are poor also. One third of all humans live in poverty today. But poverty concerns deprivation - of good health, adequate nutrition, adequate education, properly paid employment, clean water, adequate housing and good sanitation. It is a fundamental denial of opportunity and a violation of basic human rights. Despite its prevalence and persistence of poverty and the attention given it by many scholars, the causes of poverty are not well understood and hence interventions to bring poor societies out of their condition often fail. One commonly missed component in the search for solutions to poverty is the fundamental co-dependence between the state of the Earth and the state of human well-being. These relationships, are compelling but often indirect and non-linear and sometimes deeply nuanced. They are also largely empirical in nature, lacking theory or models that describe the nature of the relationships. So while it is quite apparent that the poorest people are much more vulnerable than the rich to the Earths excesses and even to relatively small natural variations in places where the base conditions are poor, we do not presently know whether the recognized vulnerability is both an outcome of poverty and a contributing cause. Are societies poor, or held from development out of poverty because of their particular relationship to Earth's natural systems? Does how we live depend on where we live? Providing answers to these questions is one of the most fundamental research challenges of our time. That research lies in a domain squarely at the boundary between the natural and social sciences and cannot be answered by studies in either domain alone. What is clear even now, is that an understanding of the Earth gained from the natural sciences is essential and could hold the key to making gains toward alleviating the burden of global poverty.

NASA Aims to Create First-Ever Space-Based Sodium Lidar to Study Poorly Understood Mesosphere

NASA Image and Video Library

2017-12-08

Caption: Mike Krainak (left) and Diego Janches recently won NASA follow-on funding to advance a spaceborne sodium lidar needed to probe Earth’s poorly understood mesosphere. Credits: NASA/W. Hrybyk More: A team of NASA scientists and engineers now believes it can leverage recent advances in a greenhouse-detecting instrument to build the world’s first space-based sodium lidar to study Earth’s poorly understood mesosphere. Scientist Diego Janches and laser experts Mike Krainak and Tony Yu, all of whom work at NASA’s Goddard Space Flight Center in Greenbelt, Maryland, are leading a research-and-development effort to further advance the sodium lidar, which the group plans to deploy on the International Space Station if it succeeds in proving its flightworthiness. Read more: go.nasa.gov/2rcGpSM NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

Transcriptional activation of short interspersed elements by DNA-damaging agents.

PubMed

Rudin, C M; Thompson, C B

2001-01-01

Short interspersed elements (SINEs), typified by the human Alu repeat, are RNA polymerase III (pol III)-transcribed sequences that replicate within the genome through an RNA intermediate. Replication of SINEs has been extensive in mammalian evolution: an estimated 5% of the human genome consists of Alu repeats. The mechanisms regulating transcription, reverse transcription, and reinsertion of SINE elements in genomic DNA are poorly understood. Here we report that expression of murine SINE transcripts of both the B1 and B2 classes is strongly upregulated after prolonged exposure to cisplatin, etoposide, or gamma radiation. A similar induction of Alu transcripts in human cells occurs under these conditions. This induction is not due to a general upregulation of pol III activity in either species. Genotoxic treatment of murine cells containing an exogenous human Alu element induced Alu transcription. Concomitant with the increased expression of SINEs, an increase in cellular reverse transcriptase was observed after exposure to these same DNA-damaging agents. These findings suggest that genomic damage may be an important activator of SINEs, and that SINE mobility may contribute to secondary malignancy after exposure to DNA-damaging chemotherapy.

Structural basis of glycan specificity in neonate-specific bovine-human reassortant rotavirus

DOE PAGES

Hu, Liya; Ramani, Sasirekha; Czako, Rita; ...

2015-09-30

We report that strain-dependent variation of glycan recognition during initial cell attachment of viruses is a critical determinant of host specificity, tissue-tropism and zoonosis. Rotaviruses (RVs), which cause life-threatening gastroenteritis in infants and children, display significant genotype-dependent variations in glycan recognition resulting from sequence alterations in the VP8* domain of the spike protein VP4. The structural basis of this genotype-dependent glycan specificity, particularly in human RVs, remains poorly understood. Here, from crystallographic studies, we show how genotypic variations configure a novel binding site in the VP8* of a neonate-specific bovine-human reassortant to uniquely recognize either type I or type IImore » precursor glycans, and to restrict type II glycan binding in the bovine counterpart. In conclusion, such a distinct glycan-binding site that allows differential recognition of the precursor glycans, which are developmentally regulated in the neonate gut and abundant in bovine and human milk provides a basis for age-restricted tropism and zoonotic transmission of G10P[11] rotaviruses.« less

Structural basis of glycan specificity in neonate-specific bovine-human reassortant rotavirus

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

Hu, Liya; Ramani, Sasirekha; Czako, Rita

We report that strain-dependent variation of glycan recognition during initial cell attachment of viruses is a critical determinant of host specificity, tissue-tropism and zoonosis. Rotaviruses (RVs), which cause life-threatening gastroenteritis in infants and children, display significant genotype-dependent variations in glycan recognition resulting from sequence alterations in the VP8* domain of the spike protein VP4. The structural basis of this genotype-dependent glycan specificity, particularly in human RVs, remains poorly understood. Here, from crystallographic studies, we show how genotypic variations configure a novel binding site in the VP8* of a neonate-specific bovine-human reassortant to uniquely recognize either type I or type IImore » precursor glycans, and to restrict type II glycan binding in the bovine counterpart. In conclusion, such a distinct glycan-binding site that allows differential recognition of the precursor glycans, which are developmentally regulated in the neonate gut and abundant in bovine and human milk provides a basis for age-restricted tropism and zoonotic transmission of G10P[11] rotaviruses.« less

Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia.

PubMed

Onorati, Marco; Li, Zhen; Liu, Fuchen; Sousa, André M M; Nakagawa, Naoki; Li, Mingfeng; Dell'Anno, Maria Teresa; Gulden, Forrest O; Pochareddy, Sirisha; Tebbenkamp, Andrew T N; Han, Wenqi; Pletikos, Mihovil; Gao, Tianliuyun; Zhu, Ying; Bichsel, Candace; Varela, Luis; Szigeti-Buck, Klara; Lisgo, Steven; Zhang, Yalan; Testen, Anze; Gao, Xiao-Bing; Mlakar, Jernej; Popovic, Mara; Flamand, Marie; Strittmatter, Stephen M; Kaczmarek, Leonard K; Anton, E S; Horvath, Tamas L; Lindenbach, Brett D; Sestan, Nenad

2016-09-06

The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. We also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. We established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Inflammatory signaling in human tuberculosis granulomas is spatially organized.

PubMed

Marakalala, Mohlopheni J; Raju, Ravikiran M; Sharma, Kirti; Zhang, Yanjia J; Eugenin, Eliseo A; Prideaux, Brendan; Daudelin, Isaac B; Chen, Pei-Yu; Booty, Matthew G; Kim, Jin Hee; Eum, Seok Yong; Via, Laura E; Behar, Samuel M; Barry, Clifton E; Mann, Matthias; Dartois, Véronique; Rubin, Eric J

2016-05-01

Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner. Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas have a pro-inflammatory environment that is characterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatory signature. These findings are consistent across a set of six human subjects and in rabbits. Although the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. From the protein and lipid snapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma.

Similarity increases altruistic punishment in humans

PubMed Central

Mussweiler, Thomas; Ockenfels, Axel

2013-01-01

Humans are attracted to similar others. As a consequence, social networks are homogeneous in sociodemographic, intrapersonal, and other characteristics—a principle called homophily. Despite abundant evidence showing the importance of interpersonal similarity and homophily for human relationships, their behavioral correlates and cognitive foundations are poorly understood. Here, we show that perceived similarity substantially increases altruistic punishment, a key mechanism underlying human cooperation. We induced (dis)similarity perception by manipulating basic cognitive mechanisms in an economic cooperation game that included a punishment phase. We found that similarity-focused participants were more willing to punish others’ uncooperative behavior. This influence of similarity is not explained by group identity, which has the opposite effect on altruistic punishment. Our findings demonstrate that pure similarity promotes reciprocity in ways known to encourage cooperation. At the same time, the increased willingness to punish norm violations among similarity-focused participants provides a rationale for why similar people are more likely to build stable social relationships. Finally, our findings show that altruistic punishment is differentially involved in encouraging cooperation under pure similarity vs. in-group conditions. PMID:24218611

Auditory Processing Disorders: Acquisition and Treatment

ERIC Educational Resources Information Center

Moore, David R.

2007-01-01

Auditory processing disorder (APD) describes a mixed and poorly understood listening problem characterised by poor speech perception, especially in challenging environments. APD may include an inherited component, and this may be major, but studies reviewed here of children with long-term otitis media with effusion (OME) provide strong evidence…

Hippo signaling impedes adult heart regeneration

PubMed Central

Heallen, Todd; Morikawa, Yuka; Leach, John; Tao, Ge; Willerson, James T.; Johnson, Randy L.; Martin, James F.

2013-01-01

Heart failure due to cardiomyocyte loss after ischemic heart disease is the leading cause of death in the United States in large part because heart muscle regenerates poorly. The endogenous mechanisms preventing mammalian cardiomyocyte regeneration are poorly understood. Hippo signaling, an ancient organ size control pathway, is a kinase cascade that inhibits developing cardiomyocyte proliferation but it has not been studied postnatally or in fully mature adult cardiomyocytes. Here, we investigated Hippo signaling in adult cardiomyocyte renewal and regeneration. We found that unstressed Hippo-deficient adult mouse cardiomyocytes re-enter the cell cycle and undergo cytokinesis. Moreover, Hippo deficiency enhances cardiomyocyte regeneration with functional recovery after adult myocardial infarction as well as after postnatal day eight (P8) cardiac apex resection and P8 myocardial infarction. In damaged hearts, Hippo mutant cardiomyocytes also have elevated proliferation. Our findings reveal that Hippo signaling is an endogenous repressor of adult cardiomyocyte renewal and regeneration. Targeting the Hippo pathway in human disease might be beneficial for the treatment of heart disease. PMID:24255096

The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation Reprogramming

PubMed Central

Cunha, Stéphanie; Lin, Yi-Chun; Goossen, Elizabeth A.; DeVette, Christa I.; Albertella, Mark R.; Thomson, Stuart; Mulvihill, Mark J.; Welm, Alana L.

2017-01-01

SUMMARY Metastasis is the major cause of death in cancer patients, yet the genetic and epigenetic programs that drive metastasis are poorly understood. Here, we report an epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by the activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in the misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo. PMID:24388747

Akt phosphorylates Prohibitin 1 to mediate its mitochondrial localization and promote proliferation of bladder cancer cells

PubMed Central

Jiang, L; Dong, P; Zhang, Z; Li, C; Li, Y; Liao, Y; Li, X; Wu, Z; Guo, S; Mai, S; Xie, D; Liu, Z; Zhou, F

2015-01-01

Bladder cancer (BC) is very common and associated with significant morbidity and mortality, though the molecular underpinnings of its origination and progression remain poorly understood. In this study, we demonstrate that Prohibitin 1 (PHB) was overexpressed in human BC tissues and that PHB upregulation was associated with poor prognosis. We also found that PHB was necessary and sufficient for BC cell proliferation. Interestingly, the overexpressed PHB was primarily found within mitochondria, and we provide the first direct evidence that phosphorylation by Akt at Thr258 of PHB induces this mitochondrial localization. Inhibiton of Akt reverses these effects and inhibited the proliferation of BC cells. Finally, the phosphorylation of PHB was required for BC cell proliferation, further implicating the importance of the Akt in BC. Taken together, these findings identify the Akt/PHB signaling cascade as a novel mechanism of cancer cell proliferation and provide the scientific basis for the establishment of PHB as a new prognostic marker and treatment target for BC. PMID:25719244

Multifaceted role of EZH2 in breast and prostate tumorigenesis: epigenetics and beyond.

PubMed

Deb, Gauri; Thakur, Vijay S; Gupta, Sanjay

2013-05-01

Overexpression of EZH2 and other PRC2 subunits, such as SUZ12, is associated with tumor progression and poor prognosis in several human malignancies. Nevertheless, the underlying mechanisms driving aberrant EZH2 expression are poorly understood. This review provides molecular insights into the essential role of EZH2 in breast and prostate tumorigenesis. We addressed the current understanding on the oncogenic role of EZH2, with an emphasis on: (1) the less known PRC2-independent role of EZH2 in gene activation, in addition to its canonical role in transcriptional silencing as a histone methyltransferase catalyzing the trimethylation of histone H3 at lysine 27; (2) causes and consequences of its deregulation in tumor cells and; (3) collaboration of EZH2 with other epigenetic and hormone receptor-mediated oncogenic signaling pathways. We also summarize how EZH2 has emerged as a promising therapeutic target in hormone-refractory cancers and the prospects for integrating EZH2 blockade with available pharmacological inhibitors.

Human mutant huntingtin disrupts vocal learning in transgenic songbirds.

PubMed

Liu, Wan-Chun; Kohn, Jessica; Szwed, Sarah K; Pariser, Eben; Sepe, Sharon; Haripal, Bhagwattie; Oshimori, Naoki; Marsala, Martin; Miyanohara, Atsushi; Lee, Ramee

2015-11-01

Speech and vocal impairments characterize many neurological disorders. However, the neurogenetic mechanisms of these disorders are not well understood, and current animal models do not have the necessary circuitry to recapitulate vocal learning deficits. We developed germline transgenic songbirds, zebra finches (Taneiopygia guttata) expressing human mutant huntingtin (mHTT), a protein responsible for the progressive deterioration of motor and cognitive function in Huntington's disease (HD). Although generally healthy, the mutant songbirds had severe vocal disorders, including poor vocal imitation, stuttering, and progressive syntax and syllable degradation. Their song abnormalities were associated with HD-related neuropathology and dysfunction of the cortical-basal ganglia (CBG) song circuit. These transgenics are, to the best of our knowledge, the first experimentally created, functional mutant songbirds. Their progressive and quantifiable vocal disorder, combined with circuit dysfunction in the CBG song system, offers a model for genetic manipulation and the development of therapeutic strategies for CBG-related vocal and motor disorders.

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

PubMed Central

Stowe, Irma B.; Mercado, Ellen L.; Stowe, Timothy R.; Bell, Erika L.; Oses-Prieto, Juan A.; Hernández, Hilda; Burlingame, Alma L.; McCormick, Frank

2012-01-01

The Ras/mitogen-activated protein kinase (MAPK) pathway plays a critical role in transducing mitogenic signals from receptor tyrosine kinases. Loss-of-function mutations in one feedback regulator of Ras/MAPK signaling, SPRED1 (Sprouty-related protein with an EVH1 domain), cause Legius syndrome, an autosomal dominant human disorder that resembles Neurofibromatosis-1 (NF1). Spred1 functions as a negative regulator of the Ras/MAPK pathway; however, the underlying molecular mechanism is poorly understood. Here we show that neurofibromin, the NF1 gene product, is a Spred1-interacting protein that is necessary for Spred1's inhibitory function. We show that Spred1 binding induces the plasma membrane localization of NF1, which subsequently down-regulates Ras-GTP levels. This novel mechanism for the regulation of neurofibromin provides a molecular bridge for understanding the overlapping pathophysiology of NF1 and Legius syndrome. PMID:22751498

Evidence of an oncogenic Gammaherpesvirus in domestic Dogs

PubMed Central

Huang, Shih-Hung; Kozak, Philip; Kim, Jessica; Habineza-Ndikuyeze, Georges; Meade, Charles; Gaurnier-Hausser, Anita; Patel, Reema; Robertson, Erle; Mason, Nicola J.

2015-01-01

In humans chronic infection with the gammaherpesvirus, Epstein-Barr Virus is usually asymptomatic however, some infected individuals develop hematological and epithelial malignancies. The exact role of EBV in lymphomagenesis is poorly understood partly because of the lack of clinically relevant animal models. Here we report the detection of serological responses against EBV capsid antigens in healthy dogs and dogs with spontaneous lymphoma and that dogs with the highest antibody titers have B-cell lymphoma. Moreover, we demonstrate the presence of EBV-like viral DNA and RNA sequences and Latent Membrane Protein-1 in malignant lymph nodes of dogs with lymphoma. Finally, electron microscopy of canine malignant B cells revealed the presence of classic herpesvirus particles. These findings suggest that dogs can be naturally infected with an EBV-like gammaherpesvirus that may contribute to lymphomagenesis and that dogs might represent a spontaneous model to investigate environmental and genetic factors that influence gammaherpesvirus-associated lymphomagenesis in humans. PMID:22405628

Breakup of a homeobox cluster after genome duplication in teleosts

PubMed Central

Mulley, John F.; Chiu, Chi-hua; Holland, Peter W. H.

2006-01-01

Several families of homeobox genes are arranged in genomic clusters in metazoan genomes, including the Hox, ParaHox, NK, Rhox, and Iroquois gene clusters. The selective pressures responsible for maintenance of these gene clusters are poorly understood. The ParaHox gene cluster is evolutionarily conserved between amphioxus and human but is fragmented in teleost fishes. We show that two basal ray-finned fish, Polypterus and Amia, each possess an intact ParaHox cluster; this implies that the selective pressure maintaining clustering was lost after whole-genome duplication in teleosts. Cluster breakup is because of gene loss, not transposition or inversion, and the total number of ParaHox genes is the same in teleosts, human, mouse, and frog. We propose that this homeobox gene cluster is held together in chordates by the existence of interdigitated control regions that could be separated after locus duplication in the teleost fish. PMID:16801555

Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation

PubMed Central

Jeon, Jessie S.; Bersini, Simone; Gilardi, Mara; Dubini, Gabriele; Charest, Joseph L.; Moretti, Matteo; Kamm, Roger D.

2015-01-01

A key aspect of cancer metastases is the tendency for specific cancer cells to home to defined subsets of secondary organs. Despite these known tendencies, the underlying mechanisms remain poorly understood. Here we develop a microfluidic 3D in vitro model to analyze organ-specific human breast cancer cell extravasation into bone- and muscle-mimicking microenvironments through a microvascular network concentrically wrapped with mural cells. Extravasation rates and microvasculature permeabilities were significantly different in the bone-mimicking microenvironment compared with unconditioned or myoblast containing matrices. Blocking breast cancer cell A3 adenosine receptors resulted in higher extravasation rates of cancer cells into the myoblast-containing matrices compared with untreated cells, suggesting a role for adenosine in reducing extravasation. These results demonstrate the efficacy of our model as a drug screening platform and a promising tool to investigate specific molecular pathways involved in cancer biology, with potential applications to personalized medicine. PMID:25524628

Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells

PubMed Central

Hepworth, Matthew R.; Fung, Thomas C.; Masur, Samuel H.; Kelsen, Judith R.; McConnell, Fiona M.; Dubrot, Juan; Withers, David R.; Hugues, Stephanie; Farrar, Michael A.; Reith, Walter; Eberl, Gerard; Baldassano, Robert N.; Laufer, Terri M.; Elson, Charles O.; Sonnenberg, Gregory F.

2015-01-01

Inflammatory CD4+ T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. While selection of self-specific T cells in the thymus limits responses to tissue antigens, the mechanisms that control selection of commensal bacteria-specific T cells remain poorly understood. Here we demonstrate that group 3 innate lymphoid cell (ILC3)-intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells, and that MHCII+ ILC3s directly induce cell death of activated commensal bacteria-specific T cells. Further, MHCII on human colonic ILC3s was reduced in pediatric IBD patients. Collectively, these results define a selection pathway for commensal bacteria-specific CD4+ T cells in the intestine, and suggest that this process is dysregulated in human IBD. PMID:25908663

Cascade of neural processing orchestrates cognitive control in human frontal cortex

PubMed Central

Tang, Hanlin; Yu, Hsiang-Yu; Chou, Chien-Chen; Crone, Nathan E; Madsen, Joseph R; Anderson, William S; Kreiman, Gabriel

2016-01-01

Rapid and flexible interpretation of conflicting sensory inputs in the context of current goals is a critical component of cognitive control that is orchestrated by frontal cortex. The relative roles of distinct subregions within frontal cortex are poorly understood. To examine the dynamics underlying cognitive control across frontal regions, we took advantage of the spatiotemporal resolution of intracranial recordings in epilepsy patients while subjects resolved color-word conflict. We observed differential activity preceding the behavioral responses to conflict trials throughout frontal cortex; this activity was correlated with behavioral reaction times. These signals emerged first in anterior cingulate cortex (ACC) before dorsolateral prefrontal cortex (dlPFC), followed by medial frontal cortex (mFC) and then by orbitofrontal cortex (OFC). These results disassociate the frontal subregions based on their dynamics, and suggest a temporal hierarchy for cognitive control in human cortex. DOI: http://dx.doi.org/10.7554/eLife.12352.001 PMID:26888070

Separase is recruited to mitotic chromosomes to dissolve sister chromatid cohesion in a DNA-dependent manner.

PubMed

Sun, Yuxiao; Kucej, Martin; Fan, Heng-Yu; Yu, Hong; Sun, Qing-Yuan; Zou, Hui

2009-04-03

Sister chromatid separation is triggered by the separase-catalyzed cleavage of cohesin. This process is temporally controlled by cell-cycle-dependent factors, but its biochemical mechanism and spatial regulation remain poorly understood. We report that cohesin cleavage by human separase requires DNA in a sequence-nonspecific manner. Separase binds to DNA in vitro, but its proteolytic activity, measured by its autocleavage, is not stimulated by DNA. Instead, biochemical characterizations suggest that DNA mediates cohesin cleavage by bridging the interaction between separase and cohesin. In human cells, a fraction of separase localizes to the mitotic chromosome. The importance of the chromosomal DNA in cohesin cleavage is further demonstrated by the observation that the cleavage of the chromosome-associated cohesins is sensitive to nuclease treatment. Our observations explain why chromosome-associated cohesins are specifically cleaved by separase and the soluble cohesins are left intact in anaphase.

Evo-devo models of tooth development and the origin of hominoid molar diversity

PubMed Central

Bailey, Shara E.; Schwartz, Gary T.; Skinner, Matthew M.

2018-01-01

The detailed anatomical features that characterize fossil hominin molars figure prominently in the reconstruction of their taxonomy, phylogeny, and paleobiology. Despite the prominence of molar form in human origins research, the underlying developmental mechanisms generating the diversity of tooth crown features remain poorly understood. A model of tooth morphogenesis—the patterning cascade model (PCM)—provides a developmental framework to explore how and why the varying molar morphologies arose throughout human evolution. We generated virtual maps of the inner enamel epithelium—an indelibly preserved record of enamel knot arrangement—in 17 living and fossil hominoid species to investigate whether the PCM explains the expression of all major accessory cusps. We found that most of the variation and evolutionary changes in hominoid molar morphology followed the general developmental rule shared by all mammals, outlined by the PCM. Our results have implications for the accurate interpretation of molar crown configuration in hominoid systematics. PMID:29651459

Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation.

PubMed

Jeon, Jessie S; Bersini, Simone; Gilardi, Mara; Dubini, Gabriele; Charest, Joseph L; Moretti, Matteo; Kamm, Roger D

2015-01-06

A key aspect of cancer metastases is the tendency for specific cancer cells to home to defined subsets of secondary organs. Despite these known tendencies, the underlying mechanisms remain poorly understood. Here we develop a microfluidic 3D in vitro model to analyze organ-specific human breast cancer cell extravasation into bone- and muscle-mimicking microenvironments through a microvascular network concentrically wrapped with mural cells. Extravasation rates and microvasculature permeabilities were significantly different in the bone-mimicking microenvironment compared with unconditioned or myoblast containing matrices. Blocking breast cancer cell A3 adenosine receptors resulted in higher extravasation rates of cancer cells into the myoblast-containing matrices compared with untreated cells, suggesting a role for adenosine in reducing extravasation. These results demonstrate the efficacy of our model as a drug screening platform and a promising tool to investigate specific molecular pathways involved in cancer biology, with potential applications to personalized medicine.

From Embryonic Development to Human Diseases: The Functional Role of Caveolae/Caveolin

PubMed Central

Sohn, Jihee; Brick, Rachel M.; Tuan, Rocky S.

2017-01-01

Caveolae, an almost ubiquitous, structural component of the plasma membrane, play a critical role in many functions essential for proper cell function, including membrane trafficking, signal transduction, extracellular matrix remodeling, and tissue regeneration. Three main types of caveolin proteins have been identified from caveolae since the discovery of caveolin-1 in the early 1990s. All three (Cav-1, Cav-2, and Cav-3) play crucial roles in mammalian physiology, and can effect pathogenesis in a wide range of human diseases. While many biological activities of caveolins have been uncovered since its discovery, their role and regulation in embryonic develop remain largely poorly understood, although there is increasing evidence that caveolins may be linked to lung and brain birth defects. Further investigations are clearly needed to decipher how caveolae/caveolins mediate cellular functions and activities of normal embryogenesis and how their perturbations contribute to developmental disorders. PMID:26991990

Spinacia oleracea L. Leaf Stomata Harboring Cryptosporidium parvum Oocysts: a Potential Threat to Food Safety ▿ †

PubMed Central

Macarisin, Dumitru; Bauchan, Gary; Fayer, Ronald

2010-01-01

Cryptosporidium parvum is a cosmopolitan microscopic protozoan parasite that causes severe diarrheal disease (cryptosporidiosis) in mammals, including humans and livestock. There is growing evidence of Cryptosporidium persistence in fresh produce that may result in food-borne infection, including sporadic cases as well as outbreaks. However, drinking and recreational waters are still considered the major sources of Cryptosporidium infection in humans, which has resulted in prioritization of studies of parasite etiology in aquatic environments, while the mechanisms of transmission and parasite persistence on edible plants remain poorly understood. Using laser scanning confocal microscopy together with fluorescein-labeled monoclonal antibodies, C. parvum oocysts were found to strongly adhere to spinach plants after contact with contaminated water, to infiltrate through the stomatal openings in spinach leaves, and to persist at the mesophyll level. These findings and the fact that this pathogenic parasite resists washing and disinfection raise concerns regarding food safety. PMID:19933348

Nuclear Matrix Association: Switching to the Invasive Cytotrophoblast

PubMed Central

Drennan, Kathryn J.; Linnemann, Amelia K.; Platts, Adrian E.; Heng, Henry H.; Armant, D. Randall; Krawetz, Stephen A.

2010-01-01

Abnormal trophoblast invasion is associated with the most common and most severe complications of human pregnancy. The biology of invasion, as well as the etiology of abnormal invasion remains poorly understood. The aim of this study was to characterize the transcriptome of the HTR-8/SVneo human cytotrophoblast cell line which displays well characterized invasive and non-invasive behavior, and to correlate the activity of the transcriptome with nuclear matrix attachment and cell phenotype. Comparison of the invasive to non-invasive HTR transcriptomes was unremarkable. In contrast, comparison of the MARs on chromosomes 14–18 revealed an increased number of MARs associated with the invasive phenotype. These attachment areas were more likely to be associated with silent rather than actively transcribed genes. This study supports that view that that nuclear matrix attachment may play an important role in cytotrophoblast invasion by ensuring specific silencing that facilitates invasion. PMID:20346505

Striatal BOLD Response Reflects the Impact of Herd Information on Financial Decisions

PubMed Central

Burke, Christopher J.; Tobler, Philippe N.; Schultz, Wolfram; Baddeley, Michelle

2010-01-01

Like other species, humans are sensitive to the decisions and actions of conspecifics, which can lead to herd behavior and undesirable outcomes such as stock market bubbles and bank runs. However, how the brain processes this socially derived influence is only poorly understood. Using functional magnetic resonance imaging (fMRI), we scanned participants as they made decisions on whether to buy stocks after observing others’ buying decisions. We demonstrate that activity in the ventral striatum, an area heavily implicated in reward processing, tracked the degree of influence on participants’ decisions arising from the observation of other peoples’ decisions. The signal did not track non-human, non-social control decisions. These findings lend weight to the notion that the ventral striatum is involved in the processing of complex social aspects of decision making and identify a possible neural basis for herd behavior. PMID:20589242

A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia.

PubMed

Skene, Nathan G; Roy, Marcia; Grant, Seth Gn

2017-09-12

The genetic mechanisms regulating the brain and behaviour across the lifespan are poorly understood. We found that lifespan transcriptome trajectories describe a calendar of gene regulatory events in the brain of humans and mice. Transcriptome trajectories defined a sequence of gene expression changes in neuronal, glial and endothelial cell-types, which enabled prediction of age from tissue samples. A major lifespan landmark was the peak change in trajectories occurring in humans at 26 years and in mice at 5 months of age. This species-conserved peak was delayed in females and marked a reorganization of expression of synaptic and schizophrenia-susceptibility genes. The lifespan calendar predicted the characteristic age of onset in young adults and sex differences in schizophrenia. We propose a genomic program generates a lifespan calendar of gene regulation that times age-dependent molecular organization of the brain and mutations that interrupt the program in young adults cause schizophrenia.

Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis.

PubMed

Darido, Charbel; Georgy, Smitha R; Wilanowski, Tomasz; Dworkin, Sebastian; Auden, Alana; Zhao, Quan; Rank, Gerhard; Srivastava, Seema; Finlay, Moira J; Papenfuss, Anthony T; Pandolfi, Pier Paolo; Pearson, Richard B; Jane, Stephen M

2011-11-15

Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC. 2011 Elsevier Inc. All rights reserved.

Dysregulation of fatty acid synthesis and glycolysis in non-Hodgkin lymphoma

PubMed Central

Bhatt, Aadra P.; Jacobs, Sarah R.; Freemerman, Alex J.; Makowski, Liza; Rathmell, Jeffrey C.; Dittmer, Dirk P.; Damania, Blossom

2012-01-01

The metabolic differences between B-NHL and primary human B cells are poorly understood. Among human B-cell non-Hodgkin lymphomas (B-NHL), primary effusion lymphoma (PEL) is a unique subset that is linked to infection with Kaposi's sarcoma-associated herpesvirus (KSHV). We report that the metabolic profiles of primary B cells are significantly different from that of PEL. Compared with primary B cells, both aerobic glycolysis and fatty acid synthesis (FAS) are up-regulated in PEL and other types of nonviral B-NHL. We found that aerobic glycolysis and FAS occur in a PI3K-dependent manner and appear to be interdependent. PEL overexpress the fatty acid synthesizing enzyme, FASN, and both PEL and other B-NHL were much more sensitive to the FAS inhibitor, C75, than primary B cells. Our findings suggest that FASN may be a unique candidate for molecular targeted therapy against PEL and other B-NHL. PMID:22752304

Simultaneous transcranial magnetic stimulation and single neuron recording in alert non-human primates

PubMed Central

Mueller, Jerel K.; Grigsby, Erinn M.; Prevosto, Vincent; Petraglia, Frank W.; Rao, Hrishikesh; Deng, Zhi-De; Peterchev, Angel V.; Sommer, Marc A.; Egner, Tobias; Platt, Michael L.; Grill, Warren M.

2014-01-01

Transcranial magnetic stimulation (TMS) is a widely used, noninvasive method for stimulating nervous tissue, yet its mechanisms of effect are poorly understood. Here we report novel methods for studying the influence of TMS on single neurons in the brain of alert non-human primates. We designed a TMS coil that focuses its effect near the tip of a recording electrode and recording electronics that enable direct acquisition of neuronal signals at the site of peak stimulus strength minimally perturbed by stimulation artifact in intact, awake monkeys (Macaca mulatta). We recorded action potentials within ~1 ms after 0.4 ms TMS pulses and observed changes in activity that differed significantly for active stimulation as compared to sham stimulation. The methodology is compatible with standard equipment in primate laboratories, allowing for easy implementation. Application of these new tools will facilitate the refinement of next generation TMS devices, experiments, and treatment protocols. PMID:24974797

U-series dating of Paleolithic art in 11 caves in Spain.

PubMed

Pike, A W G; Hoffmann, D L; García-Diez, M; Pettitt, P B; Alcolea, J; De Balbín, R; González-Sainz, C; de las Heras, C; Lasheras, J A; Montes, R; Zilhão, J

2012-06-15

Paleolithic cave art is an exceptional archive of early human symbolic behavior, but because obtaining reliable dates has been difficult, its chronology is still poorly understood after more than a century of study. We present uranium-series disequilibrium dates of calcite deposits overlying or underlying art found in 11 caves, including the United Nations Educational, Scientific, and Cultural Organization (UNESCO) World Heritage sites of Altamira, El Castillo, and Tito Bustillo, Spain. The results demonstrate that the tradition of decorating caves extends back at least to the Early Aurignacian period, with minimum ages of 40.8 thousand years for a red disk, 37.3 thousand years for a hand stencil, and 35.6 thousand years for a claviform-like symbol. These minimum ages reveal either that cave art was a part of the cultural repertoire of the first anatomically modern humans in Europe or that perhaps Neandertals also engaged in painting caves.

Evolution of Deep Brain Stimulation: Human Electrometer and Smart Devices Supporting the Next Generation of Therapy

PubMed Central

Lee, Kendall H.; Blaha, Charles D.; Garris, Paul A.; Mohseni, Pedram; Horne, April E.; Bennet, Kevin E.; Agnesi, Filippo; Bledsoe, Jonathan M.; Lester, Deranda B.; Kimble, Chris; Min, Hoon-Ki; Kim, Young-Bo; Cho, Zang-Hee

2010-01-01

Deep Brain Stimulation (DBS) provides therapeutic benefit for several neuropathologies including Parkinson’s disease (PD), epilepsy, chronic pain, and depression. Despite well established clinical efficacy, the mechanism(s) of DBS remains poorly understood. In this review we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies, e.g., human electrometer and closed-loop smart devices, for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach. PMID:20657744

Intravenous human immunoglobulin for treatment of folliculitis decalvans.

PubMed

Ismail, Nuriah; Ralph, Nicola; Murphy, Gillian

2015-10-01

We report a case of folliculitis decalvans (FD) successfully treated with intravenous human immunoglobulin (HIG). Many conventional treatments with topical agents and oral antibiotics had failed to achieve disease remission, treatment with HIG at a dose of 2 g/kg for the first month, reduced to 1 g/kg for second to fourth months was therefore started, which resulted in rapid improvement and ultimately complete resolution of FD. Clinical improvement was noted after the first infusion of HIG and remission of inflammation was achieved after the fourth infusion. Disease remission was sustained for six months following the last HIG infusion. The exact mechanism of action of HIG is poorly understood. However, it is thought to act as an immunomodulatory agent by altering different components of immune functions. To our knowledge, this is the first case reported in the literature of FD successfully treated with intravenous HIG.

3D Protein Dynamics in the Cell Nucleus.

PubMed

Singh, Anand P; Galland, Rémi; Finch-Edmondson, Megan L; Grenci, Gianluca; Sibarita, Jean-Baptiste; Studer, Vincent; Viasnoff, Virgile; Saunders, Timothy E

2017-01-10

The three-dimensional (3D) architecture of the cell nucleus plays an important role in protein dynamics and in regulating gene expression. However, protein dynamics within the 3D nucleus are poorly understood. Here, we present, to our knowledge, a novel combination of 1) single-objective based light-sheet microscopy, 2) photoconvertible proteins, and 3) fluorescence correlation microscopy, to quantitatively measure 3D protein dynamics in the nucleus. We are able to acquire >3400 autocorrelation functions at multiple spatial positions within a nucleus, without significant photobleaching, allowing us to make reliable estimates of diffusion dynamics. Using this tool, we demonstrate spatial heterogeneity in Polymerase II dynamics in live U2OS cells. Further, we provide detailed measurements of human-Yes-associated protein diffusion dynamics in a human gastric cancer epithelial cell line. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The genetic prehistory of southern Africa.

PubMed

Pickrell, Joseph K; Patterson, Nick; Barbieri, Chiara; Berthold, Falko; Gerlach, Linda; Güldemann, Tom; Kure, Blesswell; Mpoloka, Sununguko Wata; Nakagawa, Hirosi; Naumann, Christfried; Lipson, Mark; Loh, Po-Ru; Lachance, Joseph; Mountain, Joanna; Bustamante, Carlos D; Berger, Bonnie; Tishkoff, Sarah A; Henn, Brenna M; Stoneking, Mark; Reich, David; Pakendorf, Brigitte

2012-01-01

Southern and eastern African populations that speak non-Bantu languages with click consonants are known to harbour some of the most ancient genetic lineages in humans, but their relationships are poorly understood. Here, we report data from 23 populations analysed at over half a million single-nucleotide polymorphisms, using a genome-wide array designed for studying human history. The southern African Khoisan fall into two genetic groups, loosely corresponding to the northwestern and southeastern Kalahari, which we show separated within the last 30,000 years. We find that all individuals derive at least a few percent of their genomes from admixture with non-Khoisan populations that began ∼1,200 years ago. In addition, the East African Hadza and Sandawe derive a fraction of their ancestry from admixture with a population related to the Khoisan, supporting the hypothesis of an ancient link between southern and eastern Africa.

Biomechanical implications of cortical elastic properties of the macaque mandible.

PubMed

Dechow, Paul C; Panagiotopoulou, Olga; Gharpure, Poorva

2017-10-01

Knowledge of the variation in the elastic properties of mandibular cortical bone is essential for modeling bone function. Our aim was to characterize the elastic properties of rhesus macaque mandibular cortical bone and compare these to the elastic properties from mandibles of dentate humans and baboons. Thirty cylindrical samples were harvested from each of six adult female rhesus monkey mandibles. Assuming orthotropy, axes of maximum stiffness in the plane of the cortical plate were derived from ultrasound velocity measurements. Further velocity measurements with longitudinal and transverse ultrasonic transducers along with measurements of bone density were used to compute three-dimensional cortical elastic properties using equations based on Hooke's law. Results showed regional variations in the elastic properties of macaque mandibular cortical bone that have both similarities and differences with that of humans and baboons. So far, the biological and structural basis of these differences is poorly understood. Copyright © 2017 Elsevier GmbH. All rights reserved.

Human oocyte developmental potential is predicted by mechanical properties within hours after fertilization

PubMed Central

Yanez, Livia Z.; Han, Jinnuo; Behr, Barry B.; Pera, Renee A. Reijo; Camarillo, David B.

2016-01-01

The causes of embryonic arrest during pre-implantation development are poorly understood. Attempts to correlate patterns of oocyte gene expression with successful embryo development have been hampered by the lack of reliable and nondestructive predictors of viability at such an early stage. Here we report that zygote viscoelastic properties can predict blastocyst formation in humans and mice within hours after fertilization, with >90% precision, 95% specificity and 75% sensitivity. We demonstrate that there are significant differences between the transcriptomes of viable and non-viable zygotes, especially in expression of genes important for oocyte maturation. In addition, we show that low-quality oocytes may undergo insufficient cortical granule release and zona-hardening, causing altered mechanics after fertilization. Our results suggest that embryo potential is largely determined by the quality and maturation of the oocyte before fertilization, and can be predicted through a minimally invasive mechanical measurement at the zygote stage. PMID:26904963

Epigenetic regulator RBP2 is critical for breast cancer progression and metastasis

PubMed Central

Cao, Jian; Liu, Zongzhi; Cheung, William K.C.; Zhao, Minghui; Chen, Sophia Y.; Chan, Siew Wee; Booth, Carmen J.; Nguyen, Don X.; Yan, Qin

2014-01-01

Summary Metastasis is a major clinical challenge for cancer treatment. Emerging evidence suggests that epigenetic aberrations contribute significantly to tumor formation and progression. However, the drivers and roles of such epigenetic changes in tumor metastasis are still poorly understood. Using bioinformatic analysis of human breast cancer gene expression datasets, we identified histone demethylase RBP2 as a putative mediator of metastatic progression. By using both human breast cancer cells and genetically engineered mice, we demonstrated that RBP2 is critical for breast cancer metastasis to the lung in multiple in vivo models. Mechanistically, RBP2 promotes metastasis as a pleiotropic positive regulator of many metastasis genes. In addition, RBP2 loss suppresses tumor formation in the MMTV-neu transgenic mice. These results suggest that therapeutically targeting RBP2 is a potential strategy to inhibit tumor progression and metastasis. PMID:24582965

Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes

PubMed Central

Arruda, Ana Paula; Hotamisligil, Gökhan S.

2015-01-01

Summary A number of chronic metabolic pathologies, including obesity, diabetes, cardiovascular disease, asthma, and cancer cluster together to present the greatest threat to human health. As research in this field has advanced, it has become clear that unresolved metabolic inflammation, organelle dysfunction, and other cellular and metabolic stresses underlie the development of these chronic metabolic diseases. However, the relationship between these systems and pathological mechanisms is poorly understood. Here, we will discuss the role of cellular Ca2+ homeostasis as a critical mechanism integrating the myriad of cellular and subcellular dysfunctional networks found in metabolic tissues such as liver and adipose tissue in the context of metabolic disease particularly in obesity and diabetes. PMID:26190652

Potential fluoride toxicity from oral medicaments: A review.

PubMed

Ullah, Rizwan; Zafar, Muhammad Sohail; Shahani, Nazish

2017-08-01

The beneficial effects of fluoride on human oral health are well studied. There are numerous studies demonstrating that a small amount of fluoride delivered to the oral cavity decreases the prevalence of dental decay and results in stronger teeth and bones. However, ingestion of fluoride more than the recommended limit leads to toxicity and adverse effects. In order to update our understanding of fluoride and its potential toxicity, we have described the mechanisms of fluoride metabolism, toxic effects, and management of fluoride toxicity. The main aim of this review is to highlight the potential adverse effects of fluoride overdose and poorly understood toxicity. In addition, the related clinical significance of fluoride overdose and toxicity has been discussed.

Dynamic Neuroplasticity after Human Prefrontal Cortex Damage

PubMed Central

Voytek, Bradley; Davis, Matar; Yago, Elena; Barceló, Francisco; Vogel, Edward K.; Knight, Robert T.

2010-01-01

Summary Memory and attention deficits are common after prefrontal cortex (PFC) damage, yet people generally recover some function over time. Recovery is thought to be dependent upon undamaged brain regions but the temporal dynamics underlying cognitive recovery are poorly understood. Here we provide evidence that the intact PFC compensates for damage in the lesioned PFC on a trial-by-trial basis dependent on cognitive load. The extent of this rapid functional compensation is indexed by transient increases in electrophysiological measures of attention and memory in the intact PFC, detectable within a second after stimulus presentation and only when the lesioned hemisphere is challenged. These observations provide evidence supporting a dynamic and flexible model of compensatory neural plasticity. PMID:21040843

Flagellar generated flow mediates attachment of Giardia lamblia

NASA Astrophysics Data System (ADS)

Urbach, Jeffrey; Luo, Haibei; Picou, Theodore; McAllister, Ryan; Elmendorf, Heidi

2011-03-01

Giardia lamblia is a protozoan parasite responsible for widespread diarrheal disease in humans and animals worldwide. Attachment to the host intestinal mucosa and resistance to peristalsis is necessary for establishing infection, but the physical basis for this attachment is poorly understood. We report results from TIRF and confocal fluorescence microscopy that demonstrate that the regular beating of the posterior flagella generate a flow through the ventral disk, a suction-cup shaped structure that is against the substrate during attachment. Finite element simulations are used to compare the negative pressure generated by the flow to the measured attachment force and the expected performance of the flagellar pump. NIH grant 1R21AI062934-0.

Mapping risk of Nipah virus transmission across Asia and across Bangladesh.

PubMed

Peterson, A Townsend

2015-03-01

Nipah virus is a highly pathogenic but poorly known paramyxovirus from South and Southeast Asia. In spite of the risks that it poses to human health, the geography and ecology of its occurrence remain little understood-the virus is basically known from Bangladesh and peninsular Malaysia, and little in between. In this contribution, I use documented occurrences of the virus to develop ecological niche-based maps summarizing its likely broader occurrence-although rangewide maps could not be developed that had significant predictive abilities, reflecting minimal sample sizes available, maps within Bangladesh were quite successful in identifying areas in which the virus is predictably present and likely transmitted. © 2013 APJPH.

[Pulmonary hypertension in patients infected with human immunodeficiency virus: current situation].

PubMed

Soto-Abánades, Clara Itzíar; Alcolea-Batres, Sergio; Ríos-Blanco, Juan José

2013-01-01

The increase in survival that has been achieved with the new treatments in the era of highly active antiretroviral therapy, has enabled clinicians and researchers to analyze issues that emerge in the long term in patients with HIV infection. Although the majority of cardiovascular complications have been widely described, the pathogenesis of pulmonary arterial hypertension is still poorly understood, and is one of the more complex and feared complications as it worsens the prognosis and quality of life of these patients This article reviews newer aspects related to the aetiology, symptoms, diagnosis and treatment of this disease. Copyright © 2011 Elsevier España, S.L. All rights reserved.

Congenital absence of dermatoglyphs.

PubMed

Límová, M; Blacker, K L; LeBoit, P E

1993-08-01

Congenital absence or unusual patterns of human dermatoglyphs (fingerprints) occur in several syndromes that are rare and poorly understood. The abnormalities of dermatoglyphs fall into four categories: complete absence, ridge hypoplasia, ridge dissociation, and ridges-off-the-end. Complete congenital absence of ridges is an exceedingly rare syndrome that consists of neonatal blisters and milia, adult traumatic blistering and fissuring, absence of sweating, contracture of digits, and absence of dermatoglyphs on the hands and feet. The syndrome is inherited in an autosomal dominant pattern, and only two kindreds have been described in the literature. We describe a newly identified patient and kindred with findings similar to the previously reported cases and review the clinical and histopathologic findings of this syndrome.

Novel targets and stimulation paradigms for deep brain stimulation.

PubMed

De Jesus, Sol; Almeida, Leonardo; Peng-Chen, Zhongxing; Okun, Michael S; Hess, Christopher W

2015-01-01

Deep brain stimulation (DBS) is an accepted therapy for appropriately selected patients with movement disorders and psychiatric disease. The recent advances in lead technology and the advent of novel stimulation parameters have spurred a number of improvements that will likely be implemented in the clinical setting. Although the mechanisms and biology of DBS remain poorly understood, the progress in our understanding of network level dysfunction has driven the introduction of a variety of new targets and approaches to the treatment of human disease. Here we summarize the recent advances in novel stimulation patterns and customized field shaping. We also review new targets, novel applications of DBS and the immediate and long-term horizon for this therapy.

Successful treatment of dwarfism secondary to long-term steroid therapy in steroid-dependent nephrotic syndrome.

PubMed

Sun, Linlin; Chen, Dongping; Zhao, Xuezhi; Xu, Chenggang; Mei, Changlin

2010-01-01

Prolonged steroid therapy is generally used for steroid-dependent nephrotic syndrome in pediatric patients. However, dwarfism secondary to a long-term regimen and its successful reverse is rarely reported. The underlying mechanism of dwarfism is still poorly understood, as both long-term steroid use and nephrotic syndrome may interact or independently interfere with the process of growth. Here, we present a 17-year-old patient with dwarfism and steroid-dependent nephrotic syndrome and the successful treatment by recombinant human growth factor and cyclosporine A with withdrawal of steroid. We also briefly review the current understanding and the management of dwarfism in pediatric patients with nephrotic syndrome.

Zebrafish models in neuropsychopharmacology and CNS drug discovery.

PubMed

Khan, Kanza M; Collier, Adam D; Meshalkina, Darya A; Kysil, Elana V; Khatsko, Sergey L; Kolesnikova, Tatyana; Morzherin, Yury Yu; Warnick, Jason E; Kalueff, Allan V; Echevarria, David J

2017-07-01

Despite the high prevalence of neuropsychiatric disorders, their aetiology and molecular mechanisms remain poorly understood. The zebrafish (Danio rerio) is increasingly utilized as a powerful animal model in neuropharmacology research and in vivo drug screening. Collectively, this makes zebrafish a useful tool for drug discovery and the identification of disordered molecular pathways. Here, we discuss zebrafish models of selected human neuropsychiatric disorders and drug-induced phenotypes. As well as covering a broad range of brain disorders (from anxiety and psychoses to neurodegeneration), we also summarize recent developments in zebrafish genetics and small molecule screening, which markedly enhance the disease modelling and the discovery of novel drug targets. © 2017 The British Pharmacological Society.

Chronic Wound Repair and Healing in Older Adults: Current Status and Future Research

PubMed Central

Gould, Lisa; Abadir, Peter; Brem, Harold; Carter, Marissa; Conner-Kerr, Teresa; Davidson, Jeff; DiPietro, Luisa; Falanga, Vincent; Fife, Caroline; Gardner, Sue; Grice, Elizabeth; Harmon, John; Hazzard, William R.; High, Kevin P.; Houghton, Pamela; Jacobson, Nasreen; Kirsner, Robert S.; Kovacs, Elizabeth J.; Margolish, David; McFarland Horne, Frances; Reed, May J.; Sullivan, Dennis H.; Thom, Stephen; Tomic-Canic, Marjana; Walston, Jeremy; Whitney, JoAnne; Williams, John; Zieman, Susan; Schmader, Kenneth

2014-01-01

The incidence of chronic wounds is increased among older adults, and the impact of chronic wounds on quality of life is particularly profound in this population. It is well established that wound healing slows with age. However, the basic biology underlying chronic wounds and the influence of age-associated changes on wound healing are poorly understood. Most studies have used in vitro approaches and various animal models, but observed changes translate poorly to human healing conditions. The impact of age and accompanying multi-morbidity on the effectiveness of existing and emerging treatment approaches for chronic wounds is also unknown, and older adults tend to be excluded from randomized clinical trials. Poorly defined outcomes and variables, lack of standardization in data collection, and variations in the definition, measurement, and treatment of wounds also hamper clinical studies. The Association of Specialty Professors, in conjunction with the National Institute on Aging and the Wound Healing Society, held a workshop, summarized in this paper, to explore the current state of knowledge and research challenges, engage investigators across disciplines, and identify key research questions to guide future study of age-associated changes in chronic wound healing. PMID:25486905

Chronic Wound Repair and Healing in Older Adults: Current Status and Future Research

PubMed Central

Gould, Lisa; Abadir, Peter; Brem, Harold; Carter, Marissa; Conner-Kerr, Teresa; Davidson, Jeff; DiPietro, Luisa; Falanga, Vincent; Fife, Caroline; Gardner, Sue; Grice, Elizabeth; Harmon, John; Hazzard, William R.; High, Kevin P.; Houghton, Pamela; Jacobson, Nasreen; Kirsner, Robert S.; Kovacs, Elizabeth J.; Margolis, David; Horne, Frances McFarland; Reed, May J.; Sullivan, Dennis H.; Thom, Stephen; Tomic-Canic, Marjana; Walston, Jeremy; Whitney, Jo Anne; Williams, John; Zieman, Susan; Schmader, Kenneth

2015-01-01

Older adults are more likely to have chronic wounds than younger people, and the effect of chronic wounds on quality of life is particularly profound in this population. Wound healing slows with age, but the basic biology underlying chronic wounds and the influence of age-associated changes on wound healing are poorly understood. Most studies have used in vitro approaches and various animal models, but observed changes translate poorly to human healing conditions. The effect of age and accompanying multimorbidity on the effectiveness of existing and emerging treatment approaches for chronic wounds is also unknown, and older adults tend to be excluded from randomized clinical trials. Poorly defined outcomes and variables; lack of standardization in data collection; and variations in the definition, measurement, and treatment of wounds also hamper clinical studies. The Association of Specialty Professors, in conjunction with the National Institute on Aging and the Wound Healing Society, held a workshop, summarized in this article, to explore the current state of knowledge and research challenges, engage investigators across disciplines, and identify research questions to guide future study of age-associated changes in chronic wound healing. PMID:25753048

Lags in the response of mountain plant communities to climate change

PubMed Central

Alexander, Jake M.; Chalmandrier, Loïc; Lenoir, Jonathan; Burgess, Treena I.; Essl, Franz; Haider, Sylvia; Kueffer, Christoph; McDougall, Keith; Milbau, Ann; Nuñez, Martin A.; Pauchard, Aníbal; Rabitsch, Wolfgang; Rew, Lisa J.; Sanders, Nathan J.; Pellissier, Loïc

2018-01-01

Rapid climatic changes and increasing human influence at high elevations around the world will have profound impacts on mountain biodiversity. However, forecasts from statistical models (e.g. species distribution models) rarely consider that plant community changes could substantially lag behind climatic changes, hindering our ability to make temporally realistic projections for the coming century. Indeed, the magnitudes of lags, and the relative importance of the different factors giving rise to them, remain poorly understood. We review evidence for three types of lag: “dispersal lags” affecting plant species’ spread along elevational gradients, “establishment lags” following their arrival in recipient communities, and “extinction lags” of resident species. Variation in lags is explained by variation among species in physiological and demographic responses, by effects of altered biotic interactions, and by aspects of the physical environment. Of these, altered biotic interactions could contribute substantially to establishment and extinction lags, yet impacts of biotic interactions on range dynamics are poorly understood. We develop a mechanistic community model to illustrate how species turnover in future communities might lag behind simple expectations based on species’ range shifts with unlimited dispersal. The model shows a combined contribution of altered biotic interactions and dispersal lags to plant community turnover along an elevational gradient following climate warming. Our review and simulation support the view that accounting for disequilibrium range dynamics will be essential for realistic forecasts of patterns of biodiversity under climate change, with implications for the conservation of mountain species and the ecosystem functions they provide. PMID:29112781

Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders.

PubMed

Edlow, Brian L; Takahashi, Emi; Wu, Ona; Benner, Thomas; Dai, Guangping; Bu, Lihong; Grant, Patricia Ellen; Greer, David M; Greenberg, Steven M; Kinney, Hannah C; Folkerth, Rebecca D

2012-06-01

The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.

Whipworms in humans and pigs: origins and demography.

PubMed

Hawash, Mohamed B F; Betson, Martha; Al-Jubury, Azmi; Ketzis, Jennifer; LeeWillingham, Arve; Bertelsen, Mads F; Cooper, Philip J; Littlewood, D Tim J; Zhu, Xing-Quan; Nejsum, Peter

2016-01-22

Trichuris suis and T. trichiura are two different whipworm species that infect pigs and humans, respectively. T. suis is found in pigs worldwide while T. trichiura is responsible for nearly 460 million infections in people, mainly in areas of poor sanitation in tropical and subtropical areas. The evolutionary relationship and the historical factors responsible for this worldwide distribution are poorly understood. In this study, we aimed to reconstruct the demographic history of Trichuris in humans and pigs, the evolutionary origin of Trichuris in these hosts and factors responsible for parasite dispersal globally. Parts of the mitochondrial nad1 and rrnL genes were sequenced followed by population genetic and phylogenetic analyses. Populations of Trichuris examined were recovered from humans (n = 31), pigs (n = 58) and non-human primates (n = 49) in different countries on different continents, namely Denmark, USA, Uganda, Ecuador, China and St. Kitts (Caribbean). Additional sequences available from GenBank were incorporated into the analyses. We found no differentiation between human-derived Trichuris in Uganda and the majority of the Trichuris samples from non-human primates suggesting a common African origin of the parasite, which then was transmitted to Asia and further to South America. On the other hand, there was no differentiation between pig-derived Trichuris from Europe and the New World suggesting dispersal relates to human activities by transporting pigs and their parasites through colonisation and trade. Evidence for recent pig transport from China to Ecuador and from Europe to Uganda was also observed from their parasites. In contrast, there was high genetic differentiation between the pig Trichuris in Denmark and China in concordance with the host genetics. We found evidence for an African origin of T. trichiura which were then transmitted with human ancestors to Asia and further to South America. A host shift to pigs may have occurred in Asia from where T. suis seems to have been transmitted globally by a combination of natural host dispersal and anthropogenic factors.

Decision trees to characterise the roles of permeability and solubility on the prediction of oral absorption.

PubMed

Newby, Danielle; Freitas, Alex A; Ghafourian, Taravat

2015-01-27

Oral absorption of compounds depends on many physiological, physiochemical and formulation factors. Two important properties that govern oral absorption are in vitro permeability and solubility, which are commonly used as indicators of human intestinal absorption. Despite this, the nature and exact characteristics of the relationship between these parameters are not well understood. In this study a large dataset of human intestinal absorption was collated along with in vitro permeability, aqueous solubility, melting point, and maximum dose for the same compounds. The dataset allowed a permeability threshold to be established objectively to predict high or low intestinal absorption. Using this permeability threshold, classification decision trees incorporating a solubility-related parameter such as experimental or predicted solubility, or the melting point based absorption potential (MPbAP), along with structural molecular descriptors were developed and validated to predict oral absorption class. The decision trees were able to determine the individual roles of permeability and solubility in oral absorption process. Poorly permeable compounds with high solubility show low intestinal absorption, whereas poorly water soluble compounds with high or low permeability may have high intestinal absorption provided that they have certain molecular characteristics such as a small polar surface or specific topology. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Vector competence of Aedes aegypti mosquitoes for filarial nematodes is affected by age and nutrient limitation.

PubMed

Ariani, Cristina V; Juneja, Punita; Smith, Sophia; Tinsley, Matthew C; Jiggins, Francis M

2015-01-01

Mosquitoes are one of the most important vectors of human disease. The ability of mosquitoes to transmit disease is dependent on the age structure of the population, as mosquitoes must survive long enough for the parasites to complete their development and infect another human. Age could have additional effects due to mortality rates and vector competence changing as mosquitoes senesce, but these are comparatively poorly understood. We have investigated these factors using the mosquito Aedes aegypti and the filarial nematode Brugia malayi. Rather than observing any effects of immune senescence, we found that older mosquitoes were more resistant, but this only occurred if they had previously been maintained on a nutrient-poor diet of fructose. Constant blood feeding reversed this decline in vector competence, meaning that the number of parasites remained relatively unchanged as mosquitoes aged. Old females that had been maintained on fructose also experienced a sharp spike in mortality after an infected blood meal ("refeeding syndrome") and few survived long enough for the parasite to develop. Again, this effect was prevented by frequent blood meals. Our results indicate that old mosquitoes may be inefficient vectors due to low vector competence and high mortality, but that frequent blood meals can prevent these effects of age. Copyright © 2014 Elsevier Inc. All rights reserved.

Polyethylene glycol binding alters human telomere G-quadruplex structure by conformational selection

PubMed Central

Buscaglia, Robert; Miller, M. Clarke; Dean, William L.; Gray, Robert D.; Lane, Andrew N.; Trent, John O.; Chaires, Jonathan B.

2013-01-01

Polyethylene glycols (PEGs) are widely used to perturb the conformations of nucleic acids, including G-quadruplexes. The mechanism by which PEG alters G-quadruplex conformation is poorly understood. We describe here studies designed to determine how PEG and other co-solutes affect the conformation of the human telomeric quadruplex. Osmotic stress studies using acetonitrile and ethylene glycol show that conversion of the ‘hybrid’ conformation to an all-parallel ‘propeller’ conformation is accompanied by the release of about 17 water molecules per quadruplex and is energetically unfavorable in pure aqueous solutions. Sedimentation velocity experiments show that the propeller form is hydrodynamically larger than hybrid forms, ruling out a crowding mechanism for the conversion by PEG. PEGs do not alter water activity sufficiently to perturb quadruplex hydration by osmotic stress. PEG titration experiments are most consistent with a conformational selection mechanism in which PEG binds more strongly to the propeller conformation, and binding is coupled to the conformational transition between forms. Molecular dynamics simulations show that PEG binding to the propeller form is sterically feasible and energetically favorable. We conclude that PEG does not act by crowding and is a poor mimic of the intranuclear environment, keeping open the question of the physiologically relevant quadruplex conformation. PMID:23804761

Comparative peptidomic profile between human hypertrophic scar tissue and matched normal skin for identification of endogenous peptides involved in scar pathology.

PubMed

Li, Jingyun; Chen, Ling; Li, Qian; Cao, Jing; Gao, Yanli; Li, Jun

2018-08-01

Endogenous peptides recently attract increasing attention for their participation in various biological processes. Their roles in the pathogenesis of human hypertrophic scar remains poorly understood. In this study, we used liquid chromatography-tandem mass spectrometry to construct a comparative peptidomic profiling between human hypertrophic scar tissue and matched normal skin. A total of 179 peptides were significantly differentially expressed in human hypertrophic scar tissue, with 95 upregulated and 84 downregulated peptides between hypertrophic scar tissue and matched normal skin. Further bioinformatics analysis (Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis) indicated that precursor proteins of these differentially expressed peptides correlate with cellular process, biological regulation, cell part, binding and structural molecule activity ribosome, and PPAR signaling pathway occurring during pathological changes of hypertrophic scar. Based on prediction database, we found that 78 differentially expressed peptides shared homology with antimicrobial peptides and five matched known immunomodulatory peptides. In conclusion, our results show significantly altered expression profiles of peptides in human hypertrophic scar tissue. These peptides may participate in the etiology of hypertrophic scar and provide beneficial scheme for scar evaluation and treatments. © 2017 Wiley Periodicals, Inc.

Direct evidence of milk consumption from ancient human dental calculus.

PubMed

Warinner, C; Hendy, J; Speller, C; Cappellini, E; Fischer, R; Trachsel, C; Arneborg, J; Lynnerup, N; Craig, O E; Swallow, D M; Fotakis, A; Christensen, R J; Olsen, J V; Liebert, A; Montalva, N; Fiddyment, S; Charlton, S; Mackie, M; Canci, A; Bouwman, A; Rühli, F; Gilbert, M T P; Collins, M J

2014-11-27

Milk is a major food of global economic importance, and its consumption is regarded as a classic example of gene-culture evolution. Humans have exploited animal milk as a food resource for at least 8500 years, but the origins, spread, and scale of dairying remain poorly understood. Indirect lines of evidence, such as lipid isotopic ratios of pottery residues, faunal mortality profiles, and lactase persistence allele frequencies, provide a partial picture of this process; however, in order to understand how, where, and when humans consumed milk products, it is necessary to link evidence of consumption directly to individuals and their dairy livestock. Here we report the first direct evidence of milk consumption, the whey protein β-lactoglobulin (BLG), preserved in human dental calculus from the Bronze Age (ca. 3000 BCE) to the present day. Using protein tandem mass spectrometry, we demonstrate that BLG is a species-specific biomarker of dairy consumption, and we identify individuals consuming cattle, sheep, and goat milk products in the archaeological record. We then apply this method to human dental calculus from Greenland's medieval Norse colonies, and report a decline of this biomarker leading up to the abandonment of the Norse Greenland colonies in the 15(th) century CE.

Global spatio-temporal patterns in human migration: a complex network perspective.

PubMed

Davis, Kyle F; D'Odorico, Paolo; Laio, Francesco; Ridolfi, Luca

2013-01-01

Migration is a powerful adaptive strategy for humans to navigate hardship and pursue a better quality of life. As a universal vehicle facilitating exchanges of ideas, culture, money and goods, international migration is a major contributor to globalization. Consisting of countries linked by multiple connections of human movements, global migration constitutes a network. Despite the important role of human migration in connecting various communities in different parts of the world, the topology and behavior of the international migration network and its changes through time remain poorly understood. Here we show that the global human migration network became more interconnected during the latter half of the twentieth century and that migrant destination choice partly reflects colonial and postcolonial histories, language, religion, and distances. From 1960 to 2000 we found a steady increase in network transitivity (i.e. connectivity between nodes connected to the same node), a decrease in average path length and an upward shift in degree distribution, all of which strengthened the 'small-world' behavior of the migration network. Furthermore, we found that distinct groups of countries preferentially interact to form migration communities based largely on historical, cultural and economic factors.

Zika virus propagation and release in human fetal astrocytes can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869.

PubMed

Huang, Yunlong; Li, Yuju; Zhang, Hainan; Zhao, Runze; Jing, Ran; Xu, Yinghua; He, Miao; Peer, Justin; Kim, Yeong C; Luo, Jiangtao; Tong, Zenghan; Zheng, Jialin

2018-01-01

Zika virus (ZIKV) is a neurotrophic flavivirus that is capable of infecting humans, leading to brain abnormalities during fetal development. The ZIKV infectivity in neural target cells remains poorly understood. Here, we found that ZIKV specifically infected glial fibrillary acidic protein- and S100B-positive primary human astrocytes derived from fetal brains. In contrast, neuron-specific Class III β-tubulin (TuJ1)-positive neurons in the astrocyte cultures and SOX2-positive neural progenitor cells derived from the fetal brains were less susceptible to ZIKV infection compared with astrocytes. The infected astrocytes released competent viral particles and manifested programmed cell death with a progressive cytopathic effect. Interestingly, ZIKV infection in human fetal astrocytes induced a significant increase of extracellular vesicles (EVs). Treatment with GW4869, a specific inhibitor of neutral sphingomyelinase-2, decreased EV levels, suppressed ZIKV propagation, and reduced the release of infectious virions in astrocytes. Therefore, ZIKV infects primary human fetal astrocytes and the infection can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869. Further investigation into sphingomyelin metabolism and EVs may provide insights to the therapeutic treatment of ZIKV infection.

Direct evidence of milk consumption from ancient human dental calculus

PubMed Central

Warinner, C.; Hendy, J.; Speller, C.; Cappellini, E.; Fischer, R.; Trachsel, C.; Arneborg, J.; Lynnerup, N.; Craig, O. E.; Swallow, D. M.; Fotakis, A.; Christensen, R. J.; Olsen, J. V.; Liebert, A.; Montalva, N.; Fiddyment, S.; Charlton, S.; Mackie, M.; Canci, A.; Bouwman, A.; Rühli, F.; Gilbert, M. T. P.; Collins, M. J.

2014-01-01

Milk is a major food of global economic importance, and its consumption is regarded as a classic example of gene-culture evolution. Humans have exploited animal milk as a food resource for at least 8500 years, but the origins, spread, and scale of dairying remain poorly understood. Indirect lines of evidence, such as lipid isotopic ratios of pottery residues, faunal mortality profiles, and lactase persistence allele frequencies, provide a partial picture of this process; however, in order to understand how, where, and when humans consumed milk products, it is necessary to link evidence of consumption directly to individuals and their dairy livestock. Here we report the first direct evidence of milk consumption, the whey protein β-lactoglobulin (BLG), preserved in human dental calculus from the Bronze Age (ca. 3000 BCE) to the present day. Using protein tandem mass spectrometry, we demonstrate that BLG is a species-specific biomarker of dairy consumption, and we identify individuals consuming cattle, sheep, and goat milk products in the archaeological record. We then apply this method to human dental calculus from Greenland's medieval Norse colonies, and report a decline of this biomarker leading up to the abandonment of the Norse Greenland colonies in the 15th century CE. PMID:25429530

Isotopic signals of summer denitrification in a northern hardwood forested catchment

Treesearch

Sarah K. Wexler; Christine L. Goodale; Kevin J. McGuire; Scott W. Bailey; Peter M. Groffman

2014-01-01

Despite decades of measurements, the nitrogen balance of temperate forest catchments remains poorly understood. Atmospheric nitrogen deposition often greatly exceeds streamwater nitrogen losses; the fate of the remaining nitrogen is highly uncertain. Gaseous losses of nitrogen to denitrification are especially poorly documented and are often ignored. Here, we provide...

Punishment and Welfare: Paternal Incarceration and Families' Receipt of Public Assistance

ERIC Educational Resources Information Center

Sugie, Naomi F.

2012-01-01

The United States criminal justice and welfare systems are two important government institutions in the lives of the poor. Despite many theoretical discussions about their relationship, their operation at the level of offenders and families remains poorly understood. This paper utilizes Fragile Families and Child Wellbeing data to examine how…

Toxicological effects of the different substances in tobacco smoke on human embryonic development by a systems chemo-biology approach.

PubMed

Feltes, Bruno César; de Faria Poloni, Joice; Notari, Daniel Luis; Bonatto, Diego

2013-01-01

The physiological and molecular effects of tobacco smoke in adult humans and the development of cancer have been well described. In contrast, how tobacco smoke affects embryonic development remains poorly understood. Morphological studies of the fetuses of smoking pregnant women have shown various physical deformities induced by constant fetal exposure to tobacco components, especially nicotine. In addition, nicotine exposure decreases fetal body weight and bone/cartilage growth in addition to decreasing cranial diameter and tibia length. Unfortunately, the molecular pathways leading to these morphological anomalies are not completely understood. In this study, we applied interactome data mining tools and small compound interaction networks to elucidate possible molecular pathways associated with the effects of tobacco smoke components during embryonic development in pregnant female smokers. Our analysis showed a relationship between nicotine and 50 additional harmful substances involved in a variety of biological process that can cause abnormal proliferation, impaired cell differentiation, and increased oxidative stress. We also describe how nicotine can negatively affect retinoic acid signaling and cell differentiation through inhibition of retinoic acid receptors. In addition, nicotine causes a stress reaction and/or a pro-inflammatory response that inhibits the agonistic action of retinoic acid. Moreover, we show that the effect of cigarette smoke on the developing fetus could represent systemic and aggressive impacts in the short term, causing malformations during certain stages of development. Our work provides the first approach describing how different tobacco constituents affect a broad range of biological process in human embryonic development.

Intracranial microprobe for evaluating neuro-hemodynamic coupling in unanesthetized human neocortex

PubMed Central

Keller, Corey J.; Cash, Sydney S.; Narayanan, Suresh; Wang, Chunmao; Kuzniecky, Ruben; Carlson, Chad; Devinsky, Orrin; Thesen, Thomas; Doyle, Werner; Sassaroli, Angelo; Boas, David A.; Ulbert, Istvan; Halgren, Eric

2009-01-01

Measurement of the blood-oxygen-level dependent (BOLD) response with fMRI has revolutionized cognitive neuroscience and is increasingly important in clinical care. The BOLD response reflects changes in deoxy-hemoglobin concentration, blood volume, and blood flow. These hemodynamic changes ultimately result from neuronal firing and synaptic activity, but the linkage between these domains is complex, poorly understood, and may differ across species, cortical areas, diseases, and cognitive states. We describe here a technique that can measure neural and hemodynamic changes simultaneously from cortical microdomains in waking humans. We utilize a “laminar optode,” a linear array of microelectrodes for electrophysiological measures paired with a micro-optical device for hemodynamic measurements. Optical measurements include laser Doppler to estimate cerebral blood flow as well as point spectroscopy to estimate oxy- and deoxy-hemoglobin concentrations. The microelectrode array records local field potential gradients (PG) and multi-unit activity (MUA) at 24 locations spanning the cortical depth, permitting estimation of population trans-membrane current flows (Current Source Density, CSD) and population cell firing in each cortical lamina. Comparison of the laminar CSD/MUA profile with the origins and terminations of cortical circuits allows activity in specific neuronal circuits to be inferred and then directly compared to hemodynamics. Access is obtained in epileptic patients during diagnostic evaluation for surgical therapy. Validation tests with relatively well-understood manipulations (EKG, breath-holding, cortical electrical stimulation) demonstrate the expected responses. This device can provide a new and robust means for obtaining detailed, quantitative data for defining neurovascular coupling in awake humans. PMID:19428529

Intracranial microprobe for evaluating neuro-hemodynamic coupling in unanesthetized human neocortex.

PubMed

Keller, Corey J; Cash, Sydney S; Narayanan, Suresh; Wang, Chunmao; Kuzniecky, Ruben; Carlson, Chad; Devinsky, Orrin; Thesen, Thomas; Doyle, Werner; Sassaroli, Angelo; Boas, David A; Ulbert, Istvan; Halgren, Eric

2009-05-15

Measurement of the blood-oxygen-level dependent (BOLD) response with fMRI has revolutionized cognitive neuroscience and is increasingly important in clinical care. The BOLD response reflects changes in deoxy-hemoglobin concentration, blood volume, and blood flow. These hemodynamic changes ultimately result from neuronal firing and synaptic activity, but the linkage between these domains is complex, poorly understood, and may differ across species, cortical areas, diseases, and cognitive states. We describe here a technique that can measure neural and hemodynamic changes simultaneously from cortical microdomains in waking humans. We utilize a "laminar optode," a linear array of microelectrodes for electrophysiological measures paired with a micro-optical device for hemodynamic measurements. Optical measurements include laser Doppler to estimate cerebral blood flow as well as point spectroscopy to estimate oxy- and deoxy-hemoglobin concentrations. The microelectrode array records local field potential gradients (PG) and multi-unit activity (MUA) at 24 locations spanning the cortical depth, permitting estimation of population trans-membrane current flows (Current Source Density, CSD) and population cell firing in each cortical lamina. Comparison of the laminar CSD/MUA profile with the origins and terminations of cortical circuits allows activity in specific neuronal circuits to be inferred and then directly compared to hemodynamics. Access is obtained in epileptic patients during diagnostic evaluation for surgical therapy. Validation tests with relatively well-understood manipulations (EKG, breath-holding, cortical electrical stimulation) demonstrate the expected responses. This device can provide a new and robust means for obtaining detailed, quantitative data for defining neurovascular coupling in awake humans.

Toxicological Effects of the Different Substances in Tobacco Smoke on Human Embryonic Development by a Systems Chemo-Biology Approach

PubMed Central

Feltes, Bruno César; Poloni, Joice de Faria; Notari, Daniel Luis; Bonatto, Diego

2013-01-01

The physiological and molecular effects of tobacco smoke in adult humans and the development of cancer have been well described. In contrast, how tobacco smoke affects embryonic development remains poorly understood. Morphological studies of the fetuses of smoking pregnant women have shown various physical deformities induced by constant fetal exposure to tobacco components, especially nicotine. In addition, nicotine exposure decreases fetal body weight and bone/cartilage growth in addition to decreasing cranial diameter and tibia length. Unfortunately, the molecular pathways leading to these morphological anomalies are not completely understood. In this study, we applied interactome data mining tools and small compound interaction networks to elucidate possible molecular pathways associated with the effects of tobacco smoke components during embryonic development in pregnant female smokers. Our analysis showed a relationship between nicotine and 50 additional harmful substances involved in a variety of biological process that can cause abnormal proliferation, impaired cell differentiation, and increased oxidative stress. We also describe how nicotine can negatively affect retinoic acid signaling and cell differentiation through inhibition of retinoic acid receptors. In addition, nicotine causes a stress reaction and/or a pro-inflammatory response that inhibits the agonistic action of retinoic acid. Moreover, we show that the effect of cigarette smoke on the developing fetus could represent systemic and aggressive impacts in the short term, causing malformations during certain stages of development. Our work provides the first approach describing how different tobacco constituents affect a broad range of biological process in human embryonic development. PMID:23637898

Pigeons and humans use action and pose information to categorize complex human behaviors.

PubMed

Qadri, Muhammad A J; Cook, Robert G

2017-02-01

The biological mechanisms used to categorize and recognize behaviors are poorly understood in both human and non-human animals. Using animated digital models, we have recently shown that pigeons can categorize different locomotive animal gaits and types of complex human behaviors. In the current experiments, pigeons (go/no-go task) and humans (choice task) both learned to conditionally categorize two categories of human behaviors that did not repeat and were comprised of the coordinated motions of multiple limbs. These "martial arts" and "Indian dance" action sequences were depicted by a digital human model. Depending upon whether the model was in motion or not, each species was required to engage in different and opposing responses to the two behavioral categories. Both species learned to conditionally and correctly act on this dynamic and static behavioral information, indicating that both species use a combination of static pose cues that are available from stimulus onset in addition to less rapidly available action information in order to successfully discriminate between the behaviors. Human participants additionally demonstrated a bias towards the dynamic information in the display when re-learning the task. Theories that rely on generalized, non-specific visual mechanisms involving channels for motion and static cues offer a parsimonious account of how humans and pigeons recognize and categorize behaviors within and across species. Copyright © 2016 Elsevier Ltd. All rights reserved.

The spatiotemporal expansion of human rabies and its probable explanation in mainland China, 2004-2013.

PubMed

Yao, Hong-Wu; Yang, Yang; Liu, Kun; Li, Xin-Lou; Zuo, Shu-Qing; Sun, Ruo-Xi; Fang, Li-Qun; Cao, Wu-Chun

2015-02-01

Human rabies is a significant public health concern in mainland China. However, the neglect of rabies expansion and scarce analyses of the dynamics have made the spatiotemporal spread pattern of human rabies and its determinants being poorly understood. We collected geographic locations and timeline of reported human rabies cases, rabies sequences and socioeconomic variables for the years 2004-2013, and integrated multidisciplinary approaches, including epidemiological characterization, hotspots identification, risk factors analysis and phylogeographic inference, to explore the spread pattern of human rabies in mainland China during the last decade. The results show that human rabies distribution and hotspots were expanding from southeastern regions to north or west regions, which could be associated with the evolution of the virus, especially the clade I-G. A Panel Poisson Regression analysis reveals that human rabies incidences had significant correlation with the education level, GDP per capita, temperature at one-month lag and canine rabies outbreak at two-month lag. The reduction in the overall human rabies incidence was accompanied by a westward and northward expansion of the circulating region in mainland China. Higher risk of human rabies was associated with lower level of education and economic status. New clades of rabies, especial Clade I-G, played an important role in recent spread. Our findings provide valuable information for rabies control and prevention in the future.

The Spatiotemporal Expansion of Human Rabies and Its Probable Explanation in Mainland China, 2004-2013

PubMed Central

Yao, Hong-Wu; Yang, Yang; Liu, Kun; Li, Xin-Lou; Zuo, Shu-Qing; Sun, Ruo-Xi; Fang, Li-Qun; Cao, Wu-Chun

2015-01-01

Background Human rabies is a significant public health concern in mainland China. However, the neglect of rabies expansion and scarce analyses of the dynamics have made the spatiotemporal spread pattern of human rabies and its determinants being poorly understood. Methods We collected geographic locations and timeline of reported human rabies cases, rabies sequences and socioeconomic variables for the years 2004-2013, and integrated multidisciplinary approaches, including epidemiological characterization, hotspots identification, risk factors analysis and phylogeographic inference, to explore the spread pattern of human rabies in mainland China during the last decade. Results The results show that human rabies distribution and hotspots were expanding from southeastern regions to north or west regions, which could be associated with the evolution of the virus, especially the clade I-G. A Panel Poisson Regression analysis reveals that human rabies incidences had significant correlation with the education level, GDP per capita, temperature at one-month lag and canine rabies outbreak at two-month lag. Conclusions The reduction in the overall human rabies incidence was accompanied by a westward and northward expansion of the circulating region in mainland China. Higher risk of human rabies was associated with lower level of education and economic status. New clades of rabies, especial Clade I-G, played an important role in recent spread. Our findings provide valuable information for rabies control and prevention in the future. PMID:25692883

Stable isotopes reveal links between human food inputs and urban ant diets.

PubMed

Penick, Clint A; Savage, Amy M; Dunn, Robert R

2015-05-07

The amount of energy consumed within an average city block is an order of magnitude higher than that consumed in any other ecosystem over a similar area. This is driven by human food inputs, but the consequence of these resources for urban animal populations is poorly understood. We investigated the role of human foods in ant diets across an urbanization gradient in Manhattan using carbon and nitrogen stable isotopes. We found that some-but not all-ant species living in Manhattan's most urbanized habitats had δ(13)C signatures associated with processed human foods. In particular, pavement ants (Tetramorium sp. E) had increased levels of δ(13)C similar to δ(13)C levels in human fast foods. The magnitude of this effect was positively correlated with urbanization. By contrast, we detected no differences in δ(15)N, suggesting Tetramorium feeds at the same trophic level despite shifting to human foods. This pattern persisted across the broader ant community; species in traffic islands used human resources more than park species. Our results demonstrate that the degree urban ants exploit human resources changes across the city and among species, and this variation could play a key role in community structure and ecosystem processes where human and animal food webs intersect. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Perception of effort in Exercise Science: Definition, measurement and perspectives.

PubMed

Pageaux, Benjamin

2016-11-01

Perception of effort, also known as perceived exertion or sense of effort, can be described as a cognitive feeling of work associated with voluntary actions. The aim of the present review is to provide an overview of what is perception of effort in Exercise Science. Due to the addition of sensations other than effort in its definition, the neurophysiology of perceived exertion remains poorly understood. As humans have the ability to dissociate effort from other sensations related to physical exercise, the need to use a narrower definition is emphasised. Consequently, a definition and some brief guidelines for its measurement are provided. Finally, an overview of the models present in the literature aiming to explain its neurophysiology, and some perspectives for future research are offered.

Human casualties in earthquakes: Modelling and mitigation

USGS Publications Warehouse

Spence, R.J.S.; So, E.K.M.

2011-01-01

Earthquake risk modelling is needed for the planning of post-event emergency operations, for the development of insurance schemes, for the planning of mitigation measures in the existing building stock, and for the development of appropriate building regulations; in all of these applications estimates of casualty numbers are essential. But there are many questions about casualty estimation which are still poorly understood. These questions relate to the causes and nature of the injuries and deaths, and the extent to which they can be quantified. This paper looks at the evidence on these questions from recent studies. It then reviews casualty estimation models available, and finally compares the performance of some casualty models in making rapid post-event casualty estimates in recent earthquakes.

Tracking the global footprint of fisheries

NASA Astrophysics Data System (ADS)

Kroodsma, David A.; Mayorga, Juan; Hochberg, Timothy; Miller, Nathan A.; Boerder, Kristina; Ferretti, Francesco; Wilson, Alex; Bergman, Bjorn; White, Timothy D.; Block, Barbara A.; Woods, Paul; Sullivan, Brian; Costello, Christopher; Worm, Boris

2018-02-01

Although fishing is one of the most widespread activities by which humans harvest natural resources, its global footprint is poorly understood and has never been directly quantified. We processed 22 billion automatic identification system messages and tracked >70,000 industrial fishing vessels from 2012 to 2016, creating a global dynamic footprint of fishing effort with spatial and temporal resolution two to three orders of magnitude higher than for previous data sets. Our data show that industrial fishing occurs in >55% of ocean area and has a spatial extent more than four times that of agriculture. We find that global patterns of fishing have surprisingly low sensitivity to short-term economic and environmental variation and a strong response to cultural and political events such as holidays and closures.

Cocoa Bioactive Compounds: Significance and Potential for the Maintenance of Skin Health

PubMed Central

Scapagnini, Giovanni; Davinelli, Sergio; Di Renzo, Laura; De Lorenzo, Antonino; Olarte, Hector Hugo; Micali, Giuseppe; Cicero, Arrigo F.; Gonzalez, Salvador

2014-01-01

Cocoa has a rich history in human use. Skin is prone to the development of several diseases, and the mechanisms in the pathogenesis of aged skin are still poorly understood. However, a growing body of evidence from clinical and bench research has begun to provide scientific validation for the use of cocoa-derived phytochemicals as an effective approach for skin protection. Although the specific molecular and cellular mechanisms of the beneficial actions of cocoa phytochemicals remain to be elucidated, this review will provide an overview of the current literature emphasizing potential cytoprotective pathways modulated by cocoa and its polyphenolic components. Moreover, we will summarize in vivo studies showing that bioactive compounds of cocoa may have a positive impact on skin health. PMID:25116848

GABAergic anxiolytic drug in water increases migration behaviour in salmon

NASA Astrophysics Data System (ADS)

Hellström, Gustav; Klaminder, Jonatan; Finn, Fia; Persson, Lo; Alanärä, Anders; Jonsson, Micael; Fick, Jerker; Brodin, Tomas

2016-12-01

Migration is an important life-history event in a wide range of taxa, yet many migrations are influenced by anthropogenic change. Although migration dynamics are extensively studied, the potential effects of environmental contaminants on migratory physiology are poorly understood. In this study we show that an anxiolytic drug in water can promote downward migratory behaviour of Atlantic salmon (Salmo salar) in both laboratory setting and in a natural river tributary. Exposing salmon smolt to a dilute concentration of a GABAA receptor agonist (oxazepam) increased migration intensity compared with untreated smolt. These results implicate that salmon migration may be affected by human-induced changes in water chemical properties, such as acidification and pharmaceutical residues in wastewater effluent, via alterations in the GABAA receptor function.

Astrocytic calcium activation in a mouse model of tDCS—Extended discussion

PubMed Central

Monai, Hiromu; Hirase, Hajime

2016-01-01

ABSTRACT Transcranial direct current stimulation (tDCS) has been reported to be effective for alleviation of neuropsychiatric and neurological conditions as well as enhancement of memory and cognition. Despite the positive effects of tDCS in humans, its mechanism of action remains poorly understood. Recently, we reported that astrocytes, a major glial cell type in the brain, show an increase in intracellular Ca2+ levels during tDCS in the cerebral cortex of the awake mouse. This tDCS-induced elevation in astrocytic Ca2+ has subsequently been demonstrated to be important for cortical plasticity. In this commentary article, we discuss possible interpretations and implications of our findings from the viewpoint of neuron-glia interactions. PMID:27830161

Regulation of the catalytic activity of the EGF receptor

PubMed Central

Endres, Nicholas F.; Engel, Kate; Das, Rahul; Kovacs, Erika; Kuriyan, John

2011-01-01

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in cell growth that is often misregulated in cancer. Several recent studies highlight the unique structural mechanisms involved in its regulation. Some elucidate the important role that the juxtamembrane segment and the transmembrane helix play in stabilizing the activating asymmetric kinase dimer, and suggest that its activation mechanism is likely to be conserved amongst the other human EGFR-related receptors. Other studies provide new explanations for two long observed, but poorly understood phenomena, the apparent heterogeneity in ligand binding and the formation of ligand-independent dimers. New insights into the allosteric mechanisms utilized by intracellular regulators of EGFR provide hope that allosteric sites could be used as targets for drug development. PMID:21868214

Yersinia vs. host Immunity: how a pathogen evades or triggers a protective response

PubMed Central

Chung, Lawton K.; Bliska, James B.

2015-01-01

The human pathogenic Yersinia species cause diseases that represent a significant source of morbidity and mortality. Despite this, specific mechanisms underlying Yersinia pathogenesis and protective host responses remain poorly understood. Recent studies have shown that Yersinia disrupt cell death pathways, perturb inflammatory processes and exploit immune cells to promote disease. The ensuing host responses following Yersinia infection include coordination of innate and adaptive immune responses in an attempt to control bacterial replication. Here, we highlight current advances in our understanding of the interactions between the pathogenic yersiniae and host cells, as well as the protective host responses mobilized to counteract these pathogens. Together, these studies enhance our understanding of Yersinia pathogenesis and highlight the ongoing battle between host and microbe. PMID:26638030

Evolution of a sediment wave in an experimental channel

Treesearch

Thomas E. Lisle; James E. Pizzuto; Hiroshi Ikeda; Fujiko Iseya; Yoshinori Kodama

1997-01-01

Abstract - The routing of bed material through channels is poorly understood. We approach the problem by observing and modeling the fate of a low-amplitude sediment wave of poorly sorted sand that we introduced into an experimental channel transporting sediment identical to that of the introduced wave. The wave essentially dispersed upstream and downstream without...

Independent Learning--What We Do When You're Not There

ERIC Educational Resources Information Center

Hockings, Christine; Thomas, Liz; Ottaway, Jim; Jones, Rob

2018-01-01

Independent learning is one of the cornerstones of UK higher education yet it is poorly understood by students and is seen by politicians as a poor substitute for face to face teaching. This paper explores students' understandings, approaches and experiences of independent learning and how they may become more effective independent learners. This…

The role of bedrock groundwater in rainfall-runoff response at hillslope and catchment scales

Treesearch

C. Gabrielli; J.J. McDonnell; W.T. Jarvis

2012-01-01

Bedrock groundwater dynamics in headwater catchments are poorly understood and poorly characterized. Direct hydrometric measurements have been limited due to the logistical challenges associated with drilling through hard rock in steep, remote and often roadless terrain. We used a new portable bedrock drilling system to explore bedrock groundwater dynamics aimed at...

Asian and Pacific Islander American Poverty: The Working Poor and the Jobless Poor.

ERIC Educational Resources Information Center

Toji, Dean S.; Johnson, James H.

1992-01-01

Assesses the incidence of Asian-American and Pacific Islander-American poverty, and offers a theoretical explanation for its existence. It is argued that poverty of Americans of Asian and Pacific Island descent is best understood in the context of the linkage of labor migration and U.S. labor market segmentation. (SLD)

Neural and Synaptic Defects in slytherin a Zebrafish Model for Human Congenital Disorders of Glycosylation

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

Y Song; J Willer; P Scherer

2011-12-31

Congenital disorder of glycosylation type IIc (CDG IIc) is characterized by mental retardation, slowed growth and severe immunodeficiency, attributed to the lack of fucosylated glycoproteins. While impaired Notch signaling has been implicated in some aspects of CDG IIc pathogenesis, the molecular and cellular mechanisms remain poorly understood. We have identified a zebrafish mutant slytherin (srn), which harbors a missense point mutation in GDP-mannose 4,6 dehydratase (GMDS), the rate-limiting enzyme in protein fucosylation, including that of Notch. Here we report that some of the mechanisms underlying the neural phenotypes in srn and in CGD IIc are Notch-dependent, while others are Notch-independent.more » We show, for the first time in a vertebrate in vivo, that defects in protein fucosylation leads to defects in neuronal differentiation, maintenance, axon branching, and synapse formation. Srn is thus a useful and important vertebrate model for human CDG IIc that has provided new insights into the neural phenotypes that are hallmarks of the human disorder and has also highlighted the role of protein fucosylation in neural development.« less

Genotype-dependent Molecular Evolution of Sheep Bovine Spongiform Encephalopathy (BSE) Prions in Vitro Affects Their Zoonotic Potential*

PubMed Central

Krejciova, Zuzana; Barria, Marcelo A.; Jones, Michael; Ironside, James W.; Jeffrey, Martin; González, Lorenzo; Head, Mark W.

2014-01-01

Prion diseases are rare fatal neurological conditions of humans and animals, one of which (variant Creutzfeldt-Jakob disease) is known to be a zoonotic form of the cattle disease bovine spongiform encephalopathy (BSE). What makes one animal prion disease zoonotic and others not is poorly understood, but it appears to involve compatibility between the prion strain and the host prion protein sequence. Concerns have been raised that the United Kingdom sheep flock may have been exposed to BSE early in the cattle BSE epidemic and that serial BSE transmission in sheep might have resulted in adaptation of the agent, which may have come to phenotypically resemble scrapie while maintaining its pathogenicity for humans. We have modeled this scenario in vitro. Extrapolation from our results suggests that if BSE were to infect sheep in the field it may, with time and in some sheep genotypes, become scrapie-like at the molecular level. However, the results also suggest that if BSE in sheep were to come to resemble scrapie it would lose its ability to affect humans. PMID:25100723

Functional neuroanatomy of human voluntary cough and sniff production

PubMed Central

Simonyan, Kristina; Saad, Ziad S.; Loucks, Torrey M.J.; Poletto, Christopher J.; Ludlow, Christy L.

2007-01-01

Cough and sniff are both spontaneous respiratory behaviors that can be initiated voluntarily in humans. Disturbances of cough may be life threatening, while inability to sniff impairs the sense of smell in neurological patients. Cortical mechanisms of voluntary cough and sniff production have been predicted to exist; however, the localization and function of supramedullary areas responsible for these behaviors are poorly understood. We used functional magnetic resonance imaging to identify the central control of voluntary cough and sniff compared with breathing. We determined that both voluntary cough and sniff require a widespread pattern of sensorimotor activation along the Sylvian fissure convergent with voluntary breathing. Task-specific activation occurred in a ponto-mesencephalic region during voluntary coughing and in the hippocampus and piriform cortex during voluntary sniffing. Identification of the localization of cortical activation for cough control in humans may help potential drug development to target these regions in patients with chronic cough. Understanding the sensorimotor sniff control mechanisms may provide a new view on the cerebral functional reorganization of olfactory control in patients with neurological disorders. PMID:17574873

Eye movement sequence generation in humans: Motor or goal updating?

PubMed Central

Quaia, Christian; Joiner, Wilsaan M.; FitzGibbon, Edmond J.; Optican, Lance M.; Smith, Maurice A.

2011-01-01

Saccadic eye movements are often grouped in pre-programmed sequences. The mechanism underlying the generation of each saccade in a sequence is currently poorly understood. Broadly speaking, two alternative schemes are possible: first, after each saccade the retinotopic location of the next target could be estimated, and an appropriate saccade could be generated. We call this the goal updating hypothesis. Alternatively, multiple motor plans could be pre-computed, and they could then be updated after each movement. We call this the motor updating hypothesis. We used McLaughlin’s intra-saccadic step paradigm to artificially create a condition under which these two hypotheses make discriminable predictions. We found that in human subjects, when sequences of two saccades are planned, the motor updating hypothesis predicts the landing position of the second saccade in two-saccade sequences much better than the goal updating hypothesis. This finding suggests that the human saccadic system is capable of executing sequences of saccades to multiple targets by planning multiple motor commands, which are then updated by serial subtraction of ongoing motor output. PMID:21191134

A Scaled Framework for CRISPR Editing of Human Pluripotent Stem Cells to Study Psychiatric Disease.

PubMed

Hazelbaker, Dane Z; Beccard, Amanda; Bara, Anne M; Dabkowski, Nicole; Messana, Angelica; Mazzucato, Patrizia; Lam, Daisy; Manning, Danielle; Eggan, Kevin; Barrett, Lindy E

2017-10-10

Scaling of CRISPR-Cas9 technology in human pluripotent stem cells (hPSCs) represents an important step for modeling complex disease and developing drug screens in human cells. However, variables affecting the scaling efficiency of gene editing in hPSCs remain poorly understood. Here, we report a standardized CRISPR-Cas9 approach, with robust benchmarking at each step, to successfully target and genotype a set of psychiatric disease-implicated genes in hPSCs and provide a resource of edited hPSC lines for six of these genes. We found that transcriptional state and nucleosome positioning around targeted loci was not correlated with editing efficiency. However, editing frequencies varied between different hPSC lines and correlated with genomic stability, underscoring the need for careful cell line selection and unbiased assessments of genomic integrity. Together, our step-by-step quantification and in-depth analyses provide an experimental roadmap for scaling Cas9-mediated editing in hPSCs to study psychiatric disease, with broader applicability for other polygenic diseases. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The ortholog of the human proto-oncogene ROS1 is required for epithelial development in C. elegans

PubMed Central

Jones, Martin R; Rose, Ann M; Baillie, David L

2013-01-01

The orphan receptor ROS1 is a human proto-oncogene, mutations of which are found in an increasing number of cancers. Little is known about the role of ROS1, however in vertebrates it has been implicated in promoting differentiation programs in specialized epithelial tissues. In this study we show that the C. elegans ortholog of ROS1, the receptor tyrosine kinase ROL-3, has an essential role in orchestrating the morphogenesis and development of specialized epidermal tissues, highlighting a potentially conserved function in coordinating crosstalk between developing epithelial cells. We also provide evidence of a direct relationship between ROL-3, the mucin SRAP-1, and BCC-1, the homolog of mRNA regulating protein Bicaudal-C. This study answers a longstanding question as to the developmental function of ROL-3, identifies three new genes that are expressed and function in the developing epithelium of C. elegans, and introduces the nematode as a potentially powerful model system for investigating the increasingly important, yet poorly understood, human oncogene ROS1. genesis 51:545–561. PMID:23733356

Human chromokinesins promote chromosome congression and spindle microtubule dynamics during mitosis

PubMed Central

Wandke, Cornelia; Barisic, Marin; Sigl, Reinhard; Rauch, Veronika; Wolf, Frank; Amaro, Ana C.; Tan, Chia H.; Pereira, Antonio J.; Kutay, Ulrike; Maiato, Helder; Meraldi, Patrick

2012-01-01

Chromokinesins are microtubule plus end–directed motor proteins that bind to chromosome arms. In Xenopus egg cell-free extracts, Xkid and Xklp1 are essential for bipolar spindle formation but the functions of the human homologues, hKID (KIF22) and KIF4A, are poorly understood. By using RNAi-mediated protein knockdown in human cells, we find that only co-depletion delayed progression through mitosis in a Mad2-dependent manner. Depletion of hKID caused abnormal chromosome arm orientation, delayed chromosome congression, and sensitized cells to nocodazole. Knockdown of KIF4A increased the number and length of microtubules, altered kinetochore oscillations, and decreased kinetochore microtubule flux. These changes were associated with failures in establishing a tight metaphase plate and an increase in anaphase lagging chromosomes. Co-depletion of both chromokinesins aggravated chromosome attachment failures, which led to mitotic arrest. Thus, hKID and KIF4A contribute independently to the rapid and correct attachment of chromosomes by controlling the positioning of chromosome arms and the dynamics of microtubules, respectively. PMID:22945934

Arsenic Induces p62 Expression to Form a Positive Feedback Loop with Nrf2 in Human Epidermal Keratinocytes: Implications for Preventing Arsenic-Induced Skin Cancer.

PubMed

Shah, Palak; Trinh, Elaine; Qiang, Lei; Xie, Lishi; Hu, Wen-Yang; Prins, Gail S; Pi, Jingbo; He, Yu-Ying

2017-01-24

Exposure to inorganic arsenic in contaminated drinking water poses an environmental public health threat for hundreds of millions of people in the US and around the world. Arsenic is a known carcinogen for skin cancer. However, the mechanism by which arsenic induces skin cancer remains poorly understood. Here, we have shown that arsenic induces p62 expression in an autophagy-independent manner in human HaCaT keratinocytes. In mouse skin, chronic arsenic exposure through drinking water increases p62 protein levels in the epidermis. Nrf2 is required for basal and arsenic-induced p62 up-regulation. p62 knockdown reduces arsenic-induced Nrf2 activity, and induces sustained p21 up-regulation. p62 induction is associated with increased proliferation in mouse epidermis. p62 knockdown had little effect on arsenic-induced apoptosis, while it decreased cell proliferation following arsenic treatment. Our findings indicate that arsenic induces p62 expression to regulate the Nrf2 pathway in human keratinocytes and suggest that targeting p62 may help prevent arsenic-induced skin cancer.

Tumour necrosis factor-alpha-induced protein 8 (TNFAIP8) expression associated with cell survival and death in cancer cell lines infected with canine distemper virus.

PubMed

Garcia, J A; Ferreira, H L; Vieira, F V; Gameiro, R; Andrade, A L; Eugênio, F R; Flores, E F; Cardoso, T C

2017-06-01

Oncolytic virotherapy is a novel strategy for treatment of cancer in humans and companion animals as well. Canine distemper virus (CDV), a paramyxovirus, has proven to be oncolytic through induction of apoptosis in canine-derived tumour cells, yet the mechanism behind this inhibitory action is poorly understood. In this study, three human mammary tumour cell lines and one canine-derived adenofibrosarcoma cell line were tested regarding to their susceptibility to CDV infection, cell proliferation, apoptosis, mitochondrial membrane potential and expression of tumour necrosis factor-alpha-induced protein 8 (TNFAIP8). CDV replication-induced cytopathic effect, decrease of cell proliferation rates, and >45% of infected cells were considered death and/or under late apoptosis/necrosis. TNFAIP8 and CDVM gene expression were positively correlated in all cell lines. In addition, mitochondrial membrane depolarization was associated with increase in virus titres (p < 0.005). Thus, these results strongly suggest that both human and canine mammary tumour cells are potential candidates for studies concerning CDV-induced cancer therapy. © 2015 John Wiley & Sons Ltd.

Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci

PubMed Central

Philippe, Claude; Vargas-Landin, Dulce B; Doucet, Aurélien J; van Essen, Dominic; Vera-Otarola, Jorge; Kuciak, Monika; Corbin, Antoine; Nigumann, Pilvi; Cristofari, Gaël

2016-01-01

LINE-1 (L1) retrotransposons represent approximately one sixth of the human genome, but only the human-specific L1HS-Ta subfamily acts as an endogenous mutagen in modern humans, reshaping both somatic and germline genomes. Due to their high levels of sequence identity and the existence of many polymorphic insertions absent from the reference genome, the transcriptional activation of individual genomic L1HS-Ta copies remains poorly understood. Here we comprehensively mapped fixed and polymorphic L1HS-Ta copies in 12 commonly-used somatic cell lines, and identified transcriptional and epigenetic signatures allowing the unambiguous identification of active L1HS-Ta copies in their genomic context. Strikingly, only a very restricted subset of L1HS-Ta loci - some being polymorphic among individuals - significantly contributes to the bulk of L1 expression, and these loci are differentially regulated among distinct cell lines. Thus, our data support a local model of L1 transcriptional activation in somatic cells, governed by individual-, locus-, and cell-type-specific determinants. DOI: http://dx.doi.org/10.7554/eLife.13926.001 PMID:27016617

Solubilization of human cells by the styrene-maleic acid copolymer: Insights from fluorescence microscopy.

PubMed

Dörr, Jonas M; van Coevorden-Hameete, Marleen H; Hoogenraad, Casper C; Killian, J Antoinette

2017-11-01

Extracting membrane proteins from biological membranes by styrene-maleic acid copolymers (SMAs) in the form of nanodiscs has developed into a powerful tool in membrane research. However, the mode of action of membrane (protein) solubilization in a cellular context is still poorly understood and potential specificity for cellular compartments has not been investigated. Here, we use fluorescence microscopy to visualize the process of SMA solubilization of human cells, exemplified by the immortalized human HeLa cell line. Using fluorescent protein fusion constructs that mark distinct subcellular compartments, we found that SMA solubilizes membranes in a concentration-dependent multi-stage process. While all major intracellular compartments were affected without a strong preference, plasma membrane solubilization was found to be generally slower than the solubilization of organelle membranes. Interestingly, some plasma membrane-localized proteins were more resistant against solubilization than others, which might be explained by their presence in specific membrane domains with differing properties. Our results support the general applicability of SMA for the isolation of membrane proteins from different types of (sub)cellular membranes. Copyright © 2017 Elsevier B.V. All rights reserved.

Structural and functional analysis of mRNA export regulation by the nuclear pore complex.

PubMed

Lin, Daniel H; Correia, Ana R; Cai, Sarah W; Huber, Ferdinand M; Jette, Claudia A; Hoelz, André

2018-06-13

The nuclear pore complex (NPC) controls the passage of macromolecules between the nucleus and cytoplasm, but how the NPC directly participates in macromolecular transport remains poorly understood. In the final step of mRNA export, the DEAD-box helicase DDX19 is activated by the nucleoporins Gle1, Nup214, and Nup42 to remove Nxf1•Nxt1 from mRNAs. Here, we report crystal structures of Gle1•Nup42 from three organisms that reveal an evolutionarily conserved binding mode. Biochemical reconstitution of the DDX19 ATPase cycle establishes that human DDX19 activation does not require IP 6 , unlike its fungal homologs, and that Gle1 stability affects DDX19 activation. Mutations linked to motor neuron diseases cause decreased Gle1 thermostability, implicating nucleoporin misfolding as a disease determinant. Crystal structures of human Gle1•Nup42•DDX19 reveal the structural rearrangements in DDX19 from an auto-inhibited to an RNA-binding competent state. Together, our results provide the foundation for further mechanistic analyses of mRNA export in humans.

C/EBPβ Promotes Immunity to Oral Candidiasis through Regulation of β-Defensins

PubMed Central

Simpson-Abelson, Michelle R.; Childs, Erin E.; Ferreira, M. Carolina; Bishu, Shrinivas; Conti, Heather R.; Gaffen, Sarah L.

2015-01-01

Humans or mice subjected to immunosuppression, such as corticosteroids or anti-cytokine biologic therapies, are susceptible to mucosal infections by the commensal fungus Candida albicans. Recently it has become evident that the Th17/IL-17 axis is essential for immunity to candidiasis, but the downstream events that control immunity to this fungus are poorly understood. The CCAAT/Enhancer Binding Protein-β (C/EBPβ) transcription factor is important for signaling by multiple inflammatory stimuli, including IL-17. C/EBPβ is regulated in a variety of ways by IL-17, and controls several downstream IL-17 target genes. However, the role of C/EBPβ in vivo is poorly understood, in part because C/EBPβ-deficient mice are challenging to breed and work with. In this study, we sought to understand the role of C/EBPβ in the context of an IL-17-dependent immune response, using C. albicans infection as a model system. Confirming prior findings, we found that C/EBPβ is required for immunity to systemic candidiasis. In contrast, C/EBPβ-/- mice were resistant to oropharyngeal candidiasis (OPC), in a manner indistinguishable from immunocompetent WT mice. However, C/EBPβ-/- mice experienced more severe OPC than WT mice in the context of cortisone-induced immunosuppression. Expression of the antimicrobial peptide β-defensin (BD)-3 correlated strongly with susceptibility in C/EBPβ-/- mice, but no other IL-17-dependent genes were associated with susceptibility. Therefore, C/EBPβ contributes to immunity to mucosal candidiasis during cortisone immunosuppression in a manner linked to β-defensin 3 expression, but is apparently dispensable for the IL-17-dependent response. PMID:26317211

C/EBPβ Promotes Immunity to Oral Candidiasis through Regulation of β-Defensins.

PubMed

Simpson-Abelson, Michelle R; Childs, Erin E; Ferreira, M Carolina; Bishu, Shrinivas; Conti, Heather R; Gaffen, Sarah L

2015-01-01

Humans or mice subjected to immunosuppression, such as corticosteroids or anti-cytokine biologic therapies, are susceptible to mucosal infections by the commensal fungus Candida albicans. Recently it has become evident that the Th17/IL-17 axis is essential for immunity to candidiasis, but the downstream events that control immunity to this fungus are poorly understood. The CCAAT/Enhancer Binding Protein-β (C/EBPβ) transcription factor is important for signaling by multiple inflammatory stimuli, including IL-17. C/EBPβ is regulated in a variety of ways by IL-17, and controls several downstream IL-17 target genes. However, the role of C/EBPβ in vivo is poorly understood, in part because C/EBPβ-deficient mice are challenging to breed and work with. In this study, we sought to understand the role of C/EBPβ in the context of an IL-17-dependent immune response, using C. albicans infection as a model system. Confirming prior findings, we found that C/EBPβ is required for immunity to systemic candidiasis. In contrast, C/EBPβ(-/-) mice were resistant to oropharyngeal candidiasis (OPC), in a manner indistinguishable from immunocompetent WT mice. However, C/EBPβ(-/-) mice experienced more severe OPC than WT mice in the context of cortisone-induced immunosuppression. Expression of the antimicrobial peptide β-defensin (BD)-3 correlated strongly with susceptibility in C/EBPβ(-/-) mice, but no other IL-17-dependent genes were associated with susceptibility. Therefore, C/EBPβ contributes to immunity to mucosal candidiasis during cortisone immunosuppression in a manner linked to β-defensin 3 expression, but is apparently dispensable for the IL-17-dependent response.

Lags in the response of mountain plant communities to climate change.

PubMed

Alexander, Jake M; Chalmandrier, Loïc; Lenoir, Jonathan; Burgess, Treena I; Essl, Franz; Haider, Sylvia; Kueffer, Christoph; McDougall, Keith; Milbau, Ann; Nuñez, Martin A; Pauchard, Aníbal; Rabitsch, Wolfgang; Rew, Lisa J; Sanders, Nathan J; Pellissier, Loïc

2018-02-01

Rapid climatic changes and increasing human influence at high elevations around the world will have profound impacts on mountain biodiversity. However, forecasts from statistical models (e.g. species distribution models) rarely consider that plant community changes could substantially lag behind climatic changes, hindering our ability to make temporally realistic projections for the coming century. Indeed, the magnitudes of lags, and the relative importance of the different factors giving rise to them, remain poorly understood. We review evidence for three types of lag: "dispersal lags" affecting plant species' spread along elevational gradients, "establishment lags" following their arrival in recipient communities, and "extinction lags" of resident species. Variation in lags is explained by variation among species in physiological and demographic responses, by effects of altered biotic interactions, and by aspects of the physical environment. Of these, altered biotic interactions could contribute substantially to establishment and extinction lags, yet impacts of biotic interactions on range dynamics are poorly understood. We develop a mechanistic community model to illustrate how species turnover in future communities might lag behind simple expectations based on species' range shifts with unlimited dispersal. The model shows a combined contribution of altered biotic interactions and dispersal lags to plant community turnover along an elevational gradient following climate warming. Our review and simulation support the view that accounting for disequilibrium range dynamics will be essential for realistic forecasts of patterns of biodiversity under climate change, with implications for the conservation of mountain species and the ecosystem functions they provide. © 2017 John Wiley & Sons Ltd.

Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation.

PubMed

Chu, Chung-Ching; Ali, Niwa; Karagiannis, Panagiotis; Di Meglio, Paola; Skowera, Ania; Napolitano, Luca; Barinaga, Guillermo; Grys, Katarzyna; Sharif-Paghaleh, Ehsan; Karagiannis, Sophia N; Peakman, Mark; Lombardi, Giovanna; Nestle, Frank O

2012-05-07

Human skin immune homeostasis, and its regulation by specialized subsets of tissue-residing immune sentinels, is poorly understood. In this study, we identify an immunoregulatory tissue-resident dendritic cell (DC) in the dermis of human skin that is characterized by surface expression of CD141, CD14, and constitutive IL-10 secretion (CD141(+) DDCs). CD141(+) DDCs possess lymph node migratory capacity, induce T cell hyporesponsiveness, cross-present self-antigens to autoreactive T cells, and induce potent regulatory T cells that inhibit skin inflammation. Vitamin D(3) (VitD3) promotes certain phenotypic and functional properties of tissue-resident CD141(+) DDCs from human blood DCs. These CD141(+) DDC-like cells can be generated in vitro and, once transferred in vivo, have the capacity to inhibit xeno-graft versus host disease and tumor alloimmunity. These findings suggest that CD141(+) DDCs play an essential role in the maintenance of skin homeostasis and in the regulation of both systemic and tumor alloimmunity. Finally, VitD3-induced CD141(+) DDC-like cells have potential clinical use for their capacity to induce immune tolerance.

Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation

PubMed Central

Chu, Chung-Ching; Ali, Niwa; Karagiannis, Panagiotis; Di Meglio, Paola; Skowera, Ania; Napolitano, Luca; Barinaga, Guillermo; Grys, Katarzyna; Sharif-Paghaleh, Ehsan; Karagiannis, Sophia N.; Peakman, Mark; Lombardi, Giovanna

2012-01-01

Human skin immune homeostasis, and its regulation by specialized subsets of tissue-residing immune sentinels, is poorly understood. In this study, we identify an immunoregulatory tissue-resident dendritic cell (DC) in the dermis of human skin that is characterized by surface expression of CD141, CD14, and constitutive IL-10 secretion (CD141+ DDCs). CD141+ DDCs possess lymph node migratory capacity, induce T cell hyporesponsiveness, cross-present self-antigens to autoreactive T cells, and induce potent regulatory T cells that inhibit skin inflammation. Vitamin D3 (VitD3) promotes certain phenotypic and functional properties of tissue-resident CD141+ DDCs from human blood DCs. These CD141+ DDC-like cells can be generated in vitro and, once transferred in vivo, have the capacity to inhibit xeno-graft versus host disease and tumor alloimmunity. These findings suggest that CD141+ DDCs play an essential role in the maintenance of skin homeostasis and in the regulation of both systemic and tumor alloimmunity. Finally, VitD3-induced CD141+ DDC-like cells have potential clinical use for their capacity to induce immune tolerance. PMID:22547651

Piezo1 regulates mechanotransductive release of ATP from human RBCs.

PubMed

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

2015-09-22

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

A mechanical model predicts morphological abnormalities in the developing human brain

NASA Astrophysics Data System (ADS)

Budday, Silvia; Raybaud, Charles; Kuhl, Ellen

2014-07-01

The developing human brain remains one of the few unsolved mysteries of science. Advancements in developmental biology, neuroscience, and medical imaging have brought us closer than ever to understand brain development in health and disease. However, the precise role of mechanics throughout this process remains underestimated and poorly understood. Here we show that mechanical stretch plays a crucial role in brain development. Using the nonlinear field theories of mechanics supplemented by the theory of finite growth, we model the human brain as a living system with a morphogenetically growing outer surface and a stretch-driven growing inner core. This approach seamlessly integrates the two popular but competing hypotheses for cortical folding: axonal tension and differential growth. We calibrate our model using magnetic resonance images from very preterm neonates. Our model predicts that deviations in cortical growth and thickness induce morphological abnormalities. Using the gyrification index, the ratio between the total and exposed surface area, we demonstrate that these abnormalities agree with the classical pathologies of lissencephaly and polymicrogyria. Understanding the mechanisms of cortical folding in the developing human brain has direct implications in the diagnostics and treatment of neurological disorders, including epilepsy, schizophrenia, and autism.

A framework for the study of zoonotic disease emergence and its drivers: spillover of bat pathogens as a case study

PubMed Central

Wood, James L. N.; Leach, Melissa; Waldman, Linda; MacGregor, Hayley; Fooks, Anthony R.; Jones, Kate E.; Restif, Olivier; Dechmann, Dina; Hayman, David T. S.; Baker, Kate S.; Peel, Alison J.; Kamins, Alexandra O.; Fahr, Jakob; Ntiamoa-Baidu, Yaa; Suu-Ire, Richard; Breiman, Robert F.; Epstein, Jonathan H.; Field, Hume E.; Cunningham, Andrew A.

2012-01-01

Many serious emerging zoonotic infections have recently arisen from bats, including Ebola, Marburg, SARS-coronavirus, Hendra, Nipah, and a number of rabies and rabies-related viruses, consistent with the overall observation that wildlife are an important source of emerging zoonoses for the human population. Mechanisms underlying the recognized association between ecosystem health and human health remain poorly understood and responding appropriately to the ecological, social and economic conditions that facilitate disease emergence and transmission represents a substantial societal challenge. In the context of disease emergence from wildlife, wildlife and habitat should be conserved, which in turn will preserve vital ecosystem structure and function, which has broader implications for human wellbeing and environmental sustainability, while simultaneously minimizing the spillover of pathogens from wild animals into human beings. In this review, we propose a novel framework for the holistic and interdisciplinary investigation of zoonotic disease emergence and its drivers, using the spillover of bat pathogens as a case study. This study has been developed to gain a detailed interdisciplinary understanding, and it combines cutting-edge perspectives from both natural and social sciences, linked to policy impacts on public health, land use and conservation. PMID:22966143

The status of tularemia in Europe in a one-health context: a review.

PubMed

Hestvik, G; Warns-Petit, E; Smith, L A; Fox, N J; Uhlhorn, H; Artois, M; Hannant, D; Hutchings, M R; Mattsson, R; Yon, L; Gavier-Widen, D

2015-07-01

The bacterium Francisella tularensis causes the vector-borne zoonotic disease tularemia, and may infect a wide range of hosts including invertebrates, mammals and birds. Transmission to humans occurs through contact with infected animals or contaminated environments, or through arthropod vectors. Tularemia has a broad geographical distribution, and there is evidence which suggests local emergence or re-emergence of this disease in Europe. This review was developed to provide an update on the geographical distribution of F. tularensis in humans, wildlife, domestic animals and vector species, to identify potential public health hazards, and to characterize the epidemiology of tularemia in Europe. Information was collated on cases in humans, domestic animals and wildlife, and on reports of detection of the bacterium in arthropod vectors, from 38 European countries for the period 1992-2012. Multiple international databases on human and animal health were consulted, as well as published reports in the literature. Tularemia is a disease of complex epidemiology that is challenging to understand and therefore to control. Many aspects of this disease remain poorly understood. Better understanding is needed of the epidemiological role of animal hosts, potential vectors, mechanisms of maintenance in the different ecosystems, and routes of transmission of the disease.

Gemfibrozil, a lipid lowering drug, inhibits the activation of primary human microglia via peroxisome proliferator-activated receptor β.

PubMed

Jana, Malabendu; Pahan, Kalipada

2012-08-01

Microglial activation participates in the pathogenesis of various neuroinflammatory and neurodegenerative diseases. However, mechanisms by which microglial activation could be controlled are poorly understood. Peroxisome proliferator-activated receptors (PPAR) are transcription factors belonging to the nuclear receptor super family with diverse effect. This study underlines the importance of PPARβ/δ in mediating the anti-inflammatory effect of gemfibrozil, an FDA-approved lipid-lowering drug, in primary human microglia. Bacterial lipopolysachharides (LPS) induced the expression of various proinflammatory molecules and upregulated the expression of microglial surface marker CD11b in human microglia. However, gemfibrozil markedly suppressed proinflammatory molecules and CD11b in LPS-stimulated microglia. Human microglia expressed PPAR-β and -γ, but not PPAR-α. Interestingly, either antisense knockdown of PPAR-β or antagonism of PPAR-β by a specific chemical antagonist abrogated gemfibrozil-mediated inhibition of microglial activation. On the other hand, blocking of PPAR-α and -γ had no effect on gemfibrozil-mediated anti-inflammatory effect in microglia. These results highlight the fact that gemfibrozil regulates microglial activation by inhibiting inflammatory gene expression in a PPAR-β dependent pathway and further reinforce its therapeutic application in several neuroinflammatory and neurodegenerative diseases.

Linkage disequilibrium between STRPs and SNPs across the human genome.

PubMed

Payseur, Bret A; Place, Michael; Weber, James L

2008-05-01

Patterns of linkage disequilibrium (LD) reveal the action of evolutionary processes and provide crucial information for association mapping of disease genes. Although recent studies have described the landscape of LD among single nucleotide polymorphisms (SNPs) from across the human genome, associations involving other classes of molecular variation remain poorly understood. In addition to recombination and population history, mutation rate and process are expected to shape LD. To test this idea, we measured associations between short-tandem-repeat polymorphisms (STRPs), which can mutate rapidly and recurrently, and SNPs in 721 regions across the human genome. We directly compared STRP-SNP LD with SNP-SNP LD from the same genomic regions in the human HapMap populations. The intensity of STRP-SNP LD, measured by the average of D', was reduced, consistent with the action of recurrent mutation. Nevertheless, a higher fraction of STRP-SNP pairs than SNP-SNP pairs showed significant LD, on both short (up to 50 kb) and long (cM) scales. These results reveal the substantial effects of mutational processes on LD at STRPs and provide important measures of the potential of STRPs for association mapping of disease genes.

Human La binds mRNAs through contacts to the poly(A) tail.

PubMed

Vinayak, Jyotsna; Marrella, Stefano A; Hussain, Rawaa H; Rozenfeld, Leonid; Solomon, Karine; Bayfield, Mark A

2018-05-04

In addition to a role in the processing of nascent RNA polymerase III transcripts, La proteins are also associated with promoting cap-independent translation from the internal ribosome entry sites of numerous cellular and viral coding RNAs. La binding to RNA polymerase III transcripts via their common UUU-3'OH motif is well characterized, but the mechanism of La binding to coding RNAs is poorly understood. Using electromobility shift assays and cross-linking immunoprecipitation, we show that in addition to a sequence specific UUU-3'OH binding mode, human La exhibits a sequence specific and length dependent poly(A) binding mode. We demonstrate that this poly(A) binding mode uses the canonical nucleic acid interaction winged helix face of the eponymous La motif, previously shown to be vacant during uridylate binding. We also show that cytoplasmic, but not nuclear La, engages poly(A) RNA in human cells, that La entry into polysomes utilizes the poly(A) binding mode, and that La promotion of translation from the cyclin D1 internal ribosome entry site occurs in competition with cytoplasmic poly(A) binding protein (PABP). Our data are consistent with human La functioning in translation through contacts to the poly(A) tail.

Functional autonomy of distant-acting human enhancers

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

Visel, Axel; Akiyama, Jennifer A.; Shoukry, Malak

2009-02-19

Many human genes are associated with dispersed arrays of transcriptional enhancers that regulate their expression in time and space. Studies in invertebrate model systems have suggested that these elements function as discrete and independent regulatory units, but the in vivo combinatorial properties of vertebrate enhancers remain poorly understood. To explore the modularity and regulatory autonomy of human developmental enhancers, we experimentally concatenated up to four enhancers from different genes and used a transgenic mouse assay to compare the in vivo activity of these compound elements with that of the single modules. In all of the six different combinations of elementsmore » tested, the reporter gene activity patterns were additive without signs of interference between the individual modules, indicating that regulatory specificity was maintained despite the presence of closely-positioned heterologous enhancers. Even in cases where two elements drove expression in close anatomical proximity, such as within neighboring subregions of the developing limb bud, the compound patterns did not show signs of cross-inhibition between individual elements or novel expression sites. These data indicate that human developmental enhancers are highly modular and functionally autonomous and suggest that genomic enhancer shuffling may have contributed to the evolution of complex gene expression patterns in vertebrates« less

BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance

PubMed Central

Ferretti, Roberta; Bhutkar, Arjun; McNamara, Molly C.; Lees, Jacqueline A.

2016-01-01

Melanoma can switch between proliferative and invasive states, which have identifying gene expression signatures that correlate with good and poor prognosis, respectively. However, the mechanisms controlling these signatures are poorly understood. In this study, we identify BMI1 as a key determinant of melanoma metastasis by which its overexpression enhanced and its deletion impaired dissemination. Remarkably, in this tumor type, BMI1 had no effect on proliferation or primary tumor growth but enhanced every step of the metastatic cascade. Consistent with the broad spectrum of effects, BMI1 activated widespread gene expression changes, which are characteristic of melanoma progression and also chemoresistance. Accordingly, we showed that up-regulation or down-regulation of BMI1 induced resistance or sensitivity to BRAF inhibitor treatment and that induction of noncanonical Wnt by BMI1 is required for this resistance. Finally, we showed that our BMI1-induced gene signature encompasses all of the hallmarks of the previously described melanoma invasive signature. Moreover, our signature is predictive of poor prognosis in human melanoma and is able to identify primary tumors that are likely to become metastatic. These data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance of melanoma. PMID:26679841

CD271 Defines a Stem Cell-Like Population in Hypopharyngeal Cancer

PubMed Central

Imai, Takayuki; Tamai, Keiichi; Oizumi, Sayuri; Oyama, Kyoko; Yamaguchi, Kazunori; Sato, Ikuro; Satoh, Kennichi; Matsuura, Kazuto; Saijo, Shigeru; Sugamura, Kazuo; Tanaka, Nobuyuki

2013-01-01

Cancer stem cells contribute to the malignant phenotypes of a variety of cancers, but markers to identify human hypopharyngeal cancer (HPC) stem cells remain poorly understood. Here, we report that the CD271+ population sorted from xenotransplanted HPCs possesses an enhanced tumor-initiating capability in immunodeficient mice. Tumors generated from the CD271+ cells contained both CD271+ and CD271− cells, indicating that the population could undergo differentiation. Immunohistological analyses of the tumors revealed that the CD271+ cells localized to a perivascular niche near CD34+ vasculature, to invasive fronts, and to the basal layer. In accordance with these characteristics, a stemness marker, Nanog, and matrix metalloproteinases (MMPs), which are implicated in cancer invasion, were significantly up-regulated in the CD271+ compared to the CD271− cell population. Furthermore, using primary HPC specimens, we demonstrated that high CD271 expression was correlated with a poor prognosis for patients. Taken together, our findings indicate that CD271 is a novel marker for HPC stem-like cells and for HPC prognosis. PMID:23626764

The Role of Tobacco-Derived Carcinogens in Pancreas Cancer

PubMed Central

Lochan, Rajiv; Reeves, Helen L.; Daly, Anne K.; Charnley, Richard M.

2011-01-01

The extremely poor outcome from pancreas cancer is well known. However, its aetiology less well appreciated, and the molecular mechanisms underlying this are poorly understood. Tobacco usage is one of the strongest risk factors for this disease, and this is a completely avoidable hazard. In addition, there are well described hereditary diseases which predispose, and familial pancreas cancer. We have sought here to summarise the role of tobacco-derived carcinogens and the mode of their tumorigenic action on the pancreas. There is compelling evidence from animal and human studies (laboratory including cell line studies and epidemiologic) that tobacco derived carcinogens cause pancreas cancer. However, the manner in which they do so is not entirely apparent. There is also compelling evidence that synergism with genetic and other life-style factors—like diet obesity—results in a multifactorial causation of the disease. Ascertaining the role of tobacco carcinogens in the development of this cancer and their interaction with other risk factors will enable novel therapeutic and preventative strategies to improve outcome from this appalling malignancy. PMID:22084727

Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases.

PubMed

Frentzas, Sophia; Simoneau, Eve; Bridgeman, Victoria L; Vermeulen, Peter B; Foo, Shane; Kostaras, Eleftherios; Nathan, Mark; Wotherspoon, Andrew; Gao, Zu-Hua; Shi, Yu; Van den Eynden, Gert; Daley, Frances; Peckitt, Clare; Tan, Xianming; Salman, Ayat; Lazaris, Anthoula; Gazinska, Patrycja; Berg, Tracy J; Eltahir, Zak; Ritsma, Laila; Van Rheenen, Jacco; Khashper, Alla; Brown, Gina; Nystrom, Hanna; Sund, Malin; Van Laere, Steven; Loyer, Evelyne; Dirix, Luc; Cunningham, David; Metrakos, Peter; Reynolds, Andrew R

2016-11-01

The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.

Africa: continent of genome contrasts with implications for biomedical research and health.

PubMed

Ramsay, Michèle

2012-08-31

The genomic architecture of African populations is poorly understood and there is considerable variation between ethno-linguistic groups. Genome-wide approaches have been extensively applied to search for genetic associations to complex traits in Europeans, but rarely in Africans. This is largely attributed to lower levels of funding, poor infrastructure and public health systems, and to the small pool of trained scientists. High levels of genetic variation and underlying population structure in Africans present significant challenges, but lower levels of linkage disequilibrium provide an opportunity for more effective localisation of causal variants. High throughput technologies, including dense genotyping arrays, genome sequencing and epigenome studies, together with plummeting costs, are making research more affordable, even for African scientists. Understanding the interactions between genome structure and environmental influences is essential to interpreting their contributions to the increase in infectious diseases and non-communicable diseases, exacerbated by adverse environments and lifestyle choices. The unique genome dynamics in African populations have an important role to play in understanding human health and susceptibility to disease. Copyright © 2012. Published by Elsevier B.V.

Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans

PubMed Central

Darton, Thomas C.; Blohmke, Christoph J.; Giannoulatou, Eleni; Waddington, Claire S.; Jones, Claire; Sturges, Pamela; Webster, Craig; Drakesmith, Hal; Pollard, Andrew J.; Armitage, Andrew E.

2015-01-01

Background Iron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge. Methodology/Principal Findings Fifty study participants were challenged with Salmonella enterica serovar Typhi and monitored for evidence of typhoid fever. Serum hepcidin, ferritin, serum iron parameters, C-reactive protein (CRP), and plasma IL-6 and TNF-alpha concentrations were measured during the 14 days following challenge. We found that hepcidin concentrations were markedly higher during acute typhoid infection than at baseline. Hepcidin elevations mirrored the kinetics of fever, and were accompanied by profound hypoferremia, increased CRP and ferritin, despite only modest elevations in IL-6 and TNF-alpha in some individuals. During inflammation, the extent of hepcidin upregulation associated with the degree of hypoferremia. Conclusions/Significance We demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi. PMID:26394303

IL-2 receptor γ-chain molecule is critical for intestinal T-cell reconstitution in humanized mice.

PubMed

Denton, P W; Nochi, T; Lim, A; Krisko, J F; Martinez-Torres, F; Choudhary, S K; Wahl, A; Olesen, R; Zou, W; Di Santo, J P; Margolis, D M; Garcia, J V

2012-09-01

Intestinal immune cells are important in host defense, yet the determinants for human lymphoid homeostasis in the intestines are poorly understood. In contrast, lymphoid homeostasis has been studied extensively in mice, where the requirement for a functional common γ-chain molecule has been established. We hypothesized that humanized mice could offer insights into human intestinal lymphoid homeostasis if generated in a strain with an intact mouse common γ-chain molecule. To address this hypothesis, we used three mouse strains (non-obese diabetic (NOD)/severe-combined immunodeficient (SCID) (N/S); NOD/SCID γ-chain(-/-) (NSG); and Rag2(-/-) γ-chain(-/-) (DKO)) and two humanization techniques (bone marrow liver thymus (BLT) and human CD34(+) cell bone marrow transplant of newborn mice (hu)) to generate four common types of humanized mice: N/S-BLT, NSG-BLT, NSG-hu, and DKO-hu mice. The highest levels of intestinal human T cells throughout the small and large intestines were observed in N/S-BLT mice, which have an intact common γ-chain molecule. Furthermore, the small intestine lamina propria T-cell populations of N/S-BLT mice exhibit a human intestine-specific surface phenotype. Thus, the extensive intestinal immune reconstitution of N/S-BLT mice was both quantitatively and qualitatively better when compared with the other models tested such that N/S-BLT mice are well suited for the analysis of human intestinal lymphocyte trafficking and human-specific diseases affecting the intestines.

Relating dynamic brain states to dynamic machine states: Human and machine solutions to the speech recognition problem

PubMed Central

Liu, Xunying; Zhang, Chao; Woodland, Phil; Fonteneau, Elisabeth

2017-01-01

There is widespread interest in the relationship between the neurobiological systems supporting human cognition and emerging computational systems capable of emulating these capacities. Human speech comprehension, poorly understood as a neurobiological process, is an important case in point. Automatic Speech Recognition (ASR) systems with near-human levels of performance are now available, which provide a computationally explicit solution for the recognition of words in continuous speech. This research aims to bridge the gap between speech recognition processes in humans and machines, using novel multivariate techniques to compare incremental ‘machine states’, generated as the ASR analysis progresses over time, to the incremental ‘brain states’, measured using combined electro- and magneto-encephalography (EMEG), generated as the same inputs are heard by human listeners. This direct comparison of dynamic human and machine internal states, as they respond to the same incrementally delivered sensory input, revealed a significant correspondence between neural response patterns in human superior temporal cortex and the structural properties of ASR-derived phonetic models. Spatially coherent patches in human temporal cortex responded selectively to individual phonetic features defined on the basis of machine-extracted regularities in the speech to lexicon mapping process. These results demonstrate the feasibility of relating human and ASR solutions to the problem of speech recognition, and suggest the potential for further studies relating complex neural computations in human speech comprehension to the rapidly evolving ASR systems that address the same problem domain. PMID:28945744

Immunohistochemical characterization of human olfactory tissue

PubMed Central

Holbrook, Eric H.; Wu, Enming; Curry, William T.; Lin, Derrick T.; Schwob, James E.

2011-01-01

Objectives/Hypothesis The pathophysiology underlying human olfactory disorders is poorly understood because biopsying the olfactory epithelium (OE) can be unrepresentative and extensive immunohistochemical analysis is lacking. Autopsy tissue enriches our grasp of normal and abnormal olfactory immunohistology and guides the sampling of the OE by biopsy. Furthermore, a comparison of the molecular phenotype of olfactory epithelial cells between rodents and humans will improve our ability to correlate human histopathology with olfactory dysfunction. Study Design An immunohistochemical analysis of human olfactory tissue using a comprehensive battery of proven antibodies. Methods Human olfactory mucosa obtained from 21 autopsy specimens was analyzed with immunohistochemistry. The position and extent of olfactory mucosa was assayed by staining whole mounts with neuronal markers. Sections of the OE were analyzed with an extensive group of antibodies directed against cytoskeletal proteins and transcription factors, as were surgical specimens from an esthesioneuroblastoma. Results Neuron-rich epithelium is always found inferior to the cribriform plate, even at advanced age, despite the interruptions in the neuroepithelial sheet caused by patchy respiratory metaplasia. The pattern of immunostaining with our antibody panel identifies two distinct types of basal cell progenitors in human OE similar to rodents. The panel also clarifies the complex composition of the esthesioneuroblastoma. Conclusion The extent of human olfactory mucosa at autopsy can easily be delineated as a function of age and neurological disease. The similarities in human vs. rodent OE will enable us to translate knowledge from experimental animals to humans and will extend our understanding of human olfactory pathophysiology. PMID:21792956

What does productivity really mean? Towards an integrative paradigm in the search for biodiversity-productivity relationships

Treesearch

Liangjun Hu; Qinfeng Guo

2013-01-01

How species diversity relates to productivity remains a major debate. To date, however, the underlying mechanisms that regulate the ecological processes involved are still poorly understood. Three major issues persist in early efforts at resolution. First, in the context that productivity drives species diversity, how the pathways operate is poorly-explained. Second,...

Low serum omega-3 and omega-6 polyunsaturated fatty acids and other metabolites are associated with poor linear growth in young children from rural Malawi

USDA-ARS?s Scientific Manuscript database

Stunting affects ~25% of children <5 y of age and is associated with impaired cognitive and motor development and increased morbidity and mortality. The pathogenesis of stunting is poorly understood. The purpose of this study was to identify altered metabolic pathways associated with child stunting...

Belief inhibition during thinking: not always winning but at least taking part.

PubMed

De Neys, Wim; Franssens, Samuel

2009-10-01

Human thinking is often biased by intuitive beliefs. Inhibition of these tempting beliefs is considered a key component of human thinking, but the process is poorly understood. In the present study we clarify the nature of an inhibition failure and the resulting belief bias by probing the accessibility of cued beliefs after people reasoned. Results indicated that even the poorest reasoners showed an impaired memory access to words that were associated with cued beliefs after solving reasoning problems in which the beliefs conflicted with normative considerations (Experiment 1 and 2). The study further established that the impairment was only temporary in nature (Experiment 3) and did not occur when people were explicitly instructed to give mere intuitive judgments (Experiment 4). Findings present solid evidence for the postulation of an inhibition process and imply that belief bias does not result from a failure to recognize the need to inhibit inappropriate beliefs, but from a failure to complete the inhibition process. This indicates that people are far more logical than hitherto believed.

The Genetic Architecture of the Human Immune System: A Bioresource for Autoimmunity and Disease Pathogenesis

PubMed Central

Roederer, Mario; Quaye, Lydia; Mangino, Massimo; Beddall, Margaret H.; Mahnke, Yolanda; Chattopadhyay, Pratip; Tosi, Isabella; Napolitano, Luca; Barberio, Manuela Terranova; Menni, Cristina; Villanova, Federica; Di Meglio, Paola; Spector, Tim D.; Nestle, Frank O.

2015-01-01

Summary Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analysing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets, and uncovered insights into genetic control for regulatory T cells. This dataset also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases. PMID:25772697

Food Sharing among Hadza Hunter-Gatherer Children.

PubMed

Crittenden, Alyssa N; Zes, David A

2015-01-01

Human prosociality is one of the defining characteristics of our species, yet the ontogeny of altruistic behavior remains poorly understood. The evolution of widespread food sharing in humans helped shape cooperation, family formation, life history, language, and the development of economies of scale. While the behavioral and ecological correlates of food sharing among adults are widely studied, very little is known about food sharing among children. Here, in the first study to analyze the food sharing patterns of hunter-gatherer children, we show that while sharing may be biased towards kin, reciprocity characterizes the majority of all sharing dyads, both related and unrelated. These data lend support to the recent claim that discrimination among kin might be linked with reciprocal altruism theory. Furthermore, we show that age positively correlates with an increase in sharing, both in frequency and amount, supporting recent suggestions that prosocial behaviors and egalitarianism develop strongly in middle childhood when children acquire the normative rules of their society.

An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth.

PubMed

Uchimura, Tomoya; Hollander, Judith M; Nakamura, Daisy S; Liu, Zhiyi; Rosen, Clifford J; Georgakoudi, Irene; Zeng, Li

2017-10-01

Postnatal bone growth involves a dramatic increase in length and girth. Intriguingly, this period of growth is independent of growth hormone and the underlying mechanism is poorly understood. Recently, an IGF2 mutation was identified in humans with early postnatal growth restriction. Here, we show that IGF2 is essential for longitudinal and appositional murine postnatal bone development, which involves proper timing of chondrocyte maturation and perichondrial cell differentiation and survival. Importantly, the Igf2 null mouse model does not represent a simple delay of growth but instead uncoordinated growth plate development. Furthermore, biochemical and two-photon imaging analyses identified elevated and imbalanced glucose metabolism in the Igf2 null mouse. Attenuation of glycolysis rescued the mutant phenotype of premature cartilage maturation, thereby indicating that IGF2 controls bone growth by regulating glucose metabolism in chondrocytes. This work links glucose metabolism with cartilage development and provides insight into the fundamental understanding of human growth abnormalities. © 2017. Published by The Company of Biologists Ltd.

Transcriptional and Cell Cycle Alterations Mark Aging of Primary Human Adipose-Derived Stem Cells.

PubMed

Shan, Xiaoyin; Roberts, Cleresa; Kim, Eun Ji; Brenner, Ariana; Grant, Gregory; Percec, Ivona

2017-05-01

Adult stem cells play a critical role in the maintenance of tissue homeostasis and prevention of aging. While the regenerative potential of stem cells with low cellular turnover, such as adipose-derived stem cells (ASCs), is increasingly recognized, the study of chronological aging in ASCs is technically difficult and remains poorly understood. Here, we use our model of chronological aging in primary human ASCs to examine genome-wide transcriptional networks. We demonstrate first that the transcriptome of aging ASCs is distinctly more stable than that of age-matched fibroblasts, and further, that age-dependent modifications in cell cycle progression and translation initiation specifically characterize aging ASCs in conjunction with increased nascent protein synthesis and a distinctly shortened G1 phase. Our results reveal novel chronological aging mechanisms in ASCs that are inherently different from differentiated cells and that may reflect an organismal attempt to meet the increased demands of tissue and organ homeostasis during aging. Stem Cells 2017;35:1392-1401. © 2017 AlphaMed Press.

Structural Basis for Substrate Recognition by the Ankyrin Repeat Domain of Human DHHC17 Palmitoyltransferase

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

Verardi, Raffaello; Kim, Jin-Sik; Ghirlando, Rodolfo

DHHC enzymes catalyze palmitoylation, a major post-translational modification that regulates a number of key cellular processes. There are up to 24 DHHCs in mammals and hundreds of substrate proteins that get palmitoylated. However, how DHHC enzymes engage with their substrates is still poorly understood. There is currently no structural information about the interaction between any DHHC enzyme and protein substrates. In this study we have investigated the structural and thermodynamic bases of interaction between the ankyrin repeat domain of human DHHC17 (ANK17) and Snap25b. We solved a high-resolution crystal structure of the complex between ANK17 and a peptide fragment ofmore » Snap25b. Through structure-guided mutagenesis, we discovered key residues in DHHC17 that are critically important for interaction with Snap25b. We further extended our finding by showing that the same residues are also crucial for the interaction of DHHC17 with Huntingtin, one of its most physiologically relevant substrates.« less

Construction of synthetic nucleoli in human cells reveals how a major functional nuclear domain is formed and propagated through cell division.

PubMed

Grob, Alice; Colleran, Christine; McStay, Brian

2014-02-01

Human cell nuclei are functionally organized into structurally stable yet dynamic bodies whose cell cycle inheritance is poorly understood. Here, we investigate the biogenesis and propagation of nucleoli, sites of ribosome biogenesis and key regulators of cellular growth. Nucleolar and cell cycles are intimately connected. Nucleoli disappear during mitosis, reforming around prominent uncharacterized chromosomal features, nucleolar organizer regions (NORs). By examining the effects of UBF depletion on both endogenous NORs and synthetic pseudo-NORs, we reveal its essential role in maintaining competency and establishing a bookmark on mitotic NORs. Furthermore, we demonstrate that neo-NORs, UBF-binding site arrays coupled with rDNA transcription units, direct the de novo biogenesis of functional compartmentalized neonucleoli irrespective of their site of chromosomal integration. For the first time, we establish the sequence requirements for nucleolar biogenesis and provide proof that this is a staged process where UBF-dependent mitotic bookmarking precedes function-dependent nucleolar assembly.

Construction of synthetic nucleoli in human cells reveals how a major functional nuclear domain is formed and propagated through cell division

PubMed Central

Grob, Alice; Colleran, Christine; McStay, Brian

2014-01-01

Human cell nuclei are functionally organized into structurally stable yet dynamic bodies whose cell cycle inheritance is poorly understood. Here, we investigate the biogenesis and propagation of nucleoli, sites of ribosome biogenesis and key regulators of cellular growth. Nucleolar and cell cycles are intimately connected. Nucleoli disappear during mitosis, reforming around prominent uncharacterized chromosomal features, nucleolar organizer regions (NORs). By examining the effects of UBF depletion on both endogenous NORs and synthetic pseudo-NORs, we reveal its essential role in maintaining competency and establishing a bookmark on mitotic NORs. Furthermore, we demonstrate that neo-NORs, UBF-binding site arrays coupled with rDNA transcription units, direct the de novo biogenesis of functional compartmentalized neonucleoli irrespective of their site of chromosomal integration. For the first time, we establish the sequence requirements for nucleolar biogenesis and provide proof that this is a staged process where UBF-dependent mitotic bookmarking precedes function-dependent nucleolar assembly. PMID:24449107

Measuring the Meltdown: Drivers of Global Amphibian Extinction and Decline

PubMed Central

Sodhi, Navjot S.; Bickford, David; Diesmos, Arvin C.; Lee, Tien Ming; Koh, Lian Pin; Brook, Barry W.; Sekercioglu, Cagan H.; Bradshaw, Corey J. A.

2008-01-01

Habitat loss, climate change, over-exploitation, disease and other factors have been hypothesised in the global decline of amphibian biodiversity. However, the relative importance of and synergies among different drivers are still poorly understood. We present the largest global analysis of roughly 45% of known amphibians (2,583 species) to quantify the influences of life history, climate, human density and habitat loss on declines and extinction risk. Multi-model Bayesian inference reveals that large amphibian species with small geographic range and pronounced seasonality in temperature and precipitation are most likely to be Red-Listed by IUCN. Elevated habitat loss and human densities are also correlated with high threat risk. Range size, habitat loss and more extreme seasonality in precipitation contributed to decline risk in the 2,454 species that declined between 1980 and 2004, compared to species that were stable (n = 1,545) or had increased (n = 28). These empirical results show that amphibian species with restricted ranges should be urgently targeted for conservation. PMID:18286193

Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis

PubMed Central

Blanchard, Carine; Wang, Ning; Stringer, Keith F.; Mishra, Anil; Fulkerson, Patricia C.; Abonia, J. Pablo; Jameson, Sean C.; Kirby, Cassie; Konikoff, Michael R.; Collins, Margaret H.; Cohen, Mitchell B.; Akers, Rachel; Hogan, Simon P.; Assa’ad, Amal H.; Putnam, Philip E.; Aronow, Bruce J.; Rothenberg, Marc E.

2006-01-01

Eosinophilic esophagitis (EE) is an emerging disorder with a poorly understood pathogenesis. In order to define disease mechanisms, we took an empirical approach analyzing esophageal tissue by a genome-wide microarray expression analysis. EE patients had a striking transcript signature involving 1% of the human genome that was remarkably conserved across sex, age, and allergic status and was distinct from that associated with non-EE chronic esophagitis. Notably, the gene encoding the eosinophil-specific chemoattractant eotaxin-3 (also known as CCL26) was the most highly induced gene in EE patients compared with its expression level in healthy individuals. Esophageal eotaxin-3 mRNA and protein levels strongly correlated with tissue eosinophilia and mastocytosis. Furthermore, a single-nucleotide polymorphism in the human eotaxin-3 gene was associated with disease susceptibility. Finally, mice deficient in the eotaxin receptor (also known as CCR3) were protected from experimental EE. These results implicate eotaxin-3 as a critical effector molecule for EE and provide insight into disease pathogenesis. PMID:16453027

Medicine's perception of reality - a split picture: critical reflections on apparent anomalies within the biomedical theory of science.

PubMed

Kirkengen, Anna Luise; Ekeland, Tor-Johan; Getz, Linn; Hetlevik, Irene; Schei, Edvin; Ulvestad, Elling; Vetlesen, Arne Johan

2016-08-01

Escalating costs, increasing multi-morbidity, medically unexplained health problems, complex risk, poly-pharmacy and antibiotic resistance can be regarded as artefacts of the traditional knowledge production in Western medicine, arising from its particular worldview. Our paper presents a historically grounded critical analysis of this view. The materialistic shift of Enlightenment philosophy, separating subjectivity from bodily matter, became normative for modern medicine and yielded astonishing results. The traditional dichotomies of mind/body and subjective/objective are, however, incompatible with modern biological theory. Medical knowledge ignores central tenets of human existence, notably the physiological impact of subjective experience, relationships, history and sociocultural contexts. Biomedicine will not succeed in resolving today's poorly understood health problems by doing 'more of the same'. We must acknowledge that health, sickness and bodily functioning are interwoven with human meaning-production, fundamentally personal and biographical. This implies that the biomedical framework, although having engendered 'success stories' like the era of antibiotics, needs to be radically revised. © 2015 John Wiley & Sons, Ltd.

Dynamics of Tumor Heterogeneity Derived from Clonal Karyotypic Evolution.

PubMed

Laughney, Ashley M; Elizalde, Sergi; Genovese, Giulio; Bakhoum, Samuel F

2015-08-04

Numerical chromosomal instability is a ubiquitous feature of human neoplasms. Due to experimental limitations, fundamental characteristics of karyotypic changes in cancer are poorly understood. Using an experimentally inspired stochastic model, based on the potency and chromosomal distribution of oncogenes and tumor suppressor genes, we show that cancer cells have evolved to exist within a narrow range of chromosome missegregation rates that optimizes phenotypic heterogeneity and clonal survival. Departure from this range reduces clonal fitness and limits subclonal diversity. Mapping of the aneuploid fitness landscape reveals a highly favorable, commonly observed, near-triploid state onto which evolving diploid- and tetraploid-derived populations spontaneously converge, albeit at a much lower fitness cost for the latter. Finally, by analyzing 1,368 chromosomal translocation events in five human cancers, we find that karyotypic evolution also shapes chromosomal translocation patterns by selecting for more oncogenic derivative chromosomes. Thus, chromosomal instability can generate the heterogeneity required for Darwinian tumor evolution. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

The crystal structure of human GlnRS provides basis for the development of neurological disorders

DOE PAGES

Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen; ...

2016-02-10

Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggestmore » that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. As a result, this report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. Keywords« less

Zinc Chromate Induces Chromosome Instability and DNA Double Strand Breaks in Human Lung Cells

PubMed Central

Xie, Hong; Holmes, Amie L.; Young, Jamie L.; Qin, Qin; Joyce, Kellie; Pelsue, Stephen C.; Peng, Cheng; Wise, Sandra S.; Jeevarajan, Antony S.; Wallace, William T.; Hammond, Dianne; Wise, John Pierce

2014-01-01

Hexavalent chromium Cr(VI) is a respiratory toxicant and carcinogen, with solubility playing an important role in its carcinogenic potential. Zinc chromate, a water insoluble or ‘particulate’ Cr(VI) compound, has been shown to be carcinogenic in epidemiology studies and to induce tumors in experimental animals, but its genotoxicity is poorly understood. Our study shows that zinc chromate induced concentration-dependent increases in cytotoxicity, chromosome damage and DNA double strand breaks in human lung cells. In response to zinc chromate-induced breaks, MRE11 expression was increased and ATM and ATR were phosphorylated, indicating that the DNA double strand break repair system was initiated in the cells. In addition, our data show that zinc chromate-induced double strand breaks were only observed in the G2/M phase population, with no significant amount of double strand breaks observed in G1 and S phase cells. These data will aid in understanding the mechanisms of zinc chromate toxicity and carcinogenesis. PMID:19027772

Assessing the impact of engineered nanoparticles on wound healing using a novel in vitro bioassay

PubMed Central

Zhou, Enhua H; Watson, Christa; Pizzo, Richard; Cohen, Joel; Dang, Quynh; de Barros, Pedro Macul Ferreira; Park, Chan Young; Chen, Cheng; Brain, Joseph D; Butler, James P; Ruberti, Jeffrey W; Fredberg, Jeffrey J; Demokritout, Philip

2015-01-01

Aim As engineered nanoparticles (ENPs) increasingly enter consumer products, humans become increasingly exposed. The first line of defense against ENPs is the epithelium, the integrity of which can be compromised by wounds induced by trauma, infection, or surgery, but the implications of ENPs on wound healing are poorly understood. Materials & methods Herein, we developed an in vitro assay to assess the impact of ENPs on the wound healing of cells from human cornea. Results & discussion We show that industrially relevant ENPs impeded wound healing and cellular migration in a manner dependent on the composition, dose and size of the ENPs as well as cell type. CuO and ZnO ENPs impeded both viability and wound healing for both fibroblasts and epithelial cells. Carboxylated polystyrene ENPs retarded wound healing of corneal fibroblasts without affecting viability. Conclusion Our results highlight the impact of ENPs on cellular wound healing and provide useful tools for studying the physiological impact of ENPs. PMID:24823434

The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis.

PubMed

Roederer, Mario; Quaye, Lydia; Mangino, Massimo; Beddall, Margaret H; Mahnke, Yolanda; Chattopadhyay, Pratip; Tosi, Isabella; Napolitano, Luca; Terranova Barberio, Manuela; Menni, Cristina; Villanova, Federica; Di Meglio, Paola; Spector, Tim D; Nestle, Frank O

2015-04-09

Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis

PubMed Central

Walko, Gernot; Viswanathan, Priyalakshmi; Tihy, Matthieu; Nijjher, Jagdeesh; Dunn, Sara-Jane; Lamond, Angus I

2017-01-01

Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition between the two cell states, termed commitment, is poorly understood. Here, we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension to induce differentiation. Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA – promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors. Conversely, DUSP10 expression antagonises commitment. The phosphatases form a dynamic network of transient positive and negative interactions that change over time, with DUSP6 predominating at commitment. Boolean network modelling identifies a mandatory switch between two stable states (stem and differentiated) via an unstable (committed) state. Phosphatase expression is also spatially regulated in vivo and in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment. PMID:29043977

The hydrodynamics of defecation

NASA Astrophysics Data System (ADS)

Yang, Patricia; Dao, Duc; Lehner, Richard; Tennenbaum, Mike; Fernandez-Nieves, Alberto; Hu, David

2014-11-01

According to the U.S. Department of Health and Human Services, digestive disease affects 60 to 70 million people and costs over 140 billion annually. Despite the significance of the gastrointestinal tract to human health, the physics of both digestion and defecation remain poorly understood. In this combined experimental and theoretical study, we investigate the defecation of mammals, from mice to elephants. We film defecation events at Zoo Atlanta and apply plate-on-plate rheometry to measure the viscosity of mammalian feces. Among animals heavier than 3 kg, we find herbivores defecate for only 10 seconds (N = 13), while carnivores do so for 19 seconds (N = 8). We rationalize this surprising trend on the basis of the higher viscosity of carnivore feces. We compare defecation times to theoretical predictions based on a Poiseuille flow model of the rectum and parallel experiments with a synthetic defecator that extrudes pizza dough upon applied pressure. Our findings may help to diagnose digestive problems in animals. Done...processed 2801 records...13:08:35

Basal-like Breast Cancers: From Pathology to Biology and Back Again.

PubMed

Gusterson, Barry; Eaves, Connie J

2018-06-05

Human breast cancers referred to as "basal-like" are of interest because they lack effective therapies and their biology is poorly understood. The term basal-like derives from studies demonstrating tumor gene expression profiles that include some transcripts characteristic of the basal cells of the normal adult human mammary gland and others associated with a subset of normal luminal cells. Elucidating the mechanisms responsible for the profiles of basal-like tumors is an active area of investigation. More refined molecular analysis of patients' samples and genetic strategies to produce breast cancers de novo from defined populations of normal mouse mammary cells have served as complementary approaches to identify relevant pathway alterations. However, both also have limitations. Here, we review some of the underlying reasons, including the unifying concept that some normal luminal cells have both luminal and basal features, as well as some emerging new avenues of investigation. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Slug inhibits the proliferation and tumor formation of human cervical cancer cells by up-regulating the p21/p27 proteins and down-regulating the activity of the Wnt/β-catenin signaling pathway via the trans-suppression Akt1/p-Akt1 expression

PubMed Central

Cui, Nan; Yang, Wen-Ting; Zheng, Peng-Sheng

2016-01-01

Slug (Snai2) has been demonstrated to act as an oncogene or tumor suppressor in different human cancers, but the function of Slug in cervical cancer remains poorly understood. In this study, we demonstrated that Slug could suppress the proliferation of cervical cancer cells in vitro and tumor formation in vivo. Further experiments found that Slug could trans-suppress the expression of Akt1/p-Akt1 by binding to E-box motifs in the promoter of the Akt1 gene and then inhibit the cell proliferation and tumor formation of cervical cancer cells by up-regulating p21/p27 and/or down-regulating the activity of the Wnt/β-catenin signaling pathway. Therefore, Slug acts as a tumor suppressor during cervical carcinogenesis. PMID:27036045

The role of TLRs in cervical cancer with HPV infection: a review

PubMed Central

Yang, Xiao; Cheng, Yanxiang; Li, Chunsheng

2017-01-01

The main cause of cervical cancer is persistent infection with high-risk human papilloma virus (HR-HPV), but not all human papilloma virus (HPV) infections lead to cervical cancer. The key factors that determine the outcome of HPV infection remain poorly understood, and how the host immune system protects against HPV infection is unclear. Toll-like receptors (TLRs) are a group of pattern recognition receptors present in the cytoplasm and cell membrane, and can specifically recognize pathogen-associated molecular patterns. As the key molecules of innate and acquired immunity, TLRs not only play important roles in the immune defense against infectious diseases, but also are involved in the occurrence and development of a variety of malignant tumors. In cervical cancer caused by HR-HPV infection, TLRs have been found to regulate the local immune microenvironment. The role of TLRs in HR-HPV infection and HPV-induced cervical cancer and its relationship with HPV vaccine are reviewed in this article. PMID:29263932

Measuring the meltdown: drivers of global amphibian extinction and decline.

PubMed

Sodhi, Navjot S; Bickford, David; Diesmos, Arvin C; Lee, Tien Ming; Koh, Lian Pin; Brook, Barry W; Sekercioglu, Cagan H; Bradshaw, Corey J A

2008-02-20

Habitat loss, climate change, over-exploitation, disease and other factors have been hypothesised in the global decline of amphibian biodiversity. However, the relative importance of and synergies among different drivers are still poorly understood. We present the largest global analysis of roughly 45% of known amphibians (2,583 species) to quantify the influences of life history, climate, human density and habitat loss on declines and extinction risk. Multi-model Bayesian inference reveals that large amphibian species with small geographic range and pronounced seasonality in temperature and precipitation are most likely to be Red-Listed by IUCN. Elevated habitat loss and human densities are also correlated with high threat risk. Range size, habitat loss and more extreme seasonality in precipitation contributed to decline risk in the 2,454 species that declined between 1980 and 2004, compared to species that were stable (n = 1,545) or had increased (n = 28). These empirical results show that amphibian species with restricted ranges should be urgently targeted for conservation.

Lipid Panel Reference Intervals for Amazon Parrots (Amazona species).

PubMed

Ravich, Michelle; Cray, Carolyn; Hess, Laurie; Arheart, Kristopher L

2014-09-01

The lipoprotein panel is a useful diagnostic tool that allows clinicians to evaluate blood lipoprotein fractions. It is a standard diagnostic test in human medicine but is poorly understood in avian medicine. Amazon parrots (Amazona species) are popular pets that frequently lead a sedentary lifestyle and are customarily fed high-fat diets. Similar to people with comparable diets and lifestyles, Amazon parrots are prone to obesity and atherosclerosis. In human medicine, these conditions are typically correlated with abnormalities in the lipoprotein panel. To establish reference intervals for the lipoprotein panel in Amazon parrots, plasma samples from 31 captive Amazon parrots were analyzed for concentrations of cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL). The data were also grouped according to sex, diet, body condition score, and age. Aside from HDL levels, which were significantly different between male and female parrots, no intergroup differences were found for any of the lipoprotein fractions.

NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations.

PubMed

Mortimer, Leanne; Moreau, France; MacDonald, Justin A; Chadee, Kris

2016-10-01

Inflammasomes are positioned to rapidly escalate the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. However, negative regulation of inflammasomes remains poorly understood, as is the signaling cascade that dampens inflammasome activity. We found that rapid NLRP3 inflammasome activation was directly inhibited by protein kinase A (PKA), which was induced by prostaglandin E2 (PGE2) signaling via the PGE2 receptor E-prostanoid 4 (EP4). PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation. Mutations in NLRP3-encoding residues adjacent to Ser295 have been linked to the inflammatory disease CAPS (cryopyrin-associated periodic syndromes). NLRP3-S295A phenocopied the human CAPS mutants. These data suggest that negative regulation at Ser295 is critical for restraining the NLRP3 inflammasome and identify a molecular basis for CAPS-associated NLRP3 mutations.

Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis.

PubMed

Khajuria, Rajiv K; Munschauer, Mathias; Ulirsch, Jacob C; Fiorini, Claudia; Ludwig, Leif S; McFarland, Sean K; Abdulhay, Nour J; Specht, Harrison; Keshishian, Hasmik; Mani, D R; Jovanovic, Marko; Ellis, Steven R; Fulco, Charles P; Engreitz, Jesse M; Schütz, Sabina; Lian, John; Gripp, Karen W; Weinberg, Olga K; Pinkus, Geraldine S; Gehrke, Lee; Regev, Aviv; Lander, Eric S; Gazda, Hanna T; Lee, Winston Y; Panse, Vikram G; Carr, Steven A; Sankaran, Vijay G

2018-03-22

Blood cell formation is classically thought to occur through a hierarchical differentiation process, although recent studies have shown that lineage commitment may occur earlier in hematopoietic stem and progenitor cells (HSPCs). The relevance to human blood diseases and the underlying regulation of these refined models remain poorly understood. By studying a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, we are able to gain mechanistic insight into how lineage commitment is programmed normally and disrupted in disease. We show that in DBA, the pool of available ribosomes is limited, while ribosome composition remains constant. Surprisingly, this global reduction in ribosome levels more profoundly alters translation of a select subset of transcripts. We show how the reduced translation of select transcripts in HSPCs can impair erythroid lineage commitment, illuminating a regulatory role for ribosome levels in cellular differentiation. Copyright © 2018 Elsevier Inc. All rights reserved.

Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy.

PubMed

Lan, Xiaoyang; Jörg, David J; Cavalli, Florence M G; Richards, Laura M; Nguyen, Long V; Vanner, Robert J; Guilhamon, Paul; Lee, Lilian; Kushida, Michelle M; Pellacani, Davide; Park, Nicole I; Coutinho, Fiona J; Whetstone, Heather; Selvadurai, Hayden J; Che, Clare; Luu, Betty; Carles, Annaick; Moksa, Michelle; Rastegar, Naghmeh; Head, Renee; Dolma, Sonam; Prinos, Panagiotis; Cusimano, Michael D; Das, Sunit; Bernstein, Mark; Arrowsmith, Cheryl H; Mungall, Andrew J; Moore, Richard A; Ma, Yussanne; Gallo, Marco; Lupien, Mathieu; Pugh, Trevor J; Taylor, Michael D; Hirst, Martin; Eaves, Connie J; Simons, Benjamin D; Dirks, Peter B

2017-09-14

Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.

Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy

PubMed Central

Lan, Xiaoyang; Jörg, David J.; Cavalli, Florence M. G.; Richards, Laura M.; Nguyen, Long V.; Vanner, Robert J.; Guilhamon, Paul; Lee, Lilian; Kushida, Michelle; Pellacani, Davide; Park, Nicole I.; Coutinho, Fiona J.; Whetstone, Heather; Selvadurai, Hayden J.; Che, Clare; Luu, Betty; Carles, Annaick; Moksa, Michelle; Rastegar, Naghmeh; Head, Renee; Dolma, Sonam; Prinos, Panagiotis; Cusimano, Michael D.; Das, Sunit; Bernstein, Mark; Arrowsmith, Cheryl H.; Mungall, Andrew J.; Moore, Richard A.; Ma, Yussanne; Gallo, Marco; Lupien, Mathieu; Pugh, Trevor J.; Taylor, Michael D.; Hirst, Martin; Eaves, Connie J.; Simons, Benjamin D.; Dirks, Peter B.

2017-01-01

Summary Human glioblastomas (GBMs) harbour a subpopulation of glioblastoma stem cells (GSCs) that drive tumourigenesis. However, the origin of intra-tumoural functional heterogeneity between GBM cells remains poorly understood. Here we study the clonal evolution of barcoded GBM cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of GBM clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in GSCs. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, that in turn generates non-proliferative cells. We also identify rare “outlier” clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant GSCs. Finally, we show that functionally distinct GSCs can be separately targeted using epigenetic compounds, suggesting new avenues for GBM targeted therapy. PMID:28854171

Neurocomputational account of how the human brain decides when to have a break

PubMed Central

Meyniel, Florent; Sergent, Claire; Rigoux, Lionel; Daunizeau, Jean; Pessiglione, Mathias

2013-01-01

No pain, no gain: cost–benefit trade-off has been formalized in classical decision theory to account for how we choose whether to engage effort. However, how the brain decides when to have breaks in the course of effort production remains poorly understood. We propose that decisions to cease and resume work are triggered by a cost evidence accumulation signal reaching upper and lower bounds, respectively. We developed a task in which participants are free to exert a physical effort knowing that their payoff would be proportional to their effort duration. Functional MRI and magnetoencephalography recordings conjointly revealed that the theoretical cost evidence accumulation signal was expressed in proprioceptive regions (bilateral posterior insula). Furthermore, the slopes and bounds of the accumulation process were adapted to the difficulty of the task and the money at stake. Cost evidence accumulation might therefore provide a dynamical mechanistic account of how the human brain maximizes benefits while preventing exhaustion. PMID:23341598

Captive gorillas' manual laterality: The impact of gestures, manipulators and interaction specificity.

PubMed

Prieur, Jacques; Barbu, Stéphanie; Blois-Heulin, Catherine; Pika, Simone

2017-12-01

Relationships between humans' manual laterality in non-communicative and communicative functions are still poorly understood. Recently, studies showed that chimpanzees' manual laterality is influenced by functional, interactional and individual factors and their mutual intertwinement. However, what about manual laterality in species living in stable social groups? We tackled this question by studying three groups of captive gorillas (N=35) and analysed their most frequent manual signals: three manipulators and 16 gesture types. Our multifactorial investigation showed that conspecific-directed gestures were overall more right-lateralized than conspecific-directed manipulators. Furthermore, it revealed a difference between conspecific- and human-directed gestural laterality for signallers living in one of the study groups. Our results support the hypothesis that gestural laterality is a relevant marker of language left-brain specialisation. We suggest that components of communication and of manipulation (not only of an object but also of a conspecific) do not share the same lateralised cerebral system in some primate species. Copyright © 2017 Elsevier Inc. All rights reserved.

Formal Models of the Network Co-occurrence Underlying Mental Operations.

PubMed

Bzdok, Danilo; Varoquaux, Gaël; Grisel, Olivier; Eickenberg, Michael; Poupon, Cyril; Thirion, Bertrand

2016-06-01

Systems neuroscience has identified a set of canonical large-scale networks in humans. These have predominantly been characterized by resting-state analyses of the task-unconstrained, mind-wandering brain. Their explicit relationship to defined task performance is largely unknown and remains challenging. The present work contributes a multivariate statistical learning approach that can extract the major brain networks and quantify their configuration during various psychological tasks. The method is validated in two extensive datasets (n = 500 and n = 81) by model-based generation of synthetic activity maps from recombination of shared network topographies. To study a use case, we formally revisited the poorly understood difference between neural activity underlying idling versus goal-directed behavior. We demonstrate that task-specific neural activity patterns can be explained by plausible combinations of resting-state networks. The possibility of decomposing a mental task into the relative contributions of major brain networks, the "network co-occurrence architecture" of a given task, opens an alternative access to the neural substrates of human cognition.

Evidence of an oncogenic gammaherpesvirus in domestic dogs

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

Huang, Shih-Hung, E-mail: ncku309@gmail.com; Kozak, Philip J., E-mail: philj@vet.upenn.edu; Kim, Jessica, E-mail: jesskim820@gmail.com

In humans, chronic infection with the gammaherpesvirus Epstein-Barr virus is usually asymptomatic; however some infected individuals develop hematological and epithelial malignancies. The exact role of EBV in lymphomagenesis is poorly understood partly because of the lack of clinically relevant animal models. Here we report the detection of serological responses against EBV capsid antigens in healthy dogs and dogs with spontaneous lymphoma and that dogs with the highest antibody titers have B cell lymphoma. Moreover, we demonstrate the presence of EBV-like viral DNA and RNA sequences and Latent Membrane Protein-1 in malignant lymph nodes of dogs with lymphoma. Finally, electron microscopymore » of canine malignant B cells revealed the presence of classic herpesvirus particles. These findings suggest that dogs can be naturally infected with an EBV-like gammaherpesvirus that may contribute to lymphomagenesis and that dogs might represent a spontaneous model to investigate environmental and genetic factors that influence gammaherpesvirus-associated lymphomagenesis in humans.« less

Sudden cardiac death in haemodialysis: clinical epidemiology and mechanisms.

PubMed

Banerjee, Debasish

Sudden cardiac death, which causes premature loss of lives on haemodialysis of the elderly, youths and even children; cannot be prevented, because the aetiology is poorly understood and effective interventions are yet unknown. Improving our knowledge of mechanisms causing sudden cardiac death in haemodialysis patients may help us to design better interventions; and clinical epidemiology of sudden cardiac death could be an important tool to further guide human and animal studies. This review researches the clinical epidemiology of sudden cardiac death to suggest possible mechanisms, although they require further studies. The research shows how traditional cardiovascular risk factors such as age, diabetes and smoking have an impact; non-traditional risk factors such as inflammation, mineral-bone disease and even uraemia itself have higher impact; and how cardiac structural, functional and electrocardiographic markers predict sudden cardiac death in dialysis patients. More in-depth human and animal studies, guided with existing knowledge, are necessary to better understand the mechanisms and design successful interventions. Copyright © 2016 Elsevier Inc. All rights reserved.

Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes.

PubMed

Cox, Pete J; Kirk, Tom; Ashmore, Tom; Willerton, Kristof; Evans, Rhys; Smith, Alan; Murray, Andrew J; Stubbs, Brianna; West, James; McLure, Stewart W; King, M Todd; Dodd, Michael S; Holloway, Cameron; Neubauer, Stefan; Drawer, Scott; Veech, Richard L; Griffin, Julian L; Clarke, Kieran

2016-08-09

Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease. Copyright © 2016 Elsevier Inc. All rights reserved.

A Review of the Role of Food and the Food System in the Transmission and Spread of Ebolavirus

PubMed Central

Mann, Erin; Streng, Stephen; Bergeron, Justin; Kircher, Amy

2015-01-01

The current outbreak of Ebola virus disease (EVD) centered in West Africa is the largest in history, with nearly ten times more individuals contracting the disease than all previous outbreaks combined. The details of human-to-human and zoonotic ebolavirus transmission have justifiably received the largest share of research attention, and much information exists on these topics. However, although food processing—in the form of slaughtering and preparing wildlife for consumption (referred to as bushmeat)—has been implicated in EVD outbreaks, the full role of food in EVD spread is poorly understood and has been little studied. A literature search was undertaken to assess the current state of knowledge regarding how food can or may transmit ebolaviruses and how the food system contributes to EVD outbreak and spread. The literature reveals surprising preliminary evidence that food and the food system may be more implicated in ebolavirus transmission than expected and that further research is urgently needed. PMID:26633305

Structural Basis of Mitochondrial Transcription Initiation.

PubMed

Hillen, Hauke S; Morozov, Yaroslav I; Sarfallah, Azadeh; Temiakov, Dmitry; Cramer, Patrick

2017-11-16

Transcription in human mitochondria is driven by a single-subunit, factor-dependent RNA polymerase (mtRNAP). Despite its critical role in both expression and replication of the mitochondrial genome, transcription initiation by mtRNAP remains poorly understood. Here, we report crystal structures of human mitochondrial transcription initiation complexes assembled on both light and heavy strand promoters. The structures reveal how transcription factors TFAM and TFB2M assist mtRNAP to achieve promoter-dependent initiation. TFAM tethers the N-terminal region of mtRNAP to recruit the polymerase to the promoter whereas TFB2M induces structural changes in mtRNAP to enable promoter opening and trapping of the DNA non-template strand. Structural comparisons demonstrate that the initiation mechanism in mitochondria is distinct from that in the well-studied nuclear, bacterial, or bacteriophage transcription systems but that similarities are found on the topological and conceptual level. These results provide a framework for studying the regulation of gene expression and DNA replication in mitochondria. Copyright © 2017 Elsevier Inc. All rights reserved.

Traceability

PubMed Central

2010-01-01

The importance of effective and timely traceability in both the recall of substances of human origin (blood, cells, tissues and organs) implicated in infectious transmission, and in the prevention of inappropriate use of substances of human origin is now well recognised. However, traceability remains poorly understood and inadequately controlled in many cases. In particular there is: a lack of appreciation of the complexity of the traceability pathway; a fragmented approach to traceability; and, an assumption that traceability data is static. The traceability path for a single tissue donor may involve dozens or even hundreds of different organizations, each responsible for one segment of the path. Whilst responsibility within each organization may be clearly defined, responsibility for maintaining the interfaces between organizations is often less clear. Traceability is seldom regarded in a holistic manner, the assumption being made that if each segment of the pathway is correctly maintained then the full path will be intact. End to end traceability audits are not routinely performed, and the only true test of the trail occurs when recall is required—often with inadequate results. PMID:20628821

Formal Models of the Network Co-occurrence Underlying Mental Operations

PubMed Central

Bzdok, Danilo; Varoquaux, Gaël; Grisel, Olivier; Eickenberg, Michael; Poupon, Cyril; Thirion, Bertrand

2016-01-01

Systems neuroscience has identified a set of canonical large-scale networks in humans. These have predominantly been characterized by resting-state analyses of the task-unconstrained, mind-wandering brain. Their explicit relationship to defined task performance is largely unknown and remains challenging. The present work contributes a multivariate statistical learning approach that can extract the major brain networks and quantify their configuration during various psychological tasks. The method is validated in two extensive datasets (n = 500 and n = 81) by model-based generation of synthetic activity maps from recombination of shared network topographies. To study a use case, we formally revisited the poorly understood difference between neural activity underlying idling versus goal-directed behavior. We demonstrate that task-specific neural activity patterns can be explained by plausible combinations of resting-state networks. The possibility of decomposing a mental task into the relative contributions of major brain networks, the "network co-occurrence architecture" of a given task, opens an alternative access to the neural substrates of human cognition. PMID:27310288

Epigenomic Analysis of Multi-lineage Differentiation of Human Embryonic Stem Cells

PubMed Central

Xie, Wei; Schultz, Matthew D.; Lister, Ryan; Hou, Zhonggang; Rajagopal, Nisha; Ray, Pradipta; Whitaker, John W.; Tian, Shulan; Hawkins, R. David; Leung, Danny; Yang, Hongbo; Wang, Tao; Lee, Ah Young; Swanson, Scott A.; Zhang, Jiuchun; Zhu, Yun; Kim, Audrey; Nery, Joseph R.; Urich, Mark A.; Kuan, Samantha; Yen, Chia-an; Klugman, Sarit; Yu, Pengzhi; Suknuntha, Kran; Propson, Nicholas E.; Chen, Huaming; Edsall, Lee E.; Wagner, Ulrich; Li, Yan; Ye, Zhen; Kulkarni, Ashwinikumar; Xuan, Zhenyu; Chung, Wen-Yu; Chi, Neil C.; Antosiewicz-Bourget, Jessica E.; Slukvin, Igor; Stewart, Ron; Zhang, Michael Q.; Wang, Wei; Thomson, James A.; Ecker, Joseph R.; Ren, Bing

2013-01-01

SUMMARY Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells, and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in non-expressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation. PMID:23664764

LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake

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

Zhou,Z.; Zhen, J.; Karpowich, N.

2007-01-01

Tricyclic antidepressants exert their pharmacological effect -- inhibiting the reuptake of serotonin, norepinephrine, and dopamine -- by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This bindingmore » site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.« less

Pregnancy and Infants' Outcome: Nutritional and Metabolic Implications.

PubMed

Berti, C; Cetin, I; Agostoni, C; Desoye, G; Devlieger, R; Emmett, P M; Ensenauer, R; Hauner, H; Herrera, E; Hoesli, I; Krauss-Etschmann, S; Olsen, S F; Schaefer-Graf, U; Schiessl, B; Symonds, M E; Koletzko, B

2016-01-01

Pregnancy is a complex period of human growth, development, and imprinting. Nutrition and metabolism play a crucial role for the health and well-being of both mother and fetus, as well as for the long-term health of the offspring. Nevertheless, several biological and physiological mechanisms related to nutritive requirements together with their transfer and utilization across the placenta are still poorly understood. In February 2009, the Child Health Foundation invited leading experts of this field to a workshop to critically review and discuss current knowledge, with the aim to highlight priorities for future research. This paper summarizes our main conclusions with regards to maternal preconceptional body mass index, gestational weight gain, placental and fetal requirements in relation to adverse pregnancy and long-term outcomes of the fetus (nutritional programming). We conclude that there is an urgent need to develop further human investigations aimed at better understanding of the basis of biochemical mechanisms and pathophysiological events related to maternal-fetal nutrition and offspring health. An improved knowledge would help to optimize nutritional recommendations for pregnancy.

AR Signaling in Human Malignancies: Prostate Cancer and Beyond.

PubMed

Antonarakis, Emmanuel S

2018-01-18

The notion that androgens and androgen receptor (AR) signaling are the hallmarks of prostate cancer oncogenesis and disease progression is generally well accepted. What is more poorly understood is the role of AR signaling in other human malignancies. This special issue of Cancers initially reviews the role of AR in advanced prostate cancer, and then explores the potential importance of AR signaling in other epithelial malignancies. The first few articles focus on the use of novel AR-targeting therapies in castration-resistant prostate cancer and the mechanisms of resistance to novel antiandrogens, and they also outline the interaction between AR and other cellular pathways, including PI3 kinase signaling, transcriptional regulation, angiogenesis, stromal factors, Wnt signaling, and epigenetic regulation in prostate cancer. The next several articles review the possible role of androgens and AR signaling in breast cancer, bladder cancer, salivary gland cancer, and hepatocellular carcinoma, as well as the potential treatment implications of using antiandrogen therapies in these non-prostatic malignancies.

Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury

PubMed Central

Wenger, Nikolaus; Moraud, Eduardo Martin; Gandar, Jerome; Musienko, Pavel; Capogrosso, Marco; Baud, Laetitia; Le Goff, Camille G.; Barraud, Quentin; Pavlova, Natalia; Dominici, Nadia; Minev, Ivan R.; Asboth, Leonie; Hirsch, Arthur; Duis, Simone; Kreider, Julie; Mortera, Andrea; Haverbeck, Oliver; Kraus, Silvio; Schmitz, Felix; DiGiovanna, Jack; van den Brand, Rubia; Bloch, Jocelyne; Detemple, Peter; Lacour, Stéphanie P.; Bézard, Erwan; Micera, Silvestro; Courtine, Grégoire

2016-01-01

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited this therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here, we developed novel stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real–time control software that modulate extensor versus flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight–bearing capacities, endurance and skilled locomotion in multiple rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans. PMID:26779815

Sporulation: how to survive on planet Earth (and beyond).

PubMed

Huang, Mingwei; Hull, Christina M

2017-10-01

Sporulation is a strategy widely utilized by a wide variety of organisms to adapt to changes in their individual environmental niches and survive in time and/or space until they encounter conditions acceptable for vegetative growth. The spores produced by bacteria have been the subjects of extensive studies, and several systems such as Bacillus subtilis have provided ample opportunities to understand the molecular basis of spore biogenesis and germination. In contrast, the spores of other microbes, such as fungi, are relatively poorly understood. Studies of sporulation in model systems such as Saccharomyces cerevisiae and Aspergillus nidulans have established a basis for investigating eukaryotic spores, but very little is known at the molecular level about how spores function. This is especially true among the spores of human fungal pathogens such as the most common cause of fatal fungal disease, Cryptococcus neoformans. Recent proteomic studies are helping to determine the molecular mechanisms by which pathogenic fungal spores are formed, persist and germinate into actively growing agents of human disease.

Stem cells and fluid flow drive cyst formation in an invertebrate excretory organ

PubMed Central

Thi-Kim Vu, Hanh; Rink, Jochen C; McKinney, Sean A; McClain, Melainia; Lakshmanaperumal, Naharajan; Alexander, Richard; Sánchez Alvarado, Alejandro

2015-01-01

Cystic kidney diseases (CKDs) affect millions of people worldwide. The defining pathological features are fluid-filled cysts developing from nephric tubules due to defective flow sensing, cell proliferation and differentiation. The underlying molecular mechanisms, however, remain poorly understood, and the derived excretory systems of established invertebrate models (Caenorhabditis elegans and Drosophila melanogaster) are unsuitable to model CKDs. Systematic structure/function comparisons revealed that the combination of ultrafiltration and flow-associated filtrate modification that is central to CKD etiology is remarkably conserved between the planarian excretory system and the vertebrate nephron. Consistently, both RNA-mediated genetic interference (RNAi) of planarian orthologues of human CKD genes and inhibition of tubule flow led to tubular cystogenesis that share many features with vertebrate CKDs, suggesting deep mechanistic conservation. Our results demonstrate a common evolutionary origin of animal excretory systems and establish planarians as a novel and experimentally accessible invertebrate model for the study of human kidney pathologies. DOI: http://dx.doi.org/10.7554/eLife.07405.001 PMID:26057828

CNS tau efflux via exosomes is likely increased in Parkinson disease but not in Alzheimer disease

PubMed Central

Shi, Min; Kovac, Andrej; Korff, Ane; Cook, Travis J.; Ginghina, Carmen; Bullock, Kristin M.; Yang, Li; Stewart, Tessandra; Zheng, Danfeng; Aro, Patrick; Atik, Anzari; Kerr, Kathleen F.; Zabetian, Cyrus P.; Peskind, Elaine R.; Hu, Shu-Ching; Quinn, Joseph F.; Galasko, Douglas R.; Montine, Thomas J.; Banks, William A.; Zhang, Jing

2016-01-01

Background Alzheimer disease (AD) and Parkinson disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood. Methods Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by Single Molecule Array technology with 303 subjects. Results The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls, and correlated with cerebrospinal fluid tau. Conclusions Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD. PMID:27234211

LINE-1 couples EMT programming with acquisition of oncogenic phenotypes in human bronchial epithelial cells.

PubMed

Reyes-Reyes, Elsa M; Aispuro, Ivan; Tavera-Garcia, Marco A; Field, Matthew; Moore, Sara; Ramos, Irma; Ramos, Kenneth S

2017-11-28

Although several lines of evidence have established the central role of epithelial-to-mesenchymal-transition (EMT) in malignant progression of non-small cell lung cancers (NSCLCs), the molecular events connecting EMT to malignancy remain poorly understood. This study presents evidence that Long Interspersed Nuclear Element-1 (LINE-1) retrotransposon couples EMT programming with malignancy in human bronchial epithelial cells (BEAS-2B). This conclusion is supported by studies showing that: 1) activation of EMT programming by TGF-β1 increases LINE-1 mRNAs and protein; 2) the lung carcinogen benzo(a)pyrene coregulates TGF-β1 and LINE-1 mRNAs, with LINE-1 positioned downstream of TGF-β1 signaling; and, 3) forced expression of LINE-1 in BEAS-2B cells recapitulates EMT programming and induces malignant phenotypes and tumorigenesis in vivo . These findings identify a TGFβ1-LINE-1 axis as a critical effector pathway that can be targeted for the development of precision therapies during malignant progression of intractable NSCLCs.

A Consensus Model of Human Apolipoprotein A-I in its Monomeric and Lipid-free State

PubMed Central

Melchior, John T.; Walker, Ryan G.; Cooke, Allison L.; Morris, Jamie; Castleberry, Mark; Thompson, Thomas B.; Jones, Martin K.; Song, Hyun D.; Rye, Kerry-Anne; Oda, Mike N.; Sorci-Thomas, Mary G.; Thomas, Michael J.; Heinecke, Jay W.; Mei, Xiaohu; Atkinson, David; Segrest, Jere P.; Lund-Katz, Sissel; Phillips, Michael C.; Davidson, W. Sean

2017-01-01

Apolipoprotein (apo)A-I is an organizing scaffold protein that is critical to high density lipoprotein (HDL) structure and metabolism, likely mediating many of its cardioprotective properties. However, HDL biogenesis is poorly understood as lipid-free apoA-I has been notoriously resistant to high resolution structural study. Published models from low resolution techniques share certain features but vary considerably in shape and secondary structure. To tackle this central issue in lipoprotein biology, we assembled an unprecedented team of lipoprotein structural biologists and set out to build a consensus model of monomeric lipid-free human apoA-I. Combining novel and published cross-link constraints, small angle X-ray scattering (SAXS), hydrogen-deuterium exchange (H-DX) and crystallography data, we propose a time averaged model consistent with much of the experimental data published over the last 40 years. The model provides a long sought platform for understanding and testing details of HDL biogenesis, structure and function. PMID:29131142

Mechanism of IRSp53 inhibition and combinatorial activation by Cdc42 and downstream effectors.

PubMed

Kast, David J; Yang, Changsong; Disanza, Andrea; Boczkowska, Malgorzata; Madasu, Yadaiah; Scita, Giorgio; Svitkina, Tatyana; Dominguez, Roberto

2014-04-01

The Rho family GTPase effector IRSp53 has essential roles in filopodia formation and neuronal development, but its regulatory mechanism is poorly understood. IRSp53 contains a membrane-binding BAR domain followed by an unconventional CRIB motif that overlaps with a proline-rich region (CRIB-PR) and an SH3 domain that recruits actin cytoskeleton effectors. Using a fluorescence reporter assay, we show that human IRSp53 adopts a closed inactive conformation that opens synergistically with the binding of human Cdc42 to the CRIB-PR and effector proteins, such as the tumor-promoting factor Eps8, to the SH3 domain. The crystal structure of Cdc42 bound to the CRIB-PR reveals a new mode of effector binding to Rho family GTPases. Structure-inspired mutations disrupt autoinhibition and Cdc42 binding in vitro and decouple Cdc42- and IRSp53-dependent filopodia formation in cells. The data support a combinatorial mechanism of IRSp53 activation.

Recent Insights into the Control of Human Papillomavirus (HPV) Genome Stability, Loss, and Degradation.

PubMed

Fisher, Chris

2015-01-01

Most human papillomavirus (HPV) antiviral strategies have focused upon inhibiting viral DNA replication, but it is increasingly apparent that viral DNA levels can be chemically controlled by approaches that promote its instability. HPVs and other DNA viruses have a tenuous relationship with their hosts. They must replicate and hide from the DNA damage response (DDR) and innate immune systems, which serve to protect cells from foreign or "non-self" DNA, and yet they draft these same systems to support their life cycles. DNA binding antiviral agents promoting massive viral DNA instability and elimination are reviewed. Mechanistic studies of these agents have identified genetic antiviral enhancers and repressors, antiviral sensitizers, and host cell elements that protect and stabilize HPV genomes. Viral DNA degradation appears to be an important means of controlling HPV DNA levels in some cases, but the underlying mechanisms remain poorly understood. These findings may prove useful not only for understanding viral DNA persistence but also in devising future antiviral strategies.

Structural centrosome aberrations favor proliferation by abrogating microtubule-dependent tissue integrity of breast epithelial mammospheres

PubMed Central

Schnerch, D; Nigg, E A

2016-01-01

Structural centrosome aberrations are frequently observed in early stage carcinomas, but their role in malignant transformation is poorly understood. Here, we examined the impact of overexpression of Ninein-like protein (Nlp) on the architecture of polarized epithelia in three-dimensional mammospheres. When Nlp was overexpressed to levels resembling those seen in human tumors, it formed striking centrosome-related bodies (CRBs), which sequestered Ninein and affected the kinetics of microtubule (MT) nucleation and release. In turn, the profound reorganization of the MT cytoskeleton resulted in mislocalization of several adhesion and junction proteins as well as the tumor suppressor Scribble, resulting in the disruption of epithelial polarity, cell-cell interactions and mammosphere architecture. Remarkably, cells harboring Nlp-CRBs displayed an enhanced proliferative response to epidermal growth factor. These results demonstrate that structural centrosome aberrations cause not only the disruption of epithelial polarity but also favor overproliferation, two phenotypes typically associated with human carcinomas. PMID:26364601

The crystal structure of human GlnRS provides basis for the development of neurological disorders

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

Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen

Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggestmore » that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. As a result, this report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. Keywords« less

Controlling epithelial sodium channels with light using photoswitchable amilorides

NASA Astrophysics Data System (ADS)

Schönberger, Matthias; Althaus, Mike; Fronius, Martin; Clauss, Wolfgang; Trauner, Dirk

2014-08-01

Amiloride is a widely used diuretic that blocks epithelial sodium channels (ENaCs). These heterotrimeric transmembrane proteins, assembled from β, γ and α or δ subunits, effectively control water transport across epithelia and sodium influx into non-epithelial cells. The functional role of δβγENaC in various organs, including the human brain, is still poorly understood and no pharmacological tools are available for the functional differentiation between α- and δ-containing ENaCs. Here we report several photoswitchable versions of amiloride. One compound, termed PA1, enables the optical control of ENaC channels, in particular the δβγ isoform, by switching between blue and green light, or by turning on and off blue light. PA1 was used to modify functionally δβγENaC in amphibian and mammalian cells. We also show that PA1 can be used to differentiate between δβγENaC and αβγENaC in a model for the human lung epithelium.

MicroRNA-650 targets ING4 to promote gastric cancer tumorigenicity

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

Zhang, XueLi, E-mail: zhangxueli.200010@yahoo.com.cn; Zhu, WeiYing; Zhang, JiFa

2010-04-30

MicroRNAs (miRNAs) are non-coding RNAs that regulate the expression of target mRNAs. Altered expression of specific miRNAs in human gastric cancer progression has been reported; however, the role of miR-650 in gastric cancer is poorly understood. In this study, we show that miR-650 is involved in lymphatic and distant metastasis in human gastric cancer, and we find that ectopic expression of miR-650 promotes tumorigenesis and proliferation of gastric cancer cells. A luciferase reporter assay demonstrates that Inhibitor of Growth 4 (ING4) is a direct target of miR-650. Collectively, our study demonstrates that over-expression of miR-650 in gastric cancer may promotemore » proliferation and growth of cancer cells, at least partially through directly targeting ING4. These findings help clarify the molecular mechanisms involved in gastric carcinogenesis and indicate that miR-650 modulation may be a bona fide miRNA-based treatment of gastric cancer.« less

Neurocomputational account of how the human brain decides when to have a break.

PubMed

Meyniel, Florent; Sergent, Claire; Rigoux, Lionel; Daunizeau, Jean; Pessiglione, Mathias

2013-02-12

No pain, no gain: cost-benefit trade-off has been formalized in classical decision theory to account for how we choose whether to engage effort. However, how the brain decides when to have breaks in the course of effort production remains poorly understood. We propose that decisions to cease and resume work are triggered by a cost evidence accumulation signal reaching upper and lower bounds, respectively. We developed a task in which participants are free to exert a physical effort knowing that their payoff would be proportional to their effort duration. Functional MRI and magnetoencephalography recordings conjointly revealed that the theoretical cost evidence accumulation signal was expressed in proprioceptive regions (bilateral posterior insula). Furthermore, the slopes and bounds of the accumulation process were adapted to the difficulty of the task and the money at stake. Cost evidence accumulation might therefore provide a dynamical mechanistic account of how the human brain maximizes benefits while preventing exhaustion.

Extracellular matrix components expression in human pluripotent stem cell-derived retinal organoids recapitulates retinogenesis in vivo and reveals an important role for IMPG1 and CD44 in the development of photoreceptors and interphotoreceptor matrix.

PubMed

Felemban, Majed; Dorgau, Birthe; Hunt, Nicola Claire; Hallam, Dean; Zerti, Darin; Bauer, Roman; Ding, Yuchun; Collin, Joseph; Steel, David; Krasnogor, Natalio; Al-Aama, Jumana; Lindsay, Susan; Mellough, Carla; Lako, Majlinda

2018-05-17

The extracellular matrix (ECM) plays an important role in numerous processes including cellular proliferation, differentiation, migration, maturation, adhesion guidance and axonal growth. To date, there has been no detailed analysis of the ECM distribution during retinal ontogenesis in humans and the functional importance of many ECM components is poorly understood. In this study, the expression of key ECM components in adult mouse and monkey retina, developing and adult human retina and retinal organoids derived from human pluripotent stem cells was studied. Our data indicate that basement membrane ECMs (Fibronectin and Collagen IV) were expressed in Bruch's membrane and the inner limiting membrane of the developing human retina, whilst the hyalectins (Versican and Brevican), cluster of differentiation 44 (CD44), photoreceptor-specific ECMs Interphotoreceptor Matrix Proteoglycan 1 (IMPG1) and Interphotoreceptor Matrix Proteoglycan 2 (IMPG2) were detected in the developing interphotoreceptor matrix (IPM). The expression of IMPG1, Versican and Brevican in the developing IPM was conserved between human developing retina and human pluripotent stem cell-derived retinal organoids. Blocking the action of CD44 and IMPG1 in pluripotent stem cell derived retinal organoids affected the development of photoreceptors, their inner/outer segments and connecting cilia and disrupted IPM formation, with IMPG1 having an earlier and more significant impact. Together, our data suggest an important role for IMPG1 and CD44 in the development of photoreceptors and IPM formation during human retinogenesis. The expression and the role of many extracellular matrix (ECM) components during human retinal development is not fully understood. In this study, expression of key ECM components (Collagen IV, Fibronectin, Brevican, Versican, IMPG1 and IMPG2) was investigated during human retinal ontogenesis. Collagen IV and Fibronectin were expressed in Bruch's membrane; whereas Brevican, Versican, IMPG1 & IMPG2 in the developing interphotoreceptor matrix (IPM). Retinal organoids were successfully generated from pluripotent stem cells. The expression of ECM components was examined in the retinal organoids and found to recapitulate human retinal development in vivo. Using functional blocking experiments, we were able to highlight an important role for IMPG1 and CD44 in the development of photoreceptors and IPM formation. Copyright © 2018 Acta Materialia Inc. All rights reserved.

Expression of cytoskeleton regulatory protein Mena in human hepatocellular carcinoma and its prognostic significance.

PubMed

Hu, Kunpeng; Wang, Jiani; Yao, Zhicheng; Liu, Bo; Lin, Yuan; Liu, Lei; Xu, Lihua

2014-05-01

The molecular mechanisms of the development and progression of hepatocellular carcinoma (HCC) are poorly understood. The main objective of this study was to analyze the expression of Enabled [mammalian Ena (Mena)] protein and its clinical significance in human HCC. The Mena expression was examined at mRNA and protein levels by real-time quantitative polymerase chain reaction and Western blotting analysis in ten paired HCC tissues and the adjacent normal tissues. The expression of Mena protein in 81 specimens of HCC tissues was determined by immunohistochemistry. Associations of Mena expression with the clinicopathological features were analyzed, and prognosis of HCC patients was evaluated. The result shows the expression of Mena mRNA and protein was higher in HCC than in the adjacent normal tissues in ten paired samples. Mena was mainly accumulated in the cytoplasm of tumor cells and over-expressed in 40.74% (33/81) patients by immunohistochemical staining. Over-expression of Mena was significantly associated with poor cellular differentiation (P = 0.025), advanced tumor stage (P = 0.003) and worse disease-free survival (DFS, P < 0.001). In addition, Mena is an independent prognostic factor for DFS in multivariate analysis (HR 2.309, 95% CI 1.104-4.828; P = 0.026). Mena is up-regulated in HCC and associated with tumor differentiation and clinical stage. Mena may be an independent prognostic marker for DFS of HCC patients.

Human Ageing Genomic Resources: new and updated databases

PubMed Central

Tacutu, Robi; Thornton, Daniel; Johnson, Emily; Budovsky, Arie; Barardo, Diogo; Craig, Thomas; Diana, Eugene; Lehmann, Gilad; Toren, Dmitri; Wang, Jingwei; Fraifeld, Vadim E

2018-01-01

Abstract In spite of a growing body of research and data, human ageing remains a poorly understood process. Over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for studying the biology and genetics of ageing. Here, we present HAGR’s main functionalities, highlighting new additions and improvements. HAGR consists of six core databases: (i) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; (ii) the AnAge database of animal ageing and longevity, featuring >4000 species; (iii) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; (iv) the LongevityMap database of human genetic association studies of longevity with >500 entries; (v) the DrugAge database with >400 ageing or longevity-associated drugs or compounds; (vi) the CellAge database with >200 genes associated with cell senescence. All our databases are manually curated by experts and regularly updated to ensure a high quality data. Cross-links across our databases and to external resources help researchers locate and integrate relevant information. HAGR is freely available online (http://genomics.senescence.info/). PMID:29121237

The Human Release Hypothesis for biological invasions: human activity as a determinant of the abundance of invasive plant species.

PubMed

Zimmermann, Heike; Brandt, Patric; Fischer, Joern; Welk, Erik; von Wehrden, Henrik

2014-01-01

Research on biological invasions has increased rapidly over the past 30 years, generating numerous explanations of how species become invasive. While the mechanisms of invasive species establishment are well studied, the mechanisms driving abundance patterns (i.e. patterns of population density and population size) remain poorly understood. It is assumed that invasive species typically have higher abundances in their new environments than in their native ranges, and patterns of invasive species abundance differ between invaded regions. To explain differences in invasive species abundance, we propose the Human Release Hypothesis. In parallel to the established Enemy Release Hypothesis, this hypothesis states that the differences in abundance of invasive species are found between regions because population expansion is reduced in some regions through continuous land management and associated cutting of the invasive species. The Human Release Hypothesis does not negate other important drivers of species invasions, but rather should be considered as a potentially important complementary mechanism. We illustrate the hypothesis via a case study on an invasive rose species, and hypothesize which locations globally may be most likely to support high abundances of invasive species. We propose that more extensive empirical work on the Human Release Hypothesis could be useful to test its general applicability.

The Human Release Hypothesis for biological invasions: human activity as a determinant of the abundance of invasive plant species

PubMed Central

Zimmermann, Heike; Brandt, Patric; Fischer, Joern; Welk, Erik; von Wehrden, Henrik

2014-01-01

Research on biological invasions has increased rapidly over the past 30 years, generating numerous explanations of how species become invasive. While the mechanisms of invasive species establishment are well studied, the mechanisms driving abundance patterns (i.e. patterns of population density and population size) remain poorly understood. It is assumed that invasive species typically have higher abundances in their new environments than in their native ranges, and patterns of invasive species abundance differ between invaded regions. To explain differences in invasive species abundance, we propose the Human Release Hypothesis. In parallel to the established Enemy Release Hypothesis, this hypothesis states that the differences in abundance of invasive species are found between regions because population expansion is reduced in some regions through continuous land management and associated cutting of the invasive species. The Human Release Hypothesis does not negate other important drivers of species invasions, but rather should be considered as a potentially important complementary mechanism. We illustrate the hypothesis via a case study on an invasive rose species, and hypothesize which locations globally may be most likely to support high abundances of invasive species. We propose that more extensive empirical work on the Human Release Hypothesis could be useful to test its general applicability. PMID:25352979

The episode of genetic drift defining the migration of humans out of Africa is derived from a large east African population size.

PubMed

Elhassan, Nuha; Gebremeskel, Eyoab Iyasu; Elnour, Mohamed Ali; Isabirye, Dan; Okello, John; Hussien, Ayman; Kwiatksowski, Dominic; Hirbo, Jibril; Tishkoff, Sara; Ibrahim, Muntaser E

2014-01-01

Human genetic variation particularly in Africa is still poorly understood. This is despite a consensus on the large African effective population size compared to populations from other continents. Based on sequencing of the mitochondrial Cytochrome C Oxidase subunit II (MT-CO2), and genome wide microsatellite data we observe evidence suggesting the effective size (Ne) of humans to be larger than the current estimates, with a foci of increased genetic diversity in east Africa, and a population size of east Africans being at least 2-6 fold larger than other populations. Both phylogenetic and network analysis indicate that east Africans possess more ancestral lineages in comparison to various continental populations placing them at the root of the human evolutionary tree. Our results also affirm east Africa as the likely spot from which migration towards Asia has taken place. The study reflects the spectacular level of sequence variation within east Africans in comparison to the global sample, and appeals for further studies that may contribute towards filling the existing gaps in the database. The implication of these data to current genomic research, as well as the need to carry out defined studies of human genetic variation that includes more African populations; particularly east Africans is paramount.

Bacterial food-borne zoonoses.

PubMed

Thorns, C J

2000-04-01

In many countries of the world, bacterial food-borne zoonotic infections are the most common cause of human intestinal disease. Salmonella and Campylobacter account for over 90% of all reported cases of bacteria-related food poisoning world-wide. Poultry and poultry products have been incriminated in the majority of traceable food-borne illnesses caused by these bacteria, although all domestic livestock are reservoirs of infection. In contrast to the enzootic nature of most Salmonella and Campylobacter infections, Salmonella Enteritidis caused a pandemic in both poultry and humans during the latter half of the 20th Century. Salmonella Typhimurium and Campylobacter appear to be more ubiquitous in the environment, colonising a greater variety of hosts and environmental niches. Verocytotoxin-producing Escherichia coli O157 (VTEC O157) also emerged as a major food-borne zoonotic pathogen in the 1980s and 1990s. Although infection is relatively rare in humans, clinical disease is often severe, with a significant mortality rate among the young and elderly. The epidemiology of VTEC O157 is poorly understood, although ruminants, especially cattle and sheep, appear to be the major source of infection. The dissemination of S. Enteritidis along the food chain is fairly well understood, and control programmes have been developed to target key areas of poultry meat and egg production. Recent evidence indicates that these control programmes have been associated with an overall reduction of S. Enteritidis along the food chain. Unfortunately, existing controls do not appear to reduce the levels of Campylobacter and VTEC O157 infections. Future control strategies need to consider variations in the epidemiologies of food-borne zoonotic infections, and apply a quantitative risk analysis approach to ensure that the most cost-effective programmes are developed.

Digestive tract absorption of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in a nursing infant

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

McLachlan, M.S.

The digestive tract absorption of environmental contaminants is an important but poorly understood parameter in contaminant is an important but poorly understood parameter in contaminant risk assessments. The net absorption of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in a nursing infant was measured under natural conditions over 12 days. The levels of the substances in the mother's milk were typical for Germany. It was found that for almost all congeners over 90% of the ingested compound was absorbed. This indicates that the common assumption of 100% absorption in nursing infants is reasonable. No firm conclusions could be drawn regarding the absorptionmore » of Cl7- and Cl8DD/F due to high blank levels in the cotton diapers used.« less

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.

The RNA-binding protein PCBP2 facilitates gastric carcinoma growth by targeting miR-34a

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

Hu, Cheng-En; Liu, Yong-Chao; Zhang, Hui-Dong

Highlights: • PCBP2 is overexpressed in human gastric cancer. • PCBP2 high expression predicts poor survival. • PCBP2 regulates gastric cancer growth in vitro and in vivo. • PCBP2 regulates gastric cancer apoptosis by targeting miR-34a. - Abstract: Gastric carcinoma is the fourth most common cancer worldwide, with a high rate of death and low 5-year survival rate. However, the mechanism underling gastric cancer is still not fully understood. Here in the present study, we identify the RNA-binding protein PCBP2 as an oncogenic protein in human gastric carcinoma. Our results show that PCBP2 is up-regulated in human gastric cancer tissuesmore » compared to adjacent normal tissues, and that high level of PCBP2 predicts poor overall and disease-free survival. Knockdown of PCBP2 in gastric cancer cells inhibits cell proliferation and colony formation in vitro, whereas opposing results are obtained when PCBP2 is overexpressed. Our in vivo subcutaneous xenograft results also show that PCBP2 can critically regulate gastric cancer cell growth. In addition, we find that PCBP2-depletion induces apoptosis in gastric cancer cells via up-regulating expression of pro-apoptotic proteins and down-regulating anti-apoptotic proteins. Mechanically, we identify that miR-34a as a target of PCBP2, and that miR-34a is critically essential for the function of PCBP2. In summary, PCBP2 promotes gastric carcinoma development by regulating the level of miR-34a.« less

Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms

PubMed Central

2013-01-01

Synopsis Although it is widely appreciated that cats respond differently to certain drugs when compared with other companion animal species, the causes of these differences are poorly understood. This review critically evaluates published evidence for altered drug effects in cats, focusing on pharmacokinetic differences between cats, dogs and humans, and the molecular mechanisms underlying these differences. Pharmacokinetic studies indicate that acetaminophen, propofol, carprofen, and acetylsalicylic acid (aspirin) are cleared significantly more slowly in cats versus dogs and humans. All of these drugs are metabolized by conjugation. Cats lack the major phenol UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A6 and UGT1A9, that glucuronidate acetaminophen and propofol. Deficient glucuronidation may also explain slower carprofen clearance, although there is no direct evidence for this. However, poor aspirin clearance in cats appears to be mainly a consequence of slower glycine conjugation. Cats are also deficient in several other conjugation enzymes, including N-acetyltransferase (NAT) 2 and thiopurine methyltransferase (TMPT). NAT2 deficiency may be the reason cats are more prone to developing methemoglobinemia rather than hepatotoxicity from acetaminophen. TMPT deficiency may predispose cats to azathioprine toxicity. No evidence was found for slower elimination of drugs cleared by oxidation or unchanged into urine or bile. Piroxicam, an oxidized drug, was cleared much more rapidly in cats than humans and dogs, although the mechanism for this difference is unclear. More work is needed to better understand drug metabolism and disposition differences in cats, thereby enabling more rational prescribing of existing medications, and the development of safer drugs for this species. PMID:23890237

Protein Malnutrition Modifies Innate Immunity and Gene Expression by Intestinal Epithelial Cells and Human Rotavirus Infection in Neonatal Gnotobiotic Pigs

PubMed Central

Paim, Francine C.; Kandasamy, Sukumar; Alhamo, Moyasar A.; Fischer, David D.; Langel, Stephanie N.; Deblais, Loic; Kumar, Anand; Chepngeno, Juliet; Shao, Lulu; Huang, Huang-Chi; Candelero-Rueda, Rosario A.; Rajashekara, Gireesh

2017-01-01

ABSTRACT Malnutrition affects millions of children in developing countries, compromising immunity and contributing to increased rates of death from infectious diseases. Rotavirus is a major etiological agent of childhood diarrhea in developing countries, where malnutrition is prevalent. However, the interactions between the two and their combined effects on immune and intestinal functions are poorly understood. In this study, we used neonatal gnotobiotic (Gn) pigs transplanted with the fecal microbiota of a healthy 2-month-old infant (HIFM) and fed protein-deficient or -sufficient bovine milk diets. Protein deficiency induced hypoproteinemia, hypoalbuminemia, hypoglycemia, stunting, and generalized edema in Gn pigs, as observed in protein-malnourished children. Irrespective of the diet, human rotavirus (HRV) infection early, at HIFM posttransplantation day 3 (PTD3), resulted in adverse health effects and higher mortality rates (45 to 75%) than later HRV infection (PTD10). Protein malnutrition exacerbated HRV infection and affected the morphology and function of the small intestinal epithelial barrier. In pigs infected with HRV at PTD10, there was a uniform decrease in the function and/or frequencies of natural killer cells, plasmacytoid dendritic cells, and CD103+ and apoptotic mononuclear cells and altered gene expression profiles of intestinal epithelial cells (chromogranin A, mucin 2, proliferating cell nuclear antigen, SRY-Box 9, and villin). Thus, we have established the first HIFM-transplanted neonatal pig model that recapitulates major aspects of protein malnutrition in children and can be used to evaluate physiologically relevant interventions. Our findings provide an explanation of why nutrient-rich diets alone may lack efficacy in malnourished children. IMPORTANCE Malnutrition and rotavirus infection, prevalent in developing countries, individually and in combination, affect the health of millions of children, compromising their immunity and increasing the rates of death from infectious diseases. However, the interactions between the two and their combined effects on immune and intestinal functions are poorly understood. We have established the first human infant microbiota-transplanted neonatal pig model of childhood malnutrition that reproduced the impaired immune, intestinal, and other physiological functions seen in malnourished children. This model can be used to evaluate relevant dietary and other health-promoting interventions. Our findings provide an explanation of why adequate nutrition alone may lack efficacy in malnourished children. PMID:28261667

Rare, Intense, Big fires dominate the global tropics under drier conditions.

PubMed

Hantson, Stijn; Scheffer, Marten; Pueyo, Salvador; Xu, Chi; Lasslop, Gitta; van Nes, Egbert H; Holmgren, Milena; Mendelsohn, John

2017-10-30

Wildfires burn large parts of the tropics every year, shaping ecosystem structure and functioning. Yet the complex interplay between climate, vegetation and human factors that drives fire dynamics is still poorly understood. Here we show that on all continents, except Australia, tropical fire regimes change drastically as mean annual precipitation falls below 550 mm. While the frequency of fires decreases below this threshold, the size and intensity of wildfires rise sharply. This transition to a regime of Rare-Intense-Big fires (RIB-fires) corresponds to the relative disappearance of trees from the landscape. Most dry regions on the globe are projected to become substantially drier under global warming. Our findings suggest a global zone where this drying may have important implications for fire risks to society and ecosystem functioning.

Microbial community assembly and metabolic function during mammalian corpse decomposition

USGS Publications Warehouse

Metcalf, Jessica L; Xu, Zhenjiang Zech; Weiss, Sophie; Lax, Simon; Van Treuren, Will; Hyde, Embriette R.; Song, Se Jin; Amir, Amnon; Larsen, Peter; Sangwan, Naseer; Haarmann, Daniel; Humphrey, Greg C; Ackermann, Gail; Thompson, Luke R; Lauber, Christian; Bibat, Alexander; Nicholas, Catherine; Gebert, Matthew J; Petrosino, Joseph F; Reed, Sasha C.; Gilbert, Jack A; Lynne, Aaron M; Bucheli, Sibyl R; Carter, David O; Knight, Rob

2016-01-01

Vertebrate corpse decomposition provides an important stage in nutrient cycling in most terrestrial habitats, yet microbially mediated processes are poorly understood. Here we combine deep microbial community characterization, community-level metabolic reconstruction, and soil biogeochemical assessment to understand the principles governing microbial community assembly during decomposition of mouse and human corpses on different soil substrates. We find a suite of bacterial and fungal groups that contribute to nitrogen cycling and a reproducible network of decomposers that emerge on predictable time scales. Our results show that this decomposer community is derived primarily from bulk soil, but key decomposers are ubiquitous in low abundance. Soil type was not a dominant factor driving community development, and the process of decomposition is sufficiently reproducible to offer new opportunities for forensic investigations.

Current Status and Future Development of Cell Transplantation Therapy for Periodontal Tissue Regeneration

PubMed Central

Yoshida, Toshiyuki; Washio, Kaoru; Iwata, Takanori; Okano, Teruo; Ishikawa, Isao

2012-01-01

It has been shown that stem cell transplantation can regenerate periodontal tissue, and several clinical trials involving transplantation of stem cells into human patients have already begun or are in preparation. However, stem cell transplantation therapy is a new technology, and the events following transplantation are poorly understood. Several studies have reported side effects and potential risks associated with stem cell transplantation therapy. To protect patients from such risks, governments have placed regulations on stem cell transplantation therapies. It is important for the clinicians to understand the relevant risks and governmental regulations. This paper describes the ongoing clinical studies, basic research, risks, and governmental controls related to stem cell transplantation therapy. Then, one clinical study is introduced as an example of a government-approved periodontal cell transplantation therapy. PMID:22315604

Emergency warning for people with disabilities.

PubMed

Putkovich, Kenneth

2013-01-01

The intent of this article is to assess the current state of Emergency Warning capabilities in the United States and make recommendations on what needs to be done to cost effectively establish a National Emergency Warning System to best serve the people of the United States, including those with disabilities. As part of this assessment, terminology will be defined, existing systems will be examined, critical needs and functions will be explained, and recommendations made for a system to deliver emergency messages to those people immediately at risk from natural and human-caused disasters in a timely and effective manner, regardless of location or situational circumstance. The assessment will include the needs and available technologies for delivering emergency warnings to people with disabilities, which are generally little understood, poorly addressed, and often ignored.

Probiotic Bacteria Induce a ‘Glow of Health’

PubMed Central

Smillie, Christopher; Varian, Bernard J.; Ibrahim, Yassin M.; Lakritz, Jessica R.; Alm, Eric J.; Erdman, Susan E.

2013-01-01

Radiant skin and hair are universally recognized as indications of good health. However, this ‘glow of health’ display remains poorly understood. We found that feeding of probiotic bacteria to aged mice induced integumentary changes mimicking peak health and reproductive fitness characteristic of much younger animals. Eating probiotic yogurt triggered epithelial follicular anagen-phase shift with sebocytogenesis resulting in thick lustrous fur due to a bacteria-triggered interleukin-10-dependent mechanism. Aged male animals eating probiotics exhibited increased subcuticular folliculogenesis, when compared with matched controls, yielding luxuriant fur only in probiotic-fed subjects. Female animals displayed probiotic-induced hyperacidity coinciding with shinier hair, a feature that also aligns with fertility in human females. Together these data provide insights into mammalian evolution and novel strategies for integumentary health. PMID:23342023

Genes, molecules and patients—Emerging topics to guide clinical pain research

PubMed Central

Sikandar, Shafaq; Patel, Ryan; Patel, Sital; Sikander, Sanam; Bennett, David L.H.; Dickenson, Anthony H.

2013-01-01

This review selectively explores some areas of pain research that, until recently, have been poorly understood. We have chosen four topics that relate to clinical pain and we discuss the underlying mechanisms and related pathophysiologies contributing to these pain states. A key issue in pain medicine involves crucial events and mediators that contribute to normal and abnormal pain signaling, but remain unseen without genetic, biomarker or imaging analysis. Here we consider how the altered genetic make-up of familial pains reveals the human importance of channels discovered by preclinical research, followed by the contribution of receptors as stimulus transducers in cold sensing and cold pain. Finally we review recent data on the neuro-immune interactions in chronic pain and the potential targets for treatment in cancer-induced bone pain. PMID:23500200

Modeling lung cancer evolution and preclinical response by orthotopic mouse allografts.

PubMed

Ambrogio, Chiara; Carmona, Francisco J; Vidal, August; Falcone, Mattia; Nieto, Patricia; Romero, Octavio A; Puertas, Sara; Vizoso, Miguel; Nadal, Ernest; Poggio, Teresa; Sánchez-Céspedes, Montserrat; Esteller, Manel; Mulero, Francisca; Voena, Claudia; Chiarle, Roberto; Barbacid, Mariano; Santamaría, David; Villanueva, Alberto

2014-11-01

Cancer evolution is a process that is still poorly understood because of the lack of versatile in vivo longitudinal studies. By generating murine non-small cell lung cancer (NSCLC) orthoallobanks and paired primary cell lines, we provide a detailed description of an in vivo, time-dependent cancer malignization process. We identify the acquisition of metastatic dissemination potential, the selection of co-driver mutations, and the appearance of naturally occurring intratumor heterogeneity, thus recapitulating the stochastic nature of human cancer development. This approach combines the robustness of genetically engineered cancer models with the flexibility of allograft methodology. We have applied this tool for the preclinical evaluation of therapeutic approaches. This system can be implemented to improve the design of future treatments for patients with NSCLC. ©2014 American Association for Cancer Research.

The Longue Durée of Black Lives Matter.

PubMed

Nelson, Alondra

2016-10-01

Black Lives Matter was first articulated just a few years ago, but it has been the leitmotif of antiracist struggles for generations. The Movement for Black Lives extends the work of previous movements that challenged forms of oppression that act on Black bodies with impunity. It should be understood in the context of Ida B. Wells' anti-lynching campaign, Fannie Lou Hamer's reproductive justice demands, and the Black Panther Party's health activism. The 50th anniversary of the Black Panther Party is an occasion to recall that its work confronted the callous neglect and the corporeal surveillance and abuse of poor Black communities. Similar demands have been the centrifugal force of social movements that for centuries have refused to have Black lives cast beyond the human boundary.

Microbial community assembly and metabolic function during mammalian corpse decomposition

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

Metcalf, J. L.; Xu, Z. Z.; Weiss, S.

2015-12-10

Vertebrate corpse decomposition provides an important stage in nutrient cycling in most terrestrial habitats, yet microbially mediated processes are poorly understood. Here we combine deep microbial community characterization, community-level metabolic reconstruction, and soil biogeochemical assessment to understand the principles governing microbial community assembly during decomposition of mouse and human corpses on different soil substrates. We find a suite of bacterial and fungal groups that contribute to nitrogen cycling and a reproducible network of decomposers that emerge on predictable time scales. Our results show that this decomposer community is derived primarily from bulk soil, but key decomposers are ubiquitous in lowmore » abundance. Soil type was not a dominant factor driving community development, and the process of decomposition is sufficiently reproducible to offer new opportunities for forensic investigations.« less

An immunohistochemical analysis of naturally occurring chancroid.

PubMed

King, R; Gough, J; Ronald, A; Nasio, J; Ndinya-Achola, J O; Plummer, F; Wilkins, J A

1996-08-01

Haemophilus ducreyi is a major cause of genital ulcer disease in many developing countries and is associated with augmented transmission of human immunodeficiency virus (HIV). However, the mechanisms through which H. ducreyi produces ulceration are poorly understood. The characteristics of the host response to H. ducreyi and the pathobiology of its potential contribution to increased HIV susceptibility are not known. Chancroid ulcer biopsies from 8 patients were analyzed histologically and immunohistochemically. All biopsies had perivascular and interstitial mononuclear cell infiltrates that extended deep into the dermis. The infiltrate, which contained macrophages and CD4 and CD8 lymphocytes, was consistent with a delayed hypersensitivity type cell-mediated immune response. The recruitment of CD4 T lymphocytes and macrophages may in part explain the facilitation of HIV transmission in patients with chancroid.

p53 functions as a cell cycle control protein in osteosarcomas.

PubMed

Diller, L; Kassel, J; Nelson, C E; Gryka, M A; Litwak, G; Gebhardt, M; Bressac, B; Ozturk, M; Baker, S J; Vogelstein, B

1990-11-01

Mutations in the p53 gene have been associated with a wide range of human tumors, including osteosarcomas. Although it has been shown that wild-type p53 can block the ability of E1a and ras to cotransform primary rodent cells, it is poorly understood why inactivation of the p53 gene is important for tumor formation. We show that overexpression of the gene encoding wild-type p53 blocks the growth of osteosarcoma cells. The growth arrest was determined to be due to an inability of the transfected cells to progress into S phase. This suggests that the role of the p53 gene as an antioncogene may be in controlling the cell cycle in a fashion analogous to the check-point control genes in Saccharomyces cerevisiae.

Periodic and chaotic host-parasite interactions in human malaria.

PubMed Central

Kwiatkowski, D; Nowak, M

1991-01-01

It has been recognized since ancient times that malaria fever is highly periodic but the mechanism has been poorly understood. Malaria fever is related to the parasite growth cycle in erythrocytes. After a fixed period of replication, a mature parasite (schizont) causes the infected erythrocyte to rupture, releasing progeny that quickly invade other erythrocytes. Simultaneous rupture of a large number of schizonts stimulates a host fever response. Febrile temperatures are damaging to Plasmodium falciparum, particularly in the second half of its 48-hr replicative cycle. Using a mathematical model, we show that these interactions naturally tend to generate periodic fever. The model predicts chaotic parasite population dynamics at high multiplication rates, consistent with the classical observation that P. falciparum causes less regular fever than other species of parasite. PMID:2052590

Unraveling the molecular genetics of head and neck cancer through genome-wide approaches

PubMed Central

Riaz, Nadeem; Morris, Luc G.; Lee, William; Chan, Timothy A.

2014-01-01

The past decade has seen an unprecedented increase in our understanding of the biology and etiology of head and neck squamous cell carcinomas (HNSCC). Genome-wide sequencing projects have identified a number of recurrently mutated genes, including unexpected alterations in the NOTCH pathway and chromatin related genes. Gene-expression profiling has identified 4 distinct genetic subtypes which show some parallels to lung squamous cell carcinoma biology. The identification of the human papilloma virus as one causative agent in a subset of oropharyngeal cancers and their association with a favorable prognosis has opened up avenues for new therapeutic strategies. The expanding knowledge of the underlying molecular abnormalities in this once very poorly understood cancer should allow for increasingly rational clinical trial design and improved patient outcomes. PMID:25642447

In vivo imaging of the pathophysiological changes and neutrophil dynamics in influenza virus-infected mouse lungs.

PubMed

Ueki, Hiroshi; Wang, I-Hsuan; Fukuyama, Satoshi; Katsura, Hiroaki; da Silva Lopes, Tiago Jose; Neumann, Gabriele; Kawaoka, Yoshihiro

2018-06-25

The pathophysiological changes that occur in lungs infected with influenza viruses are poorly understood. Here we established an in vivo imaging system that combines two-photon excitation microscopy and fluorescent influenza viruses of different pathogenicity. This approach allowed us to monitor and correlate several parameters and physiological changes including the spread of infection, pulmonary permeability, pulmonary perfusion speed, number of recruited neutrophils in infected lungs, and neutrophil motion in the lungs of live mice. Several physiological changes were larger and occurred earlier in mice infected with a highly pathogenic H5N1 influenza virus compared with those infected with a mouse-adapted human strain. These findings demonstrate the potential of our in vivo imaging system to provide novel information about the pathophysiological consequences of virus infections.

Macrophage Activation Mechanisms in Human Monocytic Cell Line-derived Macrophages.

PubMed

Sumiya, Yu; Ishikawa, Mami; Inoue, Takahiro; Inui, Toshio; Kuchiike, Daisuke; Kubo, Kentaro; Uto, Yoshihiro; Nishikata, Takahito

2015-08-01

Although the mechanisms of macrophage activation are important for cancer immunotherapy, they are poorly understood. Recently, easy and robust assay systems for assessing the macrophage-activating factor (MAF) using monocytic cell line-derived macrophages were established. Gene-expression profiles of U937- and THP-1-derived macrophages were compared using gene expression microarray analysis and their responses against several MAFs were examined by in vitro experiments. Activated states of these macrophages could not be assigned to a specific sub-type but showed, however, different unique characteristics. The unique of monocytic cell line-derived macrophages could provide clues to understand the activation mechanism of macrophages and, therefore, help to develop effective cancer immunotherapy with MAFs. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Alkylation Damage by Lipid Electrophiles Targets Functional Protein Systems*

PubMed Central

Codreanu, Simona G.; Ullery, Jody C.; Zhu, Jing; Tallman, Keri A.; Beavers, William N.; Porter, Ned A.; Marnett, Lawrence J.; Zhang, Bing; Liebler, Daniel C.

2014-01-01

Protein alkylation by reactive electrophiles contributes to chemical toxicities and oxidative stress, but the functional impact of alkylation damage across proteomes is poorly understood. We used Click chemistry and shotgun proteomics to profile the accumulation of proteome damage in human cells treated with lipid electrophile probes. Protein target profiles revealed three damage susceptibility classes, as well as proteins that were highly resistant to alkylation. Damage occurred selectively across functional protein interaction networks, with the most highly alkylation-susceptible proteins mapping to networks involved in cytoskeletal regulation. Proteins with lower damage susceptibility mapped to networks involved in protein synthesis and turnover and were alkylated only at electrophile concentrations that caused significant toxicity. Hierarchical susceptibility of proteome systems to alkylation may allow cells to survive sublethal damage while protecting critical cell functions. PMID:24429493

Immunological features underlying viral hemorrhagic fevers.

PubMed

Messaoudi, Ilhem; Basler, Christopher F

2015-10-01

Several enveloped RNA viruses of the arenavirus, bunyavirus, filovirus and flavivirus families are associated with a syndrome known as viral hemorrhagic fever (VHF). VHF is characterized by fever, vascular leakage, coagulation defects and multi organ system failure. VHF is currently viewed as a disease precipitated by viral suppression of innate immunity, which promotes systemic virus replication and excessive proinflammatory cytokine responses that trigger the manifestations of severe disease. However, the mechanisms by which immune dysregulation contributes to disease remain poorly understood. Infection of nonhuman primates closely recapitulates human VHF, notably Ebola and yellow fever, thereby providing excellent models to better define the immunological basis for this syndrome. Here we review the current state of our knowledge and suggest future directions that will better define the immunological mechanisms underlying VHF. Copyright © 2015 Elsevier Ltd. All rights reserved.

Growth of language-related brain areas after foreign language learning.

PubMed

Mårtensson, Johan; Eriksson, Johan; Bodammer, Nils Christian; Lindgren, Magnus; Johansson, Mikael; Nyberg, Lars; Lövdén, Martin

2012-10-15

The influence of adult foreign-language acquisition on human brain organization is poorly understood. We studied cortical thickness and hippocampal volumes of conscript interpreters before and after three months of intense language studies. Results revealed increases in hippocampus volume and in cortical thickness of the left middle frontal gyrus, inferior frontal gyrus, and superior temporal gyrus for interpreters relative to controls. The right hippocampus and the left superior temporal gyrus were structurally more malleable in interpreters acquiring higher proficiency in the foreign language. Interpreters struggling relatively more to master the language displayed larger gray matter increases in the middle frontal gyrus. These findings confirm structural changes in brain regions known to serve language functions during foreign-language acquisition. Copyright © 2012 Elsevier Inc. All rights reserved.

The Longue Durée of Black Lives Matter

PubMed Central

2016-01-01

Black Lives Matter was first articulated just a few years ago, but it has been the leitmotif of antiracist struggles for generations. The Movement for Black Lives extends the work of previous movements that challenged forms of oppression that act on Black bodies with impunity. It should be understood in the context of Ida B. Wells’ anti-lynching campaign, Fannie Lou Hamer’s reproductive justice demands, and the Black Panther Party’s health activism. The 50th anniversary of the Black Panther Party is an occasion to recall that its work confronted the callous neglect and the corporeal surveillance and abuse of poor Black communities. Similar demands have been the centrifugal force of social movements that for centuries have refused to have Black lives cast beyond the human boundary. PMID:27626337

Intrinsically disordered RGG/RG domains mediate degenerate specificity in RNA binding

PubMed Central

Ozdilek, Bagdeser A.; Thompson, Valery F.; Ahmed, Nasiha S.; White, Connor I.

2017-01-01

Abstract RGG/RG domains are the second most common RNA binding domain in the human genome, yet their RNA-binding properties remain poorly understood. Here, we report a detailed analysis of the RNA binding characteristics of intrinsically disordered RGG/RG domains from Fused in Sarcoma (FUS), FMRP and hnRNPU. For FUS, previous studies defined RNA binding as mediated by its well-folded domains; however, we show that RGG/RG domains are the primary mediators of binding. RGG/RG domains coupled to adjacent folded domains can achieve affinities approaching that of full-length FUS. Analysis of RGG/RG domains from FUS, FMRP and hnRNPU against a spectrum of contrasting RNAs reveals that each display degenerate binding specificity, while still displaying different degrees of preference for RNA. PMID:28575444

Climate change and skin disease.

PubMed

Lundgren, Ashley D

2018-04-01

Despite commanding essentially universal scientific consensus, climate change remains a divisive and poorly understood topic in the United States. Familiarity with this subject is not just for climate scientists. The impact of climate change on human morbidity and mortality may be considerable; thus, physicians also should be knowledgeable in this realm. Climate change science can seem opaque and inferential, creating fertile ground for political polemics and undoubtedly contributing to confusion among the general public. This puts physicians in a pivotal position to facilitate a practical understanding of climate change in the public sphere by discussing changes in disease patterns and their possible relationship to a changing climate. This article provides a background on climate change for dermatologists and highlights how climate change may impact the management of skin disease across the United States.

Yersinia versus host immunity: how a pathogen evades or triggers a protective response.

PubMed

Chung, Lawton K; Bliska, James B

2016-02-01

The human pathogenic Yersinia species cause diseases that represent a significant source of morbidity and mortality. Despite this, specific mechanisms underlying Yersinia pathogenesis and protective host responses remain poorly understood. Recent studies have shown that Yersinia disrupt cell death pathways, perturb inflammatory processes and exploit immune cells to promote disease. The ensuing host responses following Yersinia infection include coordination of innate and adaptive immune responses in an attempt to control bacterial replication. Here, we highlight current advances in our understanding of the interactions between the pathogenic yersiniae and host cells, as well as the protective host responses mobilized to counteract these pathogens. Together, these studies enhance our understanding of Yersinia pathogenesis and highlight the ongoing battle between host and microbe. Copyright © 2015 Elsevier Ltd. All rights reserved.

Microarray analysis of glial cells resistant to JCV infection suggests a correlation between viral infection and inflammatory cytokine gene expression

PubMed Central

Manley, Kate; Gee, Gretchen V; Simkevich, Carl P; Sedivy, John M; Atwood, Walter J

2007-01-01

The human polyomavirus, JCV, has a highly restricted tropism and primarily infects glial cells. The mechanisms restricting infection of cells by JCV are poorly understood. Previously we developed and described a glial cell line that was resistant to JCV infection with the aim of using these cells to identify factors that determine JCV tropism. Gene expression profiling of susceptible and resistant glial cells revealed a direct correlation between the expression of inflammatory cytokines and susceptibility to JCV infection. This correlation manifested at the level of viral gene transcription. Previous studies have suggested a link between an increase in cytokine gene expression in HIV patients and the development of PML and these data support this hypothesis. PMID:17555786

A transition in brain state during propofol-induced unconsciousness.

PubMed

Mukamel, Eran A; Pirondini, Elvira; Babadi, Behtash; Wong, Kin Foon Kevin; Pierce, Eric T; Harrell, P Grace; Walsh, John L; Salazar-Gomez, Andres F; Cash, Sydney S; Eskandar, Emad N; Weiner, Veronica S; Brown, Emery N; Purdon, Patrick L

2014-01-15

Rhythmic oscillations shape cortical dynamics during active behavior, sleep, and general anesthesia. Cross-frequency phase-amplitude coupling is a prominent feature of cortical oscillations, but its role in organizing conscious and unconscious brain states is poorly understood. Using high-density EEG and intracranial electrocorticography during gradual induction of propofol general anesthesia in humans, we discovered a rapid drug-induced transition between distinct states with opposite phase-amplitude coupling and different cortical source distributions. One state occurs during unconsciousness and may be similar to sleep slow oscillations. A second state occurs at the loss or recovery of consciousness and resembles an enhanced slow cortical potential. These results provide objective electrophysiological landmarks of distinct unconscious brain states, and could be used to help improve EEG-based monitoring for general anesthesia.

Linking Early Environmental Exposures to Adult Diseases

MedlinePlus

... diseases. Given that many disorders arise during fetal development from disruptions in the dynamic but still poorly understood interplay of genes, environment and nutrition, prevention may have to occur decades ...

Comparative lipidomic analysis of synovial fluid in human and canine osteoarthritis.

PubMed

Kosinska, M K; Mastbergen, S C; Liebisch, G; Wilhelm, J; Dettmeyer, R B; Ishaque, B; Rickert, M; Schmitz, G; Lafeber, F P; Steinmeyer, J

2016-08-01

The lipid profile of synovial fluid (SF) is related to the health status of joints. The early stages of human osteoarthritis (OA) are poorly understood, which larger animals are expected to be able to model closely. This study examined whether the canine groove model of OA represents early OA in humans based on the changes in the lipid species profile in SF. Furthermore, the SF lipidomes of humans and dogs were compared to determine how closely canine lipid species profiles reflect the human lipidome. Lipids were extracted from cell- and cellular debris-free knee SF from nine donors with healthy joints, 17 patients with early and 13 patients with late osteoarthritic changes, and nine dogs with knee OA and healthy contralateral joints. Lipid species were quantified by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Compared with control canine SF most lipid species were elevated in canine OA SF. Moreover, the lipid species profiles in the canine OA model resembled early OA profiles in humans. The SF lipidomes between dog and human were generally similar, with differences in certain lipid species in the phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelin (SM) classes. Our lipidomic analysis demonstrates that SF in the canine OA model closely mimics the early osteoarthritic changes that occur in humans. Further, the canine SF lipidome often reflects normal human lipid metabolism. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

An inexpensive and portable drill rig for bedrock groundwater studies in headwater catchments

Treesearch

C. Gabrielli; J.J. McDonnell

2011-01-01

Bedrock groundwater dynamics in headwater catchments are poorly understood and poorly characterized. Here, we present an inexpensive and portable bedrock drilling system designed for use in remote locations. Our system is capable of drilling bedrock wells up to 11 m deep and 38 mm in diameter in a wide range of bedrock types. The drill consists of a lawn mower engine...

Bewildering Education

ERIC Educational Resources Information Center

Snaza, Nathan

2013-01-01

Theorists as diverse as Plato, Rousseau, Freire, Apple, and the New London Group have understood education as a practice that "makes" humans. Positing education as a practice of humanization has long been understood to be the highest, most lofty good. By drawing on feminism, critical race studies, and postcolonial studies, the author of…

Researchers Realize Major Breakthrough in Understanding Endometriosis

MedlinePlus

... a rarely studied and poorly understood disease that affects many, many women.” Health Terms: Women's Health RELATED LINKS RSS LISTSERV YOUTUBE FACEBOOK TWITTER GOOGLE+ NIH...T URNING D ISCOVERY I ...

Feeling understood: a melody of human becoming.

PubMed

Jonas-Simpson, C M

2001-07-01

This phenomenological-hermeneutic study centered on the phenomenon of feeling understood, which was conceptualized by the researcher as a melody of human becoming significant to quality of life. For the first time the Parse research method was used with music as part of the dialogical engagement. The study was conducted with 10 women living with an enduring health situation who volunteered to be in tape-recorded dialogue with the researcher to discuss feeling understood and to create a musical expression of this phenomenon. The finding of this study, which is the structure of the lived experience of feeling understood, surfaced from the dialogues and musical expressions: Feeling understood is an unburdening quietude with triumphant bliss arising with the attentive reverence of nurturing engagements, while fortifying integrity emerges amid potential disregard.

HIF-2α mediates hypoxia-induced LIF expression in human colorectal cancer cells

PubMed Central

Zhao, Yuhan; Zhang, Cen; Wang, Jiabei; Yue, Xuetian; Yang, Qifeng; Hu, Wenwei

2015-01-01

Leukemia inhibitory factor (LIF), a multi-functional cytokine, has a complex role in cancer. While LIF induces the differentiation of several myeloid leukemia cells and inhibits their growth, it also promotes tumor progression, metastasis and chemoresistance in many solid tumors. LIF is frequently overexpressed in a variety of human tumors and its overexpression is often associated with poor prognosis of patients. Currently, the mechanism for LIF overexpression in tumor cells is not well-understood. Here, we report that hypoxia, a hallmark of solid tumors, induced LIF mRNA expression in human colorectal cancer cells. Analysis of LIF promoter revealed several hypoxia-responsive elements (HREs) that can specifically interact with and be transactivated by HIF-2α but not HIF-1α. Consistently, ectopic expression of HIF-2α but not HIF-1α transcriptionally induced LIF expression levels in cells. Knockdown of endogenous HIF-2α but not HIF-1α by siRNA largely abolished the induction of LIF by hypoxia in cells. Furthermore, there is a strong association of HIF-2α overexpression with LIF overexpression in human colorectal cancer specimens. In summary, results from this study demonstrate that hypoxia induces LIF expression in human cancer cells mainly through HIF-2α, which could be an important underlying mechanism for LIF overexpression in human cancers. PMID:25726527

Oxytetracycline induces DNA damage and epigenetic changes: a possible risk for human and animal health?

PubMed

Gallo, Adriana; Landi, Rosaria; Rubino, Valentina; Di Cerbo, Alessandro; Giovazzino, Angela; Palatucci, Anna Teresa; Centenaro, Sara; Guidetti, Gianandrea; Canello, Sergio; Cortese, Laura; Ruggiero, Giuseppina; Alessandrini, Andrea; Terrazzano, Giuseppe

2017-01-01

Oxytetracycline (OTC), which is largely employed in zootechnical and veterinary practices to ensure wellness of farmed animals, is partially absorbed within the gastrointestinal tract depositing in several tissues. Therefore, the potential OTC toxicity is relevant when considering the putative risk derived by the entry and accumulation of such drug in human and pet food chain supply. Despite scientific literature highlights several OTC-dependent toxic effects on human and animal health, the molecular mechanisms of such toxicity are still poorly understood. Here, we evaluated DNA damages and epigenetic alterations by quantitative reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, chromatin immuno-precipitation and Western blot analysis. We observed that human peripheral blood mononuclear cells (PBMCs) expressed DNA damage features (activation of ATM and p53, phosphorylation of H2AX and modifications of histone H3 methylation of lysine K4 in the chromatin) after the in vitro exposure to OTC. These changes are linked to a robust inflammatory response indicated by an increased expression of Interferon (IFN)- γ and type 1 superoxide dismutase (SOD1). Our data reveal an unexpected biological in vitro activity of OTC able to modify DNA and chromatin in cultured human PBMC. In this regard, OTC presence in foods of animal origin could represent a potential risk for both the human and animal health.

Differential effects of antibiotic therapy on the structure and function of human gut microbiota.

PubMed

Pérez-Cobas, Ana Elena; Artacho, Alejandro; Knecht, Henrik; Ferrús, María Loreto; Friedrichs, Anette; Ott, Stephan J; Moya, Andrés; Latorre, Amparo; Gosalbes, María José

2013-01-01

The human intestinal microbiota performs many essential functions for the host. Antimicrobial agents, such as antibiotics (AB), are also known to disturb microbial community equilibrium, thereby having an impact on human physiology. While an increasing number of studies investigate the effects of AB usage on changes in human gut microbiota biodiversity, its functional effects are still poorly understood. We performed a follow-up study to explore the effect of ABs with different modes of action on human gut microbiota composition and function. Four individuals were treated with different antibiotics and samples were taken before, during and after the AB course for all of them. Changes in the total and in the active (growing) microbiota as well as the functional changes were addressed by 16S rRNA gene and metagenomic 454-based pyrosequencing approaches. We have found that the class of antibiotic, particularly its antimicrobial effect and mode of action, played an important role in modulating the gut microbiota composition and function. Furthermore, analysis of the resistome suggested that oscillatory dynamics are not only due to antibiotic-target resistance, but also to fluctuations in the surviving bacterial community. Our results indicated that the effect of AB on the human gut microbiota relates to the interaction of several factors, principally the properties of the antimicrobial agent, and the structure, functions and resistance genes of the microbial community.

Binding of Glutathione to Enterovirus Capsids Is Essential for Virion Morphogenesis

PubMed Central

Thibaut, Hendrik Jan; Thys, Bert; Canela, María-Dolores; Aguado, Leire; Wimmer, Eckard; Paul, Aniko; Pérez-Pérez, María-Jesús; van Kuppeveld, Frank J. M.; Neyts, Johan

2014-01-01

Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We report the discovery of TP219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. We show that TP219 binds directly glutathione (GSH), thereby rapidly depleting intracellular GSH levels and that this interferes with virus morphogenesis without affecting viral RNA replication. The inhibitory effect on assembly was shown not to depend on an altered reducing environment. Using TP219, we show that GSH is an essential stabilizing cofactor during the transition of protomeric particles into pentameric particles. Sequential passaging of coxsackievirus B3 in the presence of low GSH-levels selected for GSH-independent mutants that harbored a surface-exposed methionine in VP1 at the interface between two protomers. In line with this observation, enteroviruses that already contained this surface-exposed methionine, such as EV71, did not rely on GSH for virus morphogenesis. Biochemical and microscopical analysis provided strong evidence for a direct interaction between GSH and wildtype VP1 and a role for this interaction in localizing assembly intermediates to replication sites. Consistently, the interaction between GSH and mutant VP1 was abolished resulting in a relocalization of the assembly intermediates to replication sites independent from GSH. This study thus reveals GSH as a novel stabilizing host factor essential for the production of infectious enterovirus progeny and provides new insights into the poorly understood process of morphogenesis. PMID:24722756

Sequence-Level Mechanisms of Human Epigenome Evolution

PubMed Central

Prendergast, James G.D.; Chambers, Emily V.; Semple, Colin A.M.

2014-01-01

DNA methylation and chromatin states play key roles in development and disease. However, the extent of recent evolutionary divergence in the human epigenome and the influential factors that have shaped it are poorly understood. To determine the links between genome sequence and human epigenome evolution, we examined the divergence of DNA methylation and chromatin states following segmental duplication events in the human lineage. Chromatin and DNA methylation states were found to have been generally well conserved following a duplication event, with the evolution of the epigenome largely uncoupled from the total number of genetic changes in the surrounding DNA sequence. However, the epigenome at tissue-specific, distal regulatory regions was observed to be unusually prone to diverge following duplication, with particular sequence differences, altering known sequence motifs, found to be associated with divergence in patterns of DNA methylation and chromatin. Alu elements were found to have played a particularly prominent role in shaping human epigenome evolution, and we show that human-specific AluY insertion events are strongly linked to the evolution of the DNA methylation landscape and gene expression levels, including at key neurological genes in the human brain. Studying paralogous regions within the same sample enables the study of the links between genome and epigenome evolution while controlling for biological and technical variation. We show DNA methylation and chromatin divergence between duplicated regions are linked to the divergence of particular genetic motifs, with Alu elements having played a disproportionate role in the evolution of the epigenome in the human lineage. PMID:24966180

76 FR 61379 - Final Recovery Plan, Bexar County Karst Invertebrates

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-04

... 200, Austin, TX (512-490-0057 ext. 223). FOR FURTHER INFORMATION CONTACT: Adam Zerrenner, at the above... poorly understood, recovery is also dependant on incorporating research findings into adaptive management...

Fine-scale landscape genetics of the American badger (Taxidea taxus): disentangling landscape effects and sampling artifacts in a poorly understood species

PubMed Central

Kierepka, E M; Latch, E K

2016-01-01

Landscape genetics is a powerful tool for conservation because it identifies landscape features that are important for maintaining genetic connectivity between populations within heterogeneous landscapes. However, using landscape genetics in poorly understood species presents a number of challenges, namely, limited life history information for the focal population and spatially biased sampling. Both obstacles can reduce power in statistics, particularly in individual-based studies. In this study, we genotyped 233 American badgers in Wisconsin at 12 microsatellite loci to identify alternative statistical approaches that can be applied to poorly understood species in an individual-based framework. Badgers are protected in Wisconsin owing to an overall lack in life history information, so our study utilized partial redundancy analysis (RDA) and spatially lagged regressions to quantify how three landscape factors (Wisconsin River, Ecoregions and land cover) impacted gene flow. We also performed simulations to quantify errors created by spatially biased sampling. Statistical analyses first found that geographic distance was an important influence on gene flow, mainly driven by fine-scale positive spatial autocorrelations. After controlling for geographic distance, both RDA and regressions found that Wisconsin River and Agriculture were correlated with genetic differentiation. However, only Agriculture had an acceptable type I error rate (3–5%) to be considered biologically relevant. Collectively, this study highlights the benefits of combining robust statistics and error assessment via simulations and provides a method for hypothesis testing in individual-based landscape genetics. PMID:26243136

Unraveling human complexity and disease with systems biology and personalized medicine

PubMed Central

Naylor, Stephen; Chen, Jake Y

2010-01-01

We are all perplexed that current medical practice often appears maladroit in curing our individual illnesses or disease. However, as is often the case, a lack of understanding, tools and technologies are the root cause of such situations. Human individuality is an often-quoted term but, in the context of human biology, it is poorly understood. This is compounded when there is a need to consider the variability of human populations. In the case of the former, it is possible to quantify human complexity as determined by the 35,000 genes of the human genome, the 1–10 million proteins (including antibodies) and the 2000–3000 metabolites of the human metabolome. Human variability is much more difficult to assess, since many of the variables, such as the definition of race, are not even clearly agreed on. In order to accommodate human complexity, variability and its influence on health and disease, it is necessary to undertake a systematic approach. In the past decade, the emergence of analytical platforms and bioinformatics tools has led to the development of systems biology. Such an approach offers enormous potential in defining key pathways and networks involved in optimal human health, as well as disease onset, progression and treatment. The tools and technologies now available in systems biology analyses offer exciting opportunities to exploit the emerging areas of personalized medicine. In this article, we discuss the current status of human complexity, and how systems biology and personalized medicine can impact at the individual and population level. PMID:20577569

Biodiversity and ecosystem function in species-poor communities: community structure and leaf litter breakdown in a Pacific island stream

Treesearch

Jonathan P. Benstead; James G. March; Catherine M. Pringle; Katherine C. Ewel; John W. Short

2009-01-01

Pacific island stream communities are species-poor because of the effects of extreme geographic isolation on colonization rates of taxa common to continental regions. The effects of such low species richness on stream ecosystem function are not well understood. Here, we provide data on community structure and leaf litter breakdown rate in a virtually pristine stream on...

PLOD2 regulated by transcription factor FOXA1 promotes metastasis in NSCLC

PubMed Central

Du, Hongzhi; Chen, Yulong; Hou, Xiaoying; Huang, Yue; Wei, Xiaohui; Yu, Xiaowen; Feng, Shuyun; Wu, Yao; Zhan, Meixiao; Shi, Xin; Lin, Sensen; Lu, Ligong; Yuan, Shengtao; Sun, Li

2017-01-01

In multiple types of tumors, fibrotic collagen is regarded as the 'highway' for cancer cell migration, which is mainly modified by lysyl hydroxylase 2 (PLOD2). The previous findings have demonstrated that the expression of PLOD2 was regulated by multiple factors, including HIF-1α, TGF-β and microRNA-26a/b. Although PLOD2 was confirmed to be related to poor prognosis in lung adenocarcinoma, the regulatory mechanism and function of PLOD2 in human lung adenocarcinoma is poorly understood. On the other hand, upregulation or hyperactivation of epidermal growth factor receptor is considered as a prognostic marker in many cancers, especially in non-small-cell lung cancer (NSCLC). In this study, we found that PLOD2 was elevated in NSCLC specimens and positively links to NSCLC poor prognosis. Gain- and loss-of-function studies and orthotopic implantation metastasis model pinpointed that PLOD2 promotes NSCLC metastasis directly by enhancing migration and indirectly by inducing collagen reorganization. In addition, we revealed that PLOD2 was regulated by PI3K/AKT-FOXA1 axis. The transcription factor FOXA1 directly bound to the PLOD2 promoter, and turned on PLOD2 transcription. In summary, our findings revealed a regulatory mechanism of NSCLC metastasis through EGFR-PI3K/AKT-FOXA1-PLOD2 pathway, and provided PLOD2 as a therapeutic target for NSCLC treatment. PMID:29072684

Cheaper fuel and higher health costs among the poor in rural Nepal.

PubMed

Pant, Krishna Prasad

2012-05-01

Biomass fuels are used by the majority of resource poor households in low-income countries. Though biomass fuels, such as dung-briquette and firewood are apparently cheaper than the modern fuels indoor pollution from burning biomass fuels incurs high health costs. But, the health costs of these conventional fuels, mostly being indirect, are poorly understood. To address this gap, this study develops probit regression models using survey data generated through interviews from households using either dung-briquette or biogas as the primary source of fuel for cooking. The study investigates factors affecting the use of dung-briquette, assesses its impact on human health, and estimates the associated household health costs. Analysis suggests significant effects of dung-briquette on asthma and eye diseases. Despite of the perception of it being a cheap fuel, the annual health cost per household due to burning dung-briquette (US$ 16.94) is 61.3% higher than the annual cost of biogas (US$ 10.38), an alternative cleaner fuel for rural households. For reducing the use of dung-briquette and its indirect health costs, the study recommends three interventions: (1) educate women and aboriginal people, in particular, and make them aware of the benefits of switching to biogas; (2) facilitate tree planting in communal as well as private lands; and (3) create rural employment and income generation opportunities.

Mapping cortical haemodynamics during neonatal seizures using diffuse optical tomography: A case study

PubMed Central

Singh, Harsimrat; Cooper, Robert J.; Wai Lee, Chuen; Dempsey, Laura; Edwards, Andrea; Brigadoi, Sabrina; Airantzis, Dimitrios; Everdell, Nick; Michell, Andrew; Holder, David; Hebden, Jeremy C.; Austin, Topun

2014-01-01

Seizures in the newborn brain represent a major challenge to neonatal medicine. Neonatal seizures are poorly classified, under-diagnosed, difficult to treat and are associated with poor neurodevelopmental outcome. Video-EEG is the current gold-standard approach for seizure detection and monitoring. Interpreting neonatal EEG requires expertise and the impact of seizures on the developing brain remains poorly understood. In this case study we present the first ever images of the haemodynamic impact of seizures on the human infant brain, obtained using simultaneous diffuse optical tomography (DOT) and video-EEG with whole-scalp coverage. Seven discrete periods of ictal electrographic activity were observed during a 60 minute recording of an infant with hypoxic–ischaemic encephalopathy. The resulting DOT images show a remarkably consistent, high-amplitude, biphasic pattern of changes in cortical blood volume and oxygenation in response to each electrographic event. While there is spatial variation across the cortex, the dominant haemodynamic response to seizure activity consists of an initial increase in cortical blood volume prior to a large and extended decrease typically lasting several minutes. This case study demonstrates the wealth of physiologically and clinically relevant information that DOT–EEG techniques can yield. The consistency and scale of the haemodynamic responses observed here also suggest that DOT–EEG has the potential to provide improved detection of neonatal seizures. PMID:25161892

CD44 mediated hyaluronan adhesion of Toxoplasma gondii-infected leukocytes.

PubMed

Hayashi, Takeshi; Unno, Akihiro; Baba, Minami; Ohno, Tamio; Kitoh, Katsuya; Takashima, Yasuhiro

2014-04-01

Toxoplasma gondii is an obligate intracellular apicomplexan parasite that infects humans and animals. Ingested parasites cross the intestinal epithelium, invade leukocytes and are then disseminated to peripheral organs. However, the mechanism of extravasation of the infected leukocytes remains poorly understood. In this study, we demonstrate that T. gondii-invaded human and mouse leukocytes express higher level of CD44, a ligand of hyaluronan (HA), and its expression on myeloid and non-myeloid leukocytes causes T. gondii-invaded human and mouse leukocyte to adhere to HA more effectively than non-invaded leukocytes. The specific adherence of parasite-invaded leukocytes was inhibited by anti CD44 antibody. Leukocytes of CD44 knockout mice did not show parasite-invaded leukocyte specific adhesion. Our results indicate that parasite-invaded leukocytes, regardless of whether myeloid or not, gain higher ability to adhere to HA than non-invaded leukocytes, via upregulation of CD44 expression and/or selective invasion to CD44 highly expressing cells. The difference in ability to adhere to HA between parasite-invaded cells and non-invaded neighboring cells might facilitate effective delivery of parasite-invaded leukocytes to the HA-producing endothelial cell surface and/or HA-rich extra cellular matrix. © 2013.

RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex.

PubMed

Martino, Fabrizio; Pal, Mohinder; Muñoz-Hernández, Hugo; Rodríguez, Carlos F; Núñez-Ramírez, Rafael; Gil-Carton, David; Degliesposti, Gianluca; Skehel, J Mark; Roe, S Mark; Prodromou, Chrisostomos; Pearl, Laurence H; Llorca, Oscar

2018-04-16

The R2TP/Prefoldin-like co-chaperone, in concert with HSP90, facilitates assembly and cellular stability of RNA polymerase II, and complexes of PI3-kinase-like kinases such as mTOR. However, the mechanism by which this occurs is poorly understood. Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. A 3.6 Å cryo-EM structure reveals direct interaction of a C-terminal domain of RPAP3 and the ATPase domain of RUVBL2, necessary for human R2TP assembly but absent from yeast. The mobile TPR domains of RPAP3 map to the opposite face of the ring, associating with PIH1D1, which mediates client protein recruitment. Thus, RPAP3 provides a flexible platform for bringing HSP90 into proximity with diverse client proteins.

Involvement of the Calcium-sensing Receptor in Human Taste Perception

PubMed Central

Ohsu, Takeaki; Amino, Yusuke; Nagasaki, Hiroaki; Yamanaka, Tomohiko; Takeshita, Sen; Hatanaka, Toshihiro; Maruyama, Yutaka; Miyamura, Naohiro; Eto, Yuzuru

2010-01-01

By human sensory analyses, we found that various extracellular calcium-sensing receptor (CaSR) agonists enhance sweet, salty, and umami tastes, although they have no taste themselves. These characteristics are known as “kokumi taste” and often appear in traditional Japanese cuisine. Although GSH is a typical kokumi taste substance (taste enhancer), its mode of action is poorly understood. Here, we demonstrate how the kokumi taste is enhanced by the CaSR, a close relative of the class C G-protein-coupled receptors T1R1, T1R2, and T1R3 (sweet and umami receptors). We identified a large number of CaSR agonist γ-glutamyl peptides, including GSH (γ-Glu-Cys-Gly) and γ-Glu-Val-Gly, and showed that these peptides elicit the kokumi taste. Further analyses revealed that some known CaSR agonists such as Ca2+, protamine, polylysine, l-histidine, and cinacalcet (a calcium-mimetic drug) also elicit the kokumi taste and that the CaSR-specific antagonist, NPS-2143, significantly suppresses the kokumi taste. This is the first report indicating a distinct function of the CaSR in human taste perception. PMID:19892707

Parental investment and the optimization of human family size

PubMed Central

Lawson, David W.; Mace, Ruth

2011-01-01

Human reproductive behaviour is marked by exceptional variation at the population and individual level. Human behavioural ecologists propose adaptive hypotheses to explain this variation as shifting phenotypic optima in relation to local socioecological niches. Here we review evidence that variation in fertility (offspring number), in both traditional and modern industrialized populations, represents optimization of the life-history trade-off between reproductive rate and parental investment. While a reliance on correlational methods suggests the true costs of sibling resource competition are often poorly estimated, a range of anthropological and demographic studies confirm that parents balance family size against offspring success. Evidence of optimization is less forthcoming. Declines in fertility associated with modernization are particularly difficult to reconcile with adaptive models, because fertility limitation fails to enhance offspring reproductive success. Yet, considering alternative measures, we show that modern low fertility confers many advantages on offspring, which are probably transmitted to future generations. Evidence from populations that have undergone or initiated demographic transition indicate that these rewards to fertility limitation fall selectively on relatively wealthy individuals. The adaptive significance of modern reproductive behaviour remains difficult to evaluate, but may be best understood in response to rising investment costs of rearing socially and economically competitive offspring. PMID:21199838

Campaign datasets for Observations and Modeling of the Green Ocean Amazon (GOAMAZON)

DOE Data Explorer

Martin,Scot; Mei,Fan; Alexander,Lizabeth; Artaxo,Paulo; Barbosa,Henrique; Bartholomew,Mary Jane; Biscaro,Thiago; Buseck,Peter; Chand,Duli; Comstock,Jennifer; Dubey,Manvendra; Godstein,Allen; Guenther,Alex; Hubbe,John; Jardine,Kolby; Jimenez,Jose-Luis; Kim,Saewung; Kuang,Chongai; Laskin,Alexander; Long,Chuck; Paralovo,Sarah; Petaja,Tuukka; Powers,Heath; Schumacher,Courtney; Sedlacek,Arthur; Senum,Gunnar; Smith,James; Shilling,John; Springston,Stephen; Thayer,Mitchell; Tomlinson,Jason; Wang,Jian; Xie,Shaocheng

2016-05-30

The hydrologic cycle of the Amazon Basin is one of the primary heat engines of the Southern Hemisphere. Any accurate climate model must succeed in a good description of the Basin, both in its natural state and in states perturbed by regional and global human activities. At the present time, however, tropical deep convection in a natural state is poorly understood and modeled, with insufficient observational data sets for model constraint. Furthermore, future climate scenarios resulting from human activities globally show the possible drying and the eventual possible conversion of rain forest to savanna in response to global climate change. Based on our current state of knowledge, the governing conditions of this catastrophic change are not defined. Human activities locally, including the economic development activities that are growing the population and the industry within the Basin, also have the potential to shift regional climate, most immediately by an increment in aerosol number and mass concentrations, and the shift is across the range of values to which cloud properties are most sensitive. The ARM Climate Research Facility in the Amazon Basin seeks to understand aerosol and cloud life cycles, particularly the susceptibility to cloud aerosol precipitation interactions, within the Amazon Basin.

Sounding the Alarm: Health in the Anthropocene.

PubMed

Butler, Colin D

2016-06-30

There is growing scientific and public recognition that human actions, directly and indirectly, have profoundly changed the Earth system, in a still accelerating process, increasingly called the "Anthropocene". Planetary transformation, including of the atmosphere, climate, ecosystems and biodiversity, has enormous implications for human health, many of which are deeply disturbing, especially in low-income settings. A few health consequences of the Anthropocene have been partially recognized, including within environmental epidemiology, but their long-term consequences remain poorly understood and greatly under-rated. For example Syria could be a "sentinel" population, giving a glimpse to a much wider dystopian future. Health-Earth is a research network, co-founded in 2014, which seeks, with other groups, to catalyse a powerful curative response by the wider health community. This paper builds on a symposium presented by Health-Earth members at the 2015 conference of the International Society for Environmental Epidemiology. It reviews and synthesizes parts of the large literature relevant to the interaction between the changing Earth system and human health. It concludes that this topic should be prominent within future environmental epidemiology and public health. Created by our species, these challenges may be soluble, but solutions require far more understanding and resources than are currently being made available.

Dietary pectic glycans are degraded by coordinated enzyme pathways in human colonic Bacteroides.

PubMed

Luis, Ana S; Briggs, Jonathon; Zhang, Xiaoyang; Farnell, Benjamin; Ndeh, Didier; Labourel, Aurore; Baslé, Arnaud; Cartmell, Alan; Terrapon, Nicolas; Stott, Katherine; Lowe, Elisabeth C; McLean, Richard; Shearer, Kaitlyn; Schückel, Julia; Venditto, Immacolata; Ralet, Marie-Christine; Henrissat, Bernard; Martens, Eric C; Mosimann, Steven C; Abbott, D Wade; Gilbert, Harry J

2018-02-01

The major nutrients available to human colonic Bacteroides species are glycans, exemplified by pectins, a network of covalently linked plant cell wall polysaccharides containing galacturonic acid (GalA). Metabolism of complex carbohydrates by the Bacteroides genus is orchestrated by polysaccharide utilization loci (PULs). In Bacteroides thetaiotaomicron, a human colonic bacterium, the PULs activated by different pectin domains have been identified; however, the mechanism by which these loci contribute to the degradation of these GalA-containing polysaccharides is poorly understood. Here we show that each PUL orchestrates the metabolism of specific pectin molecules, recruiting enzymes from two previously unknown glycoside hydrolase families. The apparatus that depolymerizes the backbone of rhamnogalacturonan-I is particularly complex. This system contains several glycoside hydrolases that trim the remnants of other pectin domains attached to rhamnogalacturonan-I, and nine enzymes that contribute to the degradation of the backbone that makes up a rhamnose-GalA repeating unit. The catalytic properties of the pectin-degrading enzymes are optimized to protect the glycan cues that activate the specific PULs ensuring a continuous supply of inducing molecules throughout growth. The contribution of Bacteroides spp. to metabolism of the pectic network is illustrated by cross-feeding between organisms.

Population-based survey of taeniasis along the United States-Mexico border.

PubMed

Barton Behravesh, C; Mayberry, L F; Bristol, J R; Cardenas, V M; Mena, K D; Martínez-Ocaña, J; Flisser, A; Snowden, K F

2008-06-01

Taenia solium and T. saginata are zoonotic tapeworms of substantial medical and economic importance. Although human taeniasis is widely recognised as an endemic problem in Mexico, its presence in the United States is poorly understood. The first population-based study to estimate the prevalence of human infection with Taenia tapeworms along the Texas-Mexico border has recently been conducted. Households were interviewed in the Texan city of El Paso and in the neighbouring Ciudad Juárez, in Mexico. Faecal samples from household members were then checked for Taenia eggs by flotation and/or for Taenia copro-antigens in an ELISA. The overall prevalence of taeniasis in this border region was found to be 3% but, compared with the residents of Juárez, El Paso residents were 8.6-fold more likely to be tapeworm carriers. The interviews revealed some important differences between the two study sites, particularly the more frequent use of anthelminthic drugs on the Mexican side of the border. These findings have implications in terms of the planning of effective health-education campaigns to decrease the prevalence of taeniasis in the human populations along the Texas-Mexico border.

Feline fecal virome reveals novel and prevalent enteric viruses

PubMed Central

Ng, Terry Fei Fan; Mesquita, João Rodrigo; Nascimento, Maria São José; Kondov, Nikola O.; Wong, Walt; Reuter, Gábor; Knowles, Nick J.; Vega, Everardo; Esona, Mathew D.; Deng, Xutao; Vinjé, Jan; Delwart, Eric

2014-01-01

Humans keep more than 80 million cats worldwide, ensuring frequent contacts with their viruses. Despite such interactions the enteric virome of cats remains poorly understood. We analyzed a fecal sample from a single healthy cat from Portugal using viral metagenomics and detected five eukaryotic viral genomes. These viruses included a novel picornavirus (proposed genus “Sakobuvirus”) and bocavirus (feline bocavirus 2), a variant of feline astrovirus 2 and sequence fragments of a highly divergent feline rotavirus and picobirnavirus. Feline sakobuvirus A represents the prototype species of a proposed new genus in the Picornaviridae family, distantly related to human salivirus and kobuvirus. Feline astroviruses (mamastrovirus 2) are the closest relatives of the classic human astroviruses (mamastrovirus 1), suggestive of past cross-species transmission. Presence of these viruses by PCR among Portuguese cats was detected in 13% (rotavirus), 7% (astrovirus), 6% (bocavirus), 4% (sakobuvirus), and 4% (picobirnavirus) of 55 feline fecal samples. Co-infections were frequent with 40% (4/10) of cats shedding more than one of these viruses. Our study provides an initial unbiased description of the feline fecal virome indicating a high level of asymptomatic infections. Availability of the genome sequences of these viruses will facilitate future tropism and disease association studies. PMID:24793097

E3 ubiquitin ligase Pirh2 enhances tumorigenic properties of human non-small cell lung carcinoma cells

PubMed Central

Fedorova, Olga; Shuvalov, Oleg; Merkulov, Valeriy; Vasileva, Elena; Antonov, Alexey; Barlev, Nikolai A.

2016-01-01

The product of RCHY1 human gene, Pirh2, is a RING-finger containing E3 ligase that modifies p53 with ubiquitin residues resulting in its subsequent degradation in proteasomes. Transcription of RCHY1 is regulated by p53 itself thus forming a negative regulatory feedback loop. Functionally, by eliminating p53, Pirh2 facilitates tumorigenesis. However, the role of Pirh2 in cancer cells lacking p53 is yet not well understood. Therefore, we decided to elucidate the role of Pirh2 in p53-negative human non-small cell lung carcinoma cells, H1299. We found that ectopic expression of Pirh2 enhanced cell proliferation, resistance to doxorubicin, and increased migration potential. Ablation of Pirh2 by specific shRNA reversed these phenotypes. Mechanistically, Pirh2 increased mRNA and protein levels of the c-Myc oncogene. The bioinformatics data indicate that co-expression of both c-Myc and Pirh2 strongly correlated with poor survival of lung cancer patients. Collectively, our results suggest that Pirh2 can be considered as a potential pharmacological target for developing anticancer therapies to treat p53-negative cancers. PMID:28191284

Effect of Proline Mutations on the Monomer Conformations of Amylin

PubMed Central

Chiu, Chi-cheng; Singh, Sadanand; de Pablo, Juan J.

2013-01-01

The formation of human islet amyloid polypeptide (hIAPP) is implicated in the loss of pancreatic β-cells in type II diabetes. Rat amylin, which differs from human amylin at six residues, does not lead to formation of amyloid fibrils. Pramlintide is a synthetic analog of human amylin that shares three proline substitutions with rat amylin. Pramlintide has a much smaller propensity to form amyloid aggregates and has been widely prescribed in amylin replacement treatment. It is known that the three prolines attenuate β-sheet formation. However, the detailed effects of these proline substitutions on full-length hIAPP remain poorly understood. In this work, we use molecular simulations and bias-exchange metadynamics to investigate the effect of proline substitutions on the conformation of the hIAPP monomer. Our results demonstrate that hIAPP can adopt various β-sheet conformations, some of which have been reported in experiments. The proline substitutions perturb the formation of long β-sheets and reduce their stability. More importantly, we find that all three proline substitutions of pramlintide are required to inhibit β conformations and stabilize the α-helical conformation. Fewer substitutions do not have a significant inhibiting effect. PMID:24010666

Avian diversity and West Nile virus: Testing associations between biodiversity and infectious disease risk

USGS Publications Warehouse

Ezenwa, V.O.; Godsey, M.S.; King, R.J.; Guptill, S.C.

2006-01-01

The emergence of several high profile infectious diseases in recent years has focused attention on our need to understand the ecological factors contributing to the spread of infectious diseases. West Nile virus (WNV) is a mosquito-borne zoonotic disease that was first detected in the United States in 1999. The factors accounting for variation in the prevalence of WNV are poorly understood, but recent ideas suggesting links between high biodiversity and reduced vector-borne disease risk may help account for distribution patterns of this disease. Since wild birds are the primary reservoir hosts for WNV, we tested associations between passerine (Passeriform) bird diversity, non-passerine (all other orders) bird diversity and virus infection rates in mosquitoes and humans to examine the extent to which bird diversity is associated with WNV infection risk. We found that non-passerine species richness (number of non-passerine species) was significantly negatively correlated with both mosquito and human infection rates, whereas there was no significant association between passerine species richness and any measure of infection risk. Our findings suggest that non-passerine diversity may play a role in dampening WNV amplification rates in mosquitoes, minimizing human disease risk. ?? 2005 The Royal Society.

Avian diversity and West Nile virus: testing associations between biodiversity and infectious disease risk.

USGS Publications Warehouse

Ezenwa, V.O.; Godsey, M.S.; King, R.J.; Guptill, S.C.

2006-01-01

The emergence of several high profile infectious diseases in recent years has focused attention on our need to understand the ecological factors contributing to the spread of infectious diseases. West Nile virus (WNV) is a mosquito-borne zoonotic disease that was first detected in the United States in 1999. The factors accounting for variation in the prevalence of WNV are poorly understood, but recentideas suggesting links between high biodiversity and reduced vector-borne disease risk may help account for distribution patterns of this disease. Since wild birds are the primary reservoir hosts for WNV, we tested associations between passerine (Passeriform) bird diversity, non-passerine (all other orders) bird diversity and virus infection rates in mosquitoes and humans to examine the extent to which bird diversity is associated with WNV infection risk. We found t h at non-passerine species richness (number of non-passerine species) was significantly negatively correlated with both mosquito and human infection rates, whereas there was no significant association between passerine species richness and any measure of infection risk. Our findings suggest that non-passerine diversity may play a role in dampening WNV amplification rates in mosquitoes, minimizing human disease risk.

S6K2-mediated regulation of TRBP as a determinant of miRNA expression in human primary lymphatic endothelial cells

PubMed Central

Warner, Matthew J.; Bridge, Katherine S.; Hewitson, James P.; Hodgkinson, Michael R.; Heyam, Alex; Massa, Bailey C.; Haslam, Jessica C.; Chatzifrangkeskou, Maria; Evans, Gareth J.O.; Plevin, Michael J.; Sharp, Tyson V.; Lagos, Dimitris

2016-01-01

MicroRNAs (miRNAs) are short non-coding RNAs that silence mRNAs. They are generated following transcription and cleavage by the DROSHA/DGCR8 and DICER/TRBP/PACT complexes. Although it is known that components of the miRNA biogenesis machinery can be phosphorylated, it remains poorly understood how these events become engaged during physiological cellular activation. We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. We demonstrate the functional relevance of this interaction in primary human dermal lymphatic endothelial cells (HDLECs). Angiopoietin-1 (ANG1) can augment miRNA biogenesis in HDLECs through enhancing TRBP phosphorylation and expression in an S6K2-dependent manner. We propose that the S6K2/TRBP node controls miRNA biogenesis in HDLECs and provides a molecular link between the mTOR pathway and the miRNA biogenesis machinery. PMID:27407113

White matter changes linked to visual recovery after nerve decompression

PubMed Central

Paul, David A.; Gaffin-Cahn, Elon; Hintz, Eric B.; Adeclat, Giscard J.; Zhu, Tong; Williams, Zoë R.; Vates, G. Edward; Mahon, Bradford Z.

2015-01-01

The relationship between the integrity of white matter tracts and cortical function in the human brain remains poorly understood. Here we use a model of reversible white matter injury, compression of the optic chiasm by tumors of the pituitary gland, to study the structural and functional changes that attend spontaneous recovery of cortical function and visual abilities after surgical tumor removal and subsequent decompression of the nerves. We show that compression of the optic chiasm leads to demyelination of the optic tracts, which reverses as quickly as 4 weeks after nerve decompression. Furthermore, variability across patients in the severity of demyelination in the optic tracts predicts visual ability and functional activity in early cortical visual areas, and pre-operative measurements of myelination in the optic tracts predicts the magnitude of visual recovery after surgery. These data indicate that rapid regeneration of myelin in the human brain is a significant component of the normalization of cortical activity, and ultimately the recovery of sensory and cognitive function, after nerve decompression. More generally, our findings demonstrate the utility of diffusion tensor imaging as an in vivo measure of myelination in the human brain. PMID:25504884

Keyhole limpet hemocyanin induces innate immunity via Syk and Erk phosphorylation

PubMed Central

Yasuda, Kyoko; Ushio, Hideki

2016-01-01

Hemocyanin is an extracellular respiratory protein containing copper in hemolymph of invertebrates, such as Mollusk and Arthropod. Keyhole limpet hemocyanin (KLH) is one of hemocyanins and has many years of experience for vaccine developments and immunological studies in mammals including human. However, the association between KLH and the immune systems, especially the innate immune systems, remains poorly understood. The aim of this study is to clarify the direct effects of KLH on the innate immune systems. KLH activated an inflammation-related transcription factor NF-κB as much as lipopolysaccharide (LPS) in a human monocytic leukemia THP-1 reporter cell line. We have found that the KLH-induced NF-κB activation is partially involved in a spleen tyrosine kinase (Syk) pathway. We have also successfully revealed that an extracellular signal-regulated kinase (Erk), a member of mitogen-activated protein kinases, is located in an upstream of NF-κB activation induced by KLH. Furthermore, a Syk phosphorylation inhibitor partially suppressed the Erk activation in KLH-stimulated THP-1. These results suggest that both Syk and Erk associate with the KLH-induced NF-κB activation in the human monocyte. PMID:27822175

Prevalence and Risk Factors of Colonization with Staphylococcus aureus in Healthy Pet Cats Kept in the City Households

PubMed Central

Płoneczka-Janeczko, Katarzyna; Rypuła, Krzysztof

2016-01-01

Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is a significant pathogen in both human medicine and veterinary medicine. The importance of pets as reservoirs of human infections is still poorly understood. This article provides detailed information of a cross-sectional study of a S. aureus colonization in clinically healthy indoor cats. The study systematically assessed a number of different anatomical locations for the S. aureus colonization and the influence of a range of potential risk factors on the value of the final S. aureus colonization rate. The incidence rates observed for cats with at least one site positive for S. aureus or MRSA were 17.5% and 6.63%, respectively. The following risk factors were identified: one or more owners working in the healthcare industry (human or veterinary); dogs being kept with the cat under investigation; treatment of the cat under investigation with antibiotics or chemotherapeutics during the previous year. In conclusion, this study revealed a higher prevalence of MRSA than what has previously been reported in healthy pets. A combination of anatomical locations from which the samples were collected had a major influence on the final value of the S. aureus colonization rate. PMID:27766257

Asymptomatic Carriage of Group A Streptococcus Is Associated with Elimination of Capsule Production

PubMed Central

Jewell, Brittany E.; Olsen, Randall J.; Shelburne, Samuel A.; Fittipaldi, Nahuel; Beres, Stephen B.; Musser, James M.

2014-01-01

Humans commonly carry pathogenic bacteria asymptomatically, but despite decades of study, the underlying molecular contributors remain poorly understood. Here, we show that a group A streptococcus carriage strain contains a frameshift mutation in the hasA gene resulting in loss of hyaluronic acid capsule biosynthesis. This mutation was repaired by allelic replacement, resulting in restoration of capsule production in the isogenic derivative strain. The “repaired” isogenic strain was significantly more virulent than the carriage strain in a mouse model of necrotizing fasciitis and had enhanced growth ex vivo in human blood. Importantly, the repaired isogenic strain colonized the mouse oropharynx with significantly greater bacterial burden and had significantly reduced ability to internalize into cultured epithelial cells than the acapsular carriage strain. We conducted full-genome sequencing of 81 strains cultured serially from 19 epidemiologically unrelated human subjects and discovered the common theme that mutations negatively affecting capsule biosynthesis arise in vivo in the has operon. The significantly decreased capsule production is a key factor contributing to the molecular détente between pathogen and host. Our discoveries suggest a general model for bacterial pathogens in which mutations that downregulate or ablate virulence factor production contribute to carriage. PMID:25024363

Biotinidase knockout mice show cellular energy deficit and altered carbon metabolism gene expression similar to that of nutritional biotin deprivation: clues for the pathogenesis in the human inherited disorder.

PubMed

Hernández-Vázquez, A; Wolf, B; Pindolia, K; Ortega-Cuellar, D; Hernández-González, R; Heredia-Antúnez, A; Ibarra-González, I; Velázquez-Arellano, A

2013-11-01

Biotin is the prosthetic group of carboxylases that have important roles in the metabolism of glucose, fatty acids and amino acids. Biotinidase has a key role in the reutilization of the biotin, catalyzing the hydrolysis of biocytin (ε-N-biotinyl-l-lysine) and biocytin-containing peptides derived from carboxylase turnover, thus contributing substantially to the bioavailability of this vitamin. Deficient activity of biotinidase causes late-onset multiple carboxylase in humans, whose pathogenic mechanisms are poorly understood. Here we show that a knock-out biotinidase-deficient mouse from a C57BL/6 background that was fed a low biotin diet develops severe ATP deficit with activation of the energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK), inhibition of the signaling protein mTOR, driver of protein synthesis and growth, and affecting the expression of central-carbon metabolism genes. In addition, sensitivity to insulin is augmented. These changes are similar to those observed in nutritionally biotin-starved rats. These findings further our understanding of the pathogenesis of human biotinidase deficiency. © 2013 Elsevier Inc. All rights reserved.

The precedence effect and its buildup and breakdown in ferrets and humans

PubMed Central

Tolnai, Sandra; Litovsky, Ruth Y.; King, Andrew J.

2014-01-01

Although many studies have examined the precedence effect (PE), few have tested whether it shows a buildup and breakdown in nonhuman animals comparable to that seen in humans. These processes are thought to reflect the ability of the auditory system to adjust to a listener's acoustic environment, and their mechanisms are still poorly understood. In this study, ferrets were trained on a two-alternative forced-choice task to discriminate the azimuthal direction of brief sounds. In one experiment, pairs of noise bursts were presented from two loudspeakers at different interstimulus delays (ISDs). Results showed that localization performance changed as a function of ISD in a manner consistent with the PE being operative. A second experiment investigated buildup and breakdown of the PE by measuring the ability of ferrets to discriminate the direction of a click pair following presentation of a conditioning train. Human listeners were also tested using this paradigm. In both species, performance was better when the test clicks and conditioning train had the same ISD but deteriorated following a switch in the direction of the leading and lagging sounds between the conditioning train and test clicks. These results suggest that ferrets, like humans, experience a buildup and breakdown of the PE. PMID:24606278

Humans differ in their personal microbial cloud

PubMed Central

Altrichter, Adam E.; Bateman, Ashley C.; Stenson, Jason; Brown, GZ; Green, Jessica L.; Bohannan, Brendan J.M.

2015-01-01

Dispersal of microbes between humans and the built environment can occur through direct contact with surfaces or through airborne release; the latter mechanism remains poorly understood. Humans emit upwards of 106 biological particles per hour, and have long been known to transmit pathogens to other individuals and to indoor surfaces. However it has not previously been demonstrated that humans emit a detectible microbial cloud into surrounding indoor air, nor whether such clouds are sufficiently differentiated to allow the identification of individual occupants. We used high-throughput sequencing of 16S rRNA genes to characterize the airborne bacterial contribution of a single person sitting in a sanitized custom experimental climate chamber. We compared that to air sampled in an adjacent, identical, unoccupied chamber, as well as to supply and exhaust air sources. Additionally, we assessed microbial communities in settled particles surrounding each occupant, to investigate the potential long-term fate of airborne microbial emissions. Most occupants could be clearly detected by their airborne bacterial emissions, as well as their contribution to settled particles, within 1.5–4 h. Bacterial clouds from the occupants were statistically distinct, allowing the identification of some individual occupants. Our results confirm that an occupied space is microbially distinct from an unoccupied one, and demonstrate for the first time that individuals release their own personalized microbial cloud. PMID:26417541

Effect of guaifenesin on mucin production, rheology, and mucociliary transport in differentiated human airway epithelial cells.

PubMed

Seagrave, JeanClare; Albrecht, Helmut; Park, Yong Sung; Rubin, Bruce; Solomon, Gail; Kim, K Chul

2011-12-01

Guaifenesin is widely used to alleviate symptoms of excessive mucus accumulation in the respiratory tract. However, its mechanism of action is poorly understood. The authors hypothesized that guaifenesin improves mucociliary clearance in humans by reducing mucin release, by decreasing mucus viscoelasticity, and by increasing mucociliary transport. To test these hypotheses, human differentiated airway epithelial cells, cultured at an air-liquid interface, were treated with clinically relevant concentrations of guaifenesin by addition to the basolateral medium. To evaluate the effect on mucin secretion, the authors used an anzyme-linked immunosorbent assay (ELISA) to measure the amounts of MUC5AC protein in apical surface fluid and cell lysates. To measure mucociliary transportability, additional cultures were treated for 1 or 6 hours with guaifenesin, and the movement of cell debris was measured from video data. Further, the authors measured mucus dynamic viscoelasticity using a micro cone and plate rheometer with nondestructive creep transformation. Guaifenesin suppressed mucin production in a dose-dependent manner at clinically relevant concentrations. The reduced mucin production was associated with increased mucociliary transport and decreased viscoelasticity of the mucus. Viability of the cultures was not significantly affected. These results suggest that guaifenesin could improve mucociliary clearance in humans by reducing the release and/or production of mucins, thereby altering mucus rheology.

Comparison of the effects of pathogenic simian human immunodeficiency virus strains SHIV-89.6P and SHIV-KU2 in cynomolgus macaques.

PubMed

Pawar, Santosh N; Mattila, Joshua T; Sturgeon, Timothy J; Lin, Philana Ling; Narayan, Opendra; Montelaro, Ronald C; Flynn, Joanne L

2008-04-01

Factors explaining why human immunodeficiency virus (HIV) enhances the risk of reactivated tuberculosis (TB) are poorly understood. Unfortunately, experimental models of HIV-induced reactivated TB are lacking. We examined whether cynomolgus macaques, which accurately model latent TB in humans, could be used to model pathogenesis of HIV infection in the lungs and associated lymph nodes. These experiments precede studies modeling the effects of HIV infection on latent TB. We infected two groups of macaques with chimeric simian-human immunodeficiency viruses (SHIV-89.6P and SHIV-KU2) and followed viral titers and immunologic parameters including lymphocytes numbers and phenotype in the blood, bronchoalveolar lavage cells, and lymph nodes over the course of infection. Tissues from the lungs, liver, kidney, spleen, and lymph nodes were similarly examined at necropsy. Both strains produced dramatic CD4(+) T cell depletion. Plasma titers were not different between viruses, but we found more SHIV-89.6P in the lungs. Both viruses induced similar patterns of cell activation markers. SHIV-89.6P induced more IFN-gamma expression than SHIV-KU2. These results indicate SHIV-89.6P and SHIV-KU2 infect cynomolgus macaques and may be used to accurately model effects of HIV infection on latent TB.

Escherichia coli out in the cold: Dissemination of human-derived bacteria into the Antarctic microbiome.

PubMed

Power, Michelle L; Samuel, Angelingifta; Smith, James J; Stark, Jonathon S; Gillings, Michael R; Gordon, David M

2016-08-01

Discharge of untreated sewage into Antarctic environments presents a risk of introducing non-native microorganisms, but until now, adverse consequences have not been conclusively identified. Here we show that sewage disposal introduces human derived Escherichia coli carrying mobile genetic elements and virulence traits with the potential to affect the diversity and evolution of native Antarctic microbial communities. We compared E. coli recovered from environmental and animal sources in Antarctica to a reference collection of E. coli from humans and non-Antarctic animals. The distribution of phylogenetic groups and frequency of 11 virulence factors amongst the Antarctic isolates were characteristic of E. coli strains more commonly associated with humans. The rapidly emerging E. coli ST131 and ST95 clones were found amongst the Antarctic isolates, and ST95 was the predominant E. coli recovered from Weddell seals. Class 1 integrons were found in 15% of the Antarctic E. coli with 4 of 5 identified gene cassette arrays containing antibiotic resistance genes matching those common in clinical contexts. Disposing untreated sewage into the Antarctic environment does disseminate non-native microorganisms, but the extent of this impact and implications for Antarctic ecosystem health are, as yet, poorly understood. Copyright © 2016 Elsevier Ltd. All rights reserved.

Human Infants' Preference for Left-to-Right Oriented Increasing Numerical Sequences

PubMed Central

de Hevia, Maria Dolores; Girelli, Luisa; Addabbo, Margaret; Macchi Cassia, Viola

2014-01-01

While associations between number and space, in the form of a spatially oriented numerical representation, have been extensively reported in human adults, the origins of this phenomenon are still poorly understood. The commonly accepted view is that this number-space association is a product of human invention, with accounts proposing that culture, symbolic knowledge, and mathematics education are at the roots of this phenomenon. Here we show that preverbal infants aged 7 months, who lack symbolic knowledge and mathematics education, show a preference for increasing magnitude displayed in a left-to-right spatial orientation. Infants habituated to left-to-right oriented increasing or decreasing numerical sequences showed an overall higher looking time to new left-to-right oriented increasing numerical sequences at test (Experiment 1). This pattern did not hold when infants were presented with the same ordinal numerical information displayed from right to left (Experiment 2). The different pattern of results was congruent with the presence of a malleable, context-dependent baseline preference for increasing, left-to-right oriented, numerosities (Experiment 3). These findings are suggestive of an early predisposition in humans to link numerical order with a left-to-right spatial orientation, which precedes the acquisition of symbolic abilities, mathematics education, and the acquisition of reading and writing skills. PMID:24802083

The ecology and epidemiology of Ross River and Murray Valley encephalitis viruses in Western Australia: examples of One Health in Action

PubMed Central

Mackenzie, John S; Lindsay, Michael D A; Smith, David W; Imrie, Allison

2017-01-01

Abstract Arboviruses are maintained and transmitted through an alternating biological cycle in arthropods and vertebrates, with largely incidental disease in humans and animals. As such, they provide excellent examples of One Health, as their health impact is inextricably linked to their vertebrate hosts, their arthropod vectors and the environment. Prevention and control requires a comprehensive understanding of these interactions, and how they may be effectively and safely modified. This review concentrates on human disease due to Ross River and Murray Valley encephalitis viruses, the two major arboviral pathogens in Australia. It describes how their pattern of infection and disease is influenced by natural climatic and weather patterns, and by anthropogenic activities. The latter includes human-mediated environmental manipulations, such as water impoundment infrastructures, human movements and migration, and community and social changes, such as urban spread into mosquito larval habitats. Effective interventions need to be directed at the environmental precursors of risk. This can best be achieved using One Health approaches to improve collaboration and coordination between different disciplines and cross-sectoral jurisdictions in order to develop more holistic mitigation and control procedures, and to address poorly understood ecological issues through multidisciplinary research. PMID:29044370

Raman spectroscopy imaging reveals interplay between atherosclerosis and medial calcification in the human aorta

PubMed Central

You, Amanda Y. F.; Bergholt, Mads S.; St-Pierre, Jean-Philippe; Kit-Anan, Worrapong; Pence, Isaac J.; Chester, Adrian H.; Yacoub, Magdi H.; Bertazzo, Sergio; Stevens, Molly M.

2017-01-01

Medial calcification in the human aorta accumulates during aging and is known to be aggravated in several diseases. Atherosclerosis, another major cause of cardiovascular calcification, shares some common aggravators. However, the mechanisms of cardiovascular calcification remain poorly understood. To elucidate the relationship between medial aortic calcification and atherosclerosis, we characterized the cross-sectional distributions of the predominant minerals in aortic tissue, apatite and whitlockite, and the associated extracellular matrix. We also compared the cellular changes between atherosclerotic and nonatherosclerotic human aortic tissues. This was achieved through the development of Raman spectroscopy imaging methods that adapted algorithms to distinguish between the major biomolecules present within these tissues. We present a relationship between apatite, cholesterol, and triglyceride in atherosclerosis, with the relative amount of all molecules concurrently increased in the atherosclerotic plaque. Further, the increase in apatite was disproportionately large in relation to whitlockite in the aortic media directly underlying a plaque, indicating that apatite is more pathologically significant in atherosclerosis-aggravated medial calcification. We also discovered a reduction of β-carotene in the whole aortic intima, including a plaque in atherosclerotic aortic tissues compared to nonatherosclerotic tissues. This unprecedented biomolecular characterization of the aortic tissue furthers our understanding of pathological and physiological cardiovascular calcification events in humans. PMID:29226241

Low dose or low dose rate ionizing radiation-induced health effect in the human.

PubMed

Tang, Feng Ru; Loganovsky, Konstantin

2018-06-05

The extensive literature review on human epidemiological studies suggests that low dose ionizing radiation (LDIR) (≤100 mSv) or low dose rate ionizing radiation (LDRIR) (<6mSv/H) exposure could induce either negative or positive health effects. These changes may depend on genetic background, age (prenatal day for embryo), sex, nature of radiation exposure, i.e., acute or chronic irradiation, radiation sources (such as atomic bomb attack, fallout from nuclear weapon test, nuclear power plant accidents, 60 Co-contaminated building, space radiation, high background radiation, medical examinations or procedures) and radionuclide components and human epidemiological experimental designs. Epidemiological and clinical studies show that LDIR or LDRIR exposure may induce cancer, congenital abnormalities, cardiovascular and cerebrovascular diseases, cognitive and other neuropsychiatric disorders, cataracts and other eye and somatic pathology (endocrine, bronchopulmonary, digestive, etc). LDIR or LDRIR exposure may also reduce mutation and cancer mortality rates. So far, the mechanisms of LDIR- or LDRIR -induced health effect are poorly understood. Further extensive studies are still needed to clarify under what circumstances, LDIR or LDRIR exposure may induce positive or negative effects, which may facilitate development of new therapeutic approaches to prevent or treat the radiation-induced human diseases or enhance radiation-induced positive health effect. Copyright © 2018 Elsevier Ltd. All rights reserved.

Controls on methane concentrations and fluxes in streams draining human-dominated landscapes

USGS Publications Warehouse

Crawford, John T.; Stanley, Emily H.

2016-01-01

Streams and rivers are active processors of carbon, leading to significant emissions of CO2 and possibly CH4 to the atmosphere. Patterns and controls of CH4 in fluvial ecosystems remain relatively poorly understood. Furthermore, little is known regarding how major human impacts to fluvial ecosystems may be transforming their role as CH4 producers and emitters. Here, we examine the consequences of two distinct ecosystem changes as a result of human land use: increased nutrient loading (primarily as nitrate), and increased sediment loading and deposition of fine particles in the benthic zone. We did not find support for the hypothesis that enhanced nitrate loading down-regulates methane production via thermodynamic or toxic effects. We did find strong evidence that increased sedimentation and enhanced organic matter content of the benthos lead to greater methane production (diffusive + ebullitive flux) relative to pristine fluvial systems in northern Wisconsin (upper Midwest, USA). Overall, streams in a human-dominated landscape of southern Wisconsin were major regional sources of CH4 to the atmosphere, equivalent to ~20% of dairy cattle emissions, or ~50% of a landfill’s annual emissions. We suggest that restoration of the benthic environment (reduced fine deposits) could lead to reduced CH4 emissions, while decreasing nutrient loading is likely to have limited impacts to this ecosystem process.

Gemfibrozil, a lipid lowering drug, inhibits the activation of primary human microglia via peroxisome proliferator-activated receptor β

PubMed Central

Jana, Malabendu; Pahan, Kalipada

2012-01-01

Microglial activation participates in the pathogenesis of various neuroinflammatory and neurodegenerative diseases. However, mechanisms by which microglial activation could be controlled are poorly understood. Peroxisome proliferator-activated receptors (PPAR) are transcription factors belonging to the nuclear receptor super family with diverse effect. This study underlines the importance of PPARβ/δ in mediating the anti-inflammatory effect of gemfibrozil, an FDA-approved lipid-lowering drug, in primary human microglia. Bacterial lipopolysachharides (LPS) induced the expression of various proinflammatory molecules and upregulated the expression of microglial surface marker CD11b in human microglia. However, gemfibrozil markedly suppressed proinflammatory molecules and CD11b in LPS-stimulated microglia. Human microglia expressed PPAR-β and PPAR-γ, but not PPAR-α. Interestingly, either antisense knockdown of PPAR-β or antagonism of PPAR-β by a specific chemical antagonist abrogated gemfibrozil-mediated inhibition of microglial activation. On the other hand, blocking of PPAR-α and PPAR-γ had no effect on gemfibrozil-mediated anti-inflammatory effect in microglia. These results highlight the fact that gemfibrozil regulates microglial activation by inhibiting inflammatory gene expression in a PPAR-β dependent pathway and further reinforce its therapeutic application in several neuroinflammatory and neurodegenerative diseases. PMID:22528839

Profiling Lgals9 splice variant expression at the fetal-maternal interface: implications in normal and pathological human pregnancy.

PubMed

Heusschen, Roy; Freitag, Nancy; Tirado-González, Irene; Barrientos, Gabriela; Moschansky, Petra; Muñoz-Fernández, Raquel; Leno-Durán, Ester; Klapp, Burghard F; Thijssen, Victor L J L; Blois, Sandra M

2013-01-01

Disruption of fetal-maternal tolerance mechanisms can contribute to pregnancy complications, including spontaneous abortion. Galectin-9 (LGALS9), a tandem repeat lectin associated with immune modulation, is expressed in the endometrium during the mid and late secretory phases and in decidua during human early pregnancy. However, the role of LGALS9 during pregnancy remains poorly understood. We used real-time PCR and immunohistochemical staining to analyze the expression of Lgals9/LGALS9 during mouse gestation as well as in human tissues obtained from normal pregnancy and spontaneous abortions. In mice, three Lgals9 splice variants were detected, the expression of which was differentially regulated during gestation. Furthermore, decidual Lgals9 expression was deregulated in a mouse model of spontaneous abortion, whereas placental levels did not change. We further found that the LGALS9 D5 isoform suppresses interferon gamma production by decidual natural killer cells. In human patients, six Lgals9 splice variants were detected, and a decrease in Lgals9 D5/10 was associated with spontaneous abortion. Altogether, these results show a differential regulation of Lgals9 isoform expression during normal and pathological pregnancies and designate Lgals9 as a potential marker for adverse pregnancy outcomes.

Human La binds mRNAs through contacts to the poly(A) tail

PubMed Central

Vinayak, Jyotsna; Marrella, Stefano A; Hussain, Rawaa H; Rozenfeld, Leonid; Solomon, Karine; Bayfield, Mark A

2018-01-01

Abstract In addition to a role in the processing of nascent RNA polymerase III transcripts, La proteins are also associated with promoting cap-independent translation from the internal ribosome entry sites of numerous cellular and viral coding RNAs. La binding to RNA polymerase III transcripts via their common UUU-3’OH motif is well characterized, but the mechanism of La binding to coding RNAs is poorly understood. Using electromobility shift assays and cross-linking immunoprecipitation, we show that in addition to a sequence specific UUU-3’OH binding mode, human La exhibits a sequence specific and length dependent poly(A) binding mode. We demonstrate that this poly(A) binding mode uses the canonical nucleic acid interaction winged helix face of the eponymous La motif, previously shown to be vacant during uridylate binding. We also show that cytoplasmic, but not nuclear La, engages poly(A) RNA in human cells, that La entry into polysomes utilizes the poly(A) binding mode, and that La promotion of translation from the cyclin D1 internal ribosome entry site occurs in competition with cytoplasmic poly(A) binding protein (PABP). Our data are consistent with human La functioning in translation through contacts to the poly(A) tail. PMID:29447394

The public's belief about biology.

PubMed

Wolpert, L

2007-02-01

This short review is concerned with a topic that has been neglected and is still very poorly understood: what the general public think and believe about biology (including health and medicine, and bioethics), and, in particular, about biotechnology.

A Production Function Approach to Regional Environmental-Economic Assessments

EPA Science Inventory

Numerous difficulties await those creating regional-scale environmental assessments, from data having inconsistent spatial or temporal scales to poorly understood environmental processes and indicators. Including socioeconomic variables further complicates the situation. In place...

UVA Light-excited Kynurenines Oxidize Ascorbate and Modify Lens Proteins through the Formation of Advanced Glycation End Products

PubMed Central

Linetsky, Mikhail; Raghavan, Cibin T.; Johar, Kaid; Fan, Xingjun; Monnier, Vincent M.; Vasavada, Abhay R.; Nagaraj, Ram H.

2014-01-01

Advanced glycation end products (AGEs) contribute to lens protein pigmentation and cross-linking during aging and cataract formation. In vitro experiments have shown that ascorbate (ASC) oxidation products can form AGEs in proteins. However, the mechanisms of ASC oxidation and AGE formation in the human lens are poorly understood. Kynurenines are tryptophan oxidation products produced from the indoleamine 2,3-dioxygenase (IDO)-mediated kynurenine pathway and are present in the human lens. This study investigated the ability of UVA light-excited kynurenines to photooxidize ASC and to form AGEs in lens proteins. UVA light-excited kynurenines in both free and protein-bound forms rapidly oxidized ASC, and such oxidation occurred even in the absence of oxygen. High levels of GSH inhibited but did not completely block ASC oxidation. Upon UVA irradiation, pigmented proteins from human cataractous lenses also oxidized ASC. When exposed to UVA light (320–400 nm, 100 milliwatts/cm2, 45 min to 2 h), young human lenses (20–36 years), which contain high levels of free kynurenines, lost a significant portion of their ASC content and accumulated AGEs. A similar formation of AGEs was observed in UVA-irradiated lenses from human IDO/human sodium-dependent vitamin C transporter-2 mice, which contain high levels of kynurenines and ASC. Our data suggest that kynurenine-mediated ASC oxidation followed by AGE formation may be an important mechanism for lens aging and the development of senile cataracts in humans. PMID:24798334

Autophagy is essential for maintaining the growth of a human (mini-)organ: Evidence from scalp hair follicle organ culture

PubMed Central

Allavena, Giulia; Marotta, Roberto; Catelani, Tiziano; Bertolini, Marta; Paus, Ralf

2018-01-01

Autophagy plays a crucial role in health and disease, regulating central cellular processes such as adaptive stress responses, differentiation, tissue development, and homeostasis. However, the role of autophagy in human physiology is poorly understood, highlighting a need for a model human organ system to assess the efficacy and safety of strategies to therapeutically modulate autophagy. As a complete, cyclically remodelled (mini-)organ, the organ culture of human scalp hair follicles (HFs), which, after massive growth (anagen), spontaneously enter into an apoptosis-driven organ involution (catagen) process, may provide such a model. Here, we reveal that in anagen, hair matrix keratinocytes (MKs) of organ-cultured HFs exhibit an active autophagic flux, as documented by evaluation of endogenous lipidated Light Chain 3B (LC3B) and sequestosome 1 (SQSTM1/p62) proteins and the ultrastructural visualization of autophagosomes at all stages of the autophagy process. This autophagic flux is altered during catagen, and genetic inhibition of autophagy promotes catagen development. Conversely, an anti–hair loss product markedly enhances intrafollicular autophagy, leading to anagen prolongation. Collectively, our data reveal a novel role of autophagy in human hair growth. Moreover, we show that organ-cultured scalp HFs are an excellent preclinical research model for exploring the role of autophagy in human tissue physiology and for evaluating the efficacy and tissue toxicity of candidate autophagy-modulatory agents in a living human (mini-)organ. PMID:29590104

Atoll-scale patterns in coral reef community structure: Human signatures on Ulithi Atoll, Micronesia.

PubMed

Crane, Nicole L; Nelson, Peter; Abelson, Avigdor; Precoda, Kristin; Rulmal, John; Bernardi, Giacomo; Paddack, Michelle

2017-01-01

The dynamic relationship between reefs and the people who utilize them at a subsistence level is poorly understood. This paper characterizes atoll-scale patterns in shallow coral reef habitat and fish community structure, and correlates these with environmental characteristics and anthropogenic factors, critical to conservation efforts for the reefs and the people who depend on them. Hierarchical clustering analyses by site for benthic composition and fish community resulted in the same 3 major clusters: cluster 1-oceanic (close proximity to deep water) and uninhabited (low human impact); cluster 2-oceanic and inhabited (high human impact); and cluster 3-lagoonal (facing the inside of the lagoon) and inhabited (highest human impact). Distance from village, reef exposure to deep water and human population size had the greatest effect in predicting the fish and benthic community structure. Our study demonstrates a strong association between benthic and fish community structure and human use across the Ulithi Atoll (Yap State, Federated States of Micronesia) and confirms a pattern observed by local people that an 'opportunistic' scleractinian coral (Montipora sp.) is associated with more highly impacted reefs. Our findings suggest that small human populations (subsistence fishing) can nevertheless have considerable ecological impacts on reefs due, in part, to changes in fishing practices rather than overfishing per se, as well as larger global trends. Findings from this work can assist in building local capacity to manage reef resources across an atoll-wide scale, and illustrates the importance of anthropogenic impact even in small communities.

Risk-prone individuals prefer the wrong options on a rat version of the Iowa Gambling Task.

PubMed

Rivalan, Marion; Ahmed, Serge H; Dellu-Hagedorn, Françoise

2009-10-15

Decision making in complex and conflicting situations, as measured in the widely used Iowa Gambling Task (IGT), can be profoundly impaired in psychiatric disorders, such as attention-deficit/hyperactivity disorder, drug addiction, and also in healthy individuals for whom immediate gratification prevails over long-term gain. The cognitive processes underlying these deficits are poorly understood, in part due to a lack of suitable animal models assessing complex decision making with good construct validity. We developed a rat gambling task analogous to the IGT that tracks, for the first time, the ongoing decision process within a single session in an operant cage. Rats could choose between various options. Disadvantageous options, as opposed to advantageous ones, offered bigger immediate food reward but were followed by longer, unpredictable penalties (time-out). The majority of rats can evaluate and deduce favorable options more or less rapidly according to task complexity, whereas others systematically choose disadvantageously. These interindividual differences are stable over time and do not depend on task difficulty or on the level of food restriction. We find that poor decision making does not result from a failure to acquire relevant information but from hypersensitivity to reward and higher risk taking in anxiogenic situations. These results suggest that rats, as well as human poor performers, share similar traits to those observed in decision-making related psychiatric disorders. These traits could constitute risk factors of developing such disorders. The rapid identification of poor decision makers using the rat gambling task should promote the discovery of the specific brain dysfunctions that cause maladapted decision making.

Expression profiling during ocular development identifies 2 Nlz genes with a critical role in optic fissure closure.

PubMed

Brown, Jacob D; Dutta, Sunit; Bharti, Kapil; Bonner, Robert F; Munson, Peter J; Dawid, Igor B; Akhtar, Amana L; Onojafe, Ighovie F; Alur, Ramakrishna P; Gross, Jeffrey M; Hejtmancik, J Fielding; Jiao, Xiaodong; Chan, Wai-Yee; Brooks, Brian P

2009-02-03

The gene networks underlying closure of the optic fissure during vertebrate eye development are poorly understood. Here, we profile global gene expression during optic fissure closure using laser capture microdissected (LCM) tissue from the margins of the fissure. From these data, we identify a unique role for the C(2)H(2) zinc finger proteins Nlz1 and Nlz2 in normal fissure closure. Gene knockdown of nlz1 and/or nlz2 in zebrafish leads to a failure of the optic fissure to close, a phenotype which closely resembles that seen in human uveal coloboma. We also identify misregulation of pax2 in the developing eye of morphant fish, suggesting that Nlz1 and Nlz2 act upstream of the Pax2 pathway in directing proper closure of the optic fissure.

Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response.

PubMed

Surace, Laura; Lysenko, Veronika; Fontana, Andrea Orlando; Cecconi, Virginia; Janssen, Hans; Bicvic, Antonela; Okoniewski, Michal; Pruschy, Martin; Dummer, Reinhard; Neefjes, Jacques; Knuth, Alexander; Gupta, Anurag; van den Broek, Maries

2015-04-21

Radiotherapy induces DNA damage and cell death, but recent data suggest that concomitant immune stimulation is an integral part of the therapeutic action of ionizing radiation. It is poorly understood how radiotherapy supports tumor-specific immunity. Here we report that radiotherapy induced tumor cell death and transiently activated complement both in murine and human tumors. The local production of pro-inflammatory anaphylatoxins C3a and C5a was crucial to the tumor response to radiotherapy and concomitant stimulation of tumor-specific immunity. Dexamethasone, a drug frequently given during radiotherapy, limited complement activation and the anti-tumor effects of the immune system. Overall, our findings indicate that anaphylatoxins are key players in radiotherapy-induced tumor-specific immunity and the ensuing clinical responses. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic models of homosexuality: generating testable predictions

PubMed Central

Gavrilets, Sergey; Rice, William R

2006-01-01

Homosexuality is a common occurrence in humans and other species, yet its genetic and evolutionary basis is poorly understood. Here, we formulate and study a series of simple mathematical models for the purpose of predicting empirical patterns that can be used to determine the form of selection that leads to polymorphism of genes influencing homosexuality. Specifically, we develop theory to make contrasting predictions about the genetic characteristics of genes influencing homosexuality including: (i) chromosomal location, (ii) dominance among segregating alleles and (iii) effect sizes that distinguish between the two major models for their polymorphism: the overdominance and sexual antagonism models. We conclude that the measurement of the genetic characteristics of quantitative trait loci (QTLs) found in genomic screens for genes influencing homosexuality can be highly informative in resolving the form of natural selection maintaining their polymorphism. PMID:17015344

Mechanisms and pathways of growth failure in primordial dwarfism.

PubMed

Klingseisen, Anna; Jackson, Andrew P

2011-10-01

The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial dwarfism is a group of human single-gene disorders with extreme global growth failure (which includes Seckel syndrome, microcephalic osteodysplastic primordial dwarfism I [MOPD] types I and II, and Meier-Gorlin syndrome). Ten genes have now been identified for microcephalic primordial dwarfism, encoding proteins involved in fundamental cellular processes including genome replication (ORC1 [origin recognition complex 1], ORC4, ORC6, CDT1, and CDC6), DNA damage response (ATR [ataxia-telangiectasia and Rad3-related]), mRNA splicing (U4atac), and centrosome function (CEP152, PCNT, and CPAP). Here, we review the cellular and developmental mechanisms underlying the pathogenesis of these conditions and address whether further study of these genes could provide novel insight into the physiological regulation of organism growth.

mTORC2 Promotes Tumorigenesis via Lipid Synthesis.

PubMed

Guri, Yakir; Colombi, Marco; Dazert, Eva; Hindupur, Sravanth K; Roszik, Jason; Moes, Suzette; Jenoe, Paul; Heim, Markus H; Riezman, Isabelle; Riezman, Howard; Hall, Michael N

2017-12-11

Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development, indicating a causal effect in tumorigenesis. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Furthermore, increased lipogenesis correlated with elevated mTORC2 activity and HCC in human patients. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production. Copyright © 2017 Elsevier Inc. All rights reserved.

Treatment of Chagas Cardiomyopathy

PubMed Central

Botoni, Fernando A.; Ribeiro, Antonio Luiz P.; Marinho, Carolina Coimbra; Lima, Marcia Maria Oliveira; Nunes, Maria do Carmo Pereira; Rocha, Manoel Otávio C.

2013-01-01

Chagas' disease (ChD), caused by the protozoa Trypanosoma cruzi (T. cruzi), was discovered and described by the Brazilian physician Carlos Chagas in 1909. After a century of original description, trypanosomiasis still brings much misery to humanity and is classified as a neglected tropical disease prevalent in underdeveloped countries, particularly in South America. It is an increasing worldwide problem due to the number of cases in endemic areas and the migration of infected subjects to more developed regions, mainly North America and Europe. Despite its importance, chronic chagas cardiomyopathy (CCC) pathophysiology is yet poorly understood, and independently of its social, clinical, and epidemiological importance, the therapeutic approach of CCC is still transposed from the knowledge acquired from other cardiomyopathies. Therefore, the objective of this review is to describe the treatment of Chagas cardiomyopathy with emphasis on its peculiarities. PMID:24350293

The Trichoplax Genome and the Nature of Placozoans

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

Srivastava, Mansi; Begovic, Emina; Chapman, Jarrod

2008-08-01

Placozoans are arguably the simplest free-living animals, possibly evoking an early stage in metazoan evolution, yet their biology is poorly understood. Here we report the sequencing and analysis of the {approx}98 million base pair nuclear genome of the placozoan Trichoplax adhaerens. Whole genome phylogenetic analysis suggests that placozoans belong to a 'eumetazoan' clade that includes cnidarians and bilaterians, with sponges as the earliest diverging animals. The compact genome exhibits conserved gene content, gene structure, and synteny relative to the human and other complex eumetazoan genomes. Despite the apparent cellular and organismal simplicity of Trichoplax, its genome encodes a rich arraymore » of transcription factor and signaling pathway genes that are typically associated with diverse cell types and developmental processes in eumetazoans, motivating further searches for cryptic cellular complexity and/or as yet unobserved life history stages.« less

Tagging methyl-CpG-binding domain proteins reveals different spatiotemporal expression and supports distinct functions.

PubMed

Wood, Kathleen H; Johnson, Brian S; Welsh, Sarah A; Lee, Jun Y; Cui, Yue; Krizman, Elizabeth; Brodkin, Edward S; Blendy, Julie A; Robinson, Michael B; Bartolomei, Marisa S; Zhou, Zhaolan

2016-04-01

DNA methylation is recognized by methyl-CpG-binding domain (MBD) proteins. Multiple MBDs are linked to neurodevelopmental disorders in humans and mice. However, the functions of MBD2 are poorly understood. We characterized Mbd2 knockout mice and determined spatiotemporal expression of MBDs and MBD2-NuRD (nucleosome remodeling deacetylase) interactions. We analyzed behavioral phenotypes, generated biotin-tagged MBD1 and MBD2 knockin mice, and performed biochemical studies of MBD2-NuRD. Most behavioral measures are minimally affected in Mbd2 knockout mice. In contrast to other MBDs, MBD2 shows distinct expression patterns. Unlike most MBDs, MBD2 is ubiquitously expressed in all tissues examined and appears dispensable for brain functions measured in this study. We provide novel genetic tools and reveal new directions to investigate MBD2 functions in vivo.

The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4+ T cells

PubMed Central

Bertin, Samuel; Aoki-Nonaka, Yukari; de Jong, Petrus Rudolf; Stanwood, Shawna R.; Srikanth, Sonal; Lee, Jihyung; To, Keith; Abramson, Lior; Yu, Timothy; Han, Tiffany; Touma, Ranim; Li, Xiangli; González-Navajas, José M.; Herdman, Scott; Corr, Maripat; Fu, Guo; Dong, Hui; Gwack, Yousang; Franco, Alessandra; Jefferies, Wilfred A.; Raz, Eyal

2016-01-01

TRPV1 is a Ca2+-permeable channel mostly studied as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here, we demonstrate that TRPV1 is functionally expressed in CD4+ T cells where it acts as a non-store-operated Ca2+ channel and contributes to T cell receptor (TCR)-induced Ca2+ influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promotes colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4+ T cells recapitulates the phenotype of murine Trpv1−/− CD4+ T cells. These findings suggest that TRPV1 inhibition could represent a new therapeutic strategy to restrain proinflammatory T cell responses. PMID:25282159

Differentiation of emotions in laughter at the behavioral level.

PubMed

Szameitat, Diana P; Alter, Kai; Szameitat, André J; Darwin, Chris J; Wildgruber, Dirk; Dietrich, Susanne; Sterr, Annette

2009-06-01

Although laughter is important in human social interaction, its role as a communicative signal is poorly understood. Because laughter is expressed in various emotional contexts, the question arises as to whether different emotions are communicated. In the present study, participants had to appraise 4 types of laughter sounds (joy, tickling, taunting, schadenfreude) either by classifying them according to the underlying emotion or by rating them according to different emotional dimensions. The authors found that emotions in laughter (a) can be classified into different emotional categories, and (b) can have distinctive profiles on W. Wundt's (1905) emotional dimensions. This shows that laughter is a multifaceted social behavior that can adopt various emotional connotations. The findings support the postulated function of laughter in establishing group structure, whereby laughter is used either to include or to exclude individuals from group coherence.

Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms

PubMed Central

Karshikoff, Bianka; Sundelin, Tina; Lasselin, Julie

2017-01-01

Fatigue is a highly disabling symptom in various medical conditions. While inflammation has been suggested as a potential contributor to the development of fatigue, underlying mechanisms remain poorly understood. In this review, we propose that a better assessment of central fatigue, taking into account its multidimensional features, could help elucidate the role and mechanisms of inflammation in fatigue development. A description of the features of central fatigue is provided, and the current evidence describing the association between inflammation and fatigue in various medical conditions is reviewed. Additionally, the effect of inflammation on specific neuronal processes that may be involved in distinct fatigue dimensions is described. We suggest that the multidimensional aspects of fatigue should be assessed in future studies of inflammation-induced fatigue and that this would benefit the development of effective therapeutic interventions. PMID:28163706

Single molecule fate of HIV-1 envelope reveals late-stage viral lattice incorporation.

PubMed

Buttler, Carmen A; Pezeshkian, Nairi; Fernandez, Melissa V; Aaron, Jesse; Norman, Sofya; Freed, Eric O; van Engelenburg, Schuyler B

2018-05-10

Human immunodeficiency virus type 1 (HIV-1) assembly occurs on the inner leaflet of the host cell plasma membrane, incorporating the essential viral envelope glycoprotein (Env) within a budding lattice of HIV-1 Gag structural proteins. The mechanism by which Env incorporates into viral particles remains poorly understood. To determine the mechanism of recruitment of Env to assembly sites, we interrogate the subviral angular distribution of Env on cell-associated virus using multicolor, three-dimensional (3D) superresolution microscopy. We demonstrate that, in a manner dependent on cell type and on the long cytoplasmic tail of Env, the distribution of Env is biased toward the necks of cell-associated particles. We postulate that this neck-biased distribution is regulated by vesicular retention and steric complementarity of Env during independent Gag lattice formation.

p53 functions as a cell cycle control protein in osteosarcomas.

PubMed Central

Diller, L; Kassel, J; Nelson, C E; Gryka, M A; Litwak, G; Gebhardt, M; Bressac, B; Ozturk, M; Baker, S J; Vogelstein, B

1990-01-01

Mutations in the p53 gene have been associated with a wide range of human tumors, including osteosarcomas. Although it has been shown that wild-type p53 can block the ability of E1a and ras to cotransform primary rodent cells, it is poorly understood why inactivation of the p53 gene is important for tumor formation. We show that overexpression of the gene encoding wild-type p53 blocks the growth of osteosarcoma cells. The growth arrest was determined to be due to an inability of the transfected cells to progress into S phase. This suggests that the role of the p53 gene as an antioncogene may be in controlling the cell cycle in a fashion analogous to the check-point control genes in Saccharomyces cerevisiae. Images PMID:2233717

Spontaneous telangiectatic osteosarcoma in a rhesus macaque (Macaca mulatta).

PubMed

Goldschmidt, B; Calado, M I Z; Resende, F C; Caldas, R M; Pinto, L W; Lopes, C A A; França, F G O; Meireles, B S; Souza, I V

2017-04-01

Osteosarcoma (OS) is the most common type of bone cancer, especially in young. Telangiectatic osteosarcoma (TO) is a rare variant of OS, and hence, its occurrence, presentation, and prognosis are poorly understood. A 4-year-old female rhesus monkey presenting lameness and swelling was examined for a mass on the right humerus. Radiography revealed fracture and disorganized structure of bone tissue. Histopathological examination revealed malignant neoplasm composed of anaplastic osteoblasts, which invaded the bone marrow and surrounded blood-filled cysts in the epiphysis and diaphysis forming septa. Cytogenetic analysis showed aneuploid cells, supernumerary AgNORs, and a marker fragment. The neoplasm was diagnosed as TO. To our knowledge, the occurrence of TO and its cytogenetic analysis were reported for the first time in non-human primates. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Emerging Importance of IgG Fab Glycosylation in Immunity.

PubMed

van de Bovenkamp, Fleur S; Hafkenscheid, Lise; Rispens, Theo; Rombouts, Yoann

2016-02-15

Human IgG is the most abundant glycoprotein in serum and is crucial for protective immunity. In addition to conserved IgG Fc glycans, ∼15-25% of serum IgG contains glycans within the variable domains. These so-called "Fab glycans" are primarily highly processed complex-type biantennary N-glycans linked to N-glycosylation sites that emerge during somatic hypermutation. Specific patterns of Fab glycosylation are concurrent with physiological and pathological conditions, such as pregnancy and rheumatoid arthritis. With respect to function, Fab glycosylation can significantly affect stability, half-life, and binding characteristics of Abs and BCRs. Moreover, Fab glycans are associated with the anti-inflammatory activity of IVIgs. Consequently, IgG Fab glycosylation appears to be an important, yet poorly understood, process that modulates immunity. Copyright © 2016 by The American Association of Immunologists, Inc.

Algorithms in the historical emergence of word senses.

PubMed

Ramiro, Christian; Srinivasan, Mahesh; Malt, Barbara C; Xu, Yang

2018-03-06

Human language relies on a finite lexicon to express a potentially infinite set of ideas. A key result of this tension is that words acquire novel senses over time. However, the cognitive processes that underlie the historical emergence of new word senses are poorly understood. Here, we present a computational framework that formalizes competing views of how new senses of a word might emerge by attaching to existing senses of the word. We test the ability of the models to predict the temporal order in which the senses of individual words have emerged, using an historical lexicon of English spanning the past millennium. Our findings suggest that word senses emerge in predictable ways, following an historical path that reflects cognitive efficiency, predominantly through a process of nearest-neighbor chaining. Our work contributes a formal account of the generative processes that underlie lexical evolution.

Genetic alterations of m6A regulators predict poorer survival in acute myeloid leukemia.

PubMed

Kwok, Chau-To; Marshall, Amy D; Rasko, John E J; Wong, Justin J L

2017-02-02

Methylation of N 6 adenosine (m 6 A) is known to be important for diverse biological processes including gene expression control, translation of protein, and messenger RNA (mRNA) splicing. However, its role in the development of human cancers is poorly understood. By analyzing datasets from the Cancer Genome Atlas Research Network (TCGA) acute myeloid leukemia (AML) study, we discover that mutations and/or copy number variations of m 6 A regulatory genes are strongly associated with the presence of TP53 mutations in AML patients. Further, our analyses reveal that alterations in m 6 A regulatory genes confer a worse survival in AML. Our work indicates that genetic alterations of m 6 A regulatory genes may cooperate with TP53 and/or its regulator/downstream targets in the pathogenesis and/or maintenance of AML.

A PR-1-like Protein of Fusarium oxysporum Functions in Virulence on Mammalian Hosts*

PubMed Central

Prados-Rosales, Rafael C.; Roldán-Rodríguez, Raquel; Serena, Carolina; López-Berges, Manuel S.; Guarro, Josep; Martínez-del-Pozo, Álvaro; Di Pietro, Antonio

2012-01-01

The pathogenesis-related PR-1-like protein family comprises secreted proteins from the animal, plant, and fungal kingdoms whose biological function remains poorly understood. Here we have characterized a PR-1-like protein, Fpr1, from Fusarium oxysporum, an ubiquitous fungal pathogen that causes vascular wilt disease on a wide range of plant species and can produce life-threatening infections in immunocompromised humans. Fpr1 is secreted and proteolytically processed by the fungus. The fpr1 gene is required for virulence in a disseminated immunodepressed mouse model, and its function depends on the integrity of the proposed active site of PR-1-like proteins. Fpr1 belongs to a gene family that has expanded in plant pathogenic Sordariomycetes. These results suggest that secreted PR-1-like proteins play important roles in fungal pathogenicity. PMID:22553200

Deciphering the genomic targets of alkylating polyamide conjugates using high-throughput sequencing

PubMed Central

Chandran, Anandhakumar; Syed, Junetha; Taylor, Rhys D.; Kashiwazaki, Gengo; Sato, Shinsuke; Hashiya, Kaori; Bando, Toshikazu; Sugiyama, Hiroshi

2016-01-01

Chemically engineered small molecules targeting specific genomic sequences play an important role in drug development research. Pyrrole-imidazole polyamides (PIPs) are a group of molecules that can bind to the DNA minor-groove and can be engineered to target specific sequences. Their biological effects rely primarily on their selective DNA binding. However, the binding mechanism of PIPs at the chromatinized genome level is poorly understood. Herein, we report a method using high-throughput sequencing to identify the DNA-alkylating sites of PIP-indole-seco-CBI conjugates. High-throughput sequencing analysis of conjugate 2 showed highly similar DNA-alkylating sites on synthetic oligos (histone-free DNA) and on human genomes (chromatinized DNA context). To our knowledge, this is the first report identifying alkylation sites across genomic DNA by alkylating PIP conjugates using high-throughput sequencing. PMID:27098039

Why does starvation make bones fat?

PubMed Central

Devlin, Maureen J.

2011-01-01

Body fat, or adipose tissue, is a crucial energetic buffer against starvation in humans and other mammals, and reserves of white adipose tissue (WAT) rise and fall in parallel with food intake. Much less is known about the function of bone marrow adipose tissue (BMAT), which are fat cells found in bone marrow. BMAT mass actually increases during starvation, even as other fat depots are being mobilized for energy. Here I review the possible reasons for this poorly understood phenomenon. Is BMAT a passive filler that occupies spaces left by dying bone cells, a pathological consequence of suppressed bone formation, or potentially an adaptation for surviving starvation? To evaluate these possibilities, here I review what is known about the effects of starvation on the body, particularly the skeleton, and the mechanisms involved in storing and metabolizing BMAT during negative energy balance. PMID:21793093

Why does starvation make bones fat?

PubMed

Devlin, Maureen J

2011-01-01

Body fat, or adipose tissue, is a crucial energetic buffer against starvation in humans and other mammals, and reserves of white adipose tissue (WAT) rise and fall in parallel with food intake. Much less is known about the function of bone marrow adipose tissue (BMAT), which are fat cells found in bone marrow. BMAT mass actually increases during starvation, even as other fat depots are being mobilized for energy. This review considers several possible reasons for this poorly understood phenomenon. Is BMAT a passive filler that occupies spaces left by dying bone cells, a pathological consequence of suppressed bone formation, or potentially an adaptation for surviving starvation? These possibilities are evaluated in terms of the effects of starvation on the body, particularly the skeleton, and the mechanisms involved in storing and metabolizing BMAT during negative energy balance. Copyright © 2011 Wiley-Liss, Inc.

Microbial community assembly and metabolic function during mammalian corpse decomposition.

PubMed

Metcalf, Jessica L; Xu, Zhenjiang Zech; Weiss, Sophie; Lax, Simon; Van Treuren, Will; Hyde, Embriette R; Song, Se Jin; Amir, Amnon; Larsen, Peter; Sangwan, Naseer; Haarmann, Daniel; Humphrey, Greg C; Ackermann, Gail; Thompson, Luke R; Lauber, Christian; Bibat, Alexander; Nicholas, Catherine; Gebert, Matthew J; Petrosino, Joseph F; Reed, Sasha C; Gilbert, Jack A; Lynne, Aaron M; Bucheli, Sibyl R; Carter, David O; Knight, Rob

2016-01-08

Vertebrate corpse decomposition provides an important stage in nutrient cycling in most terrestrial habitats, yet microbially mediated processes are poorly understood. Here we combine deep microbial community characterization, community-level metabolic reconstruction, and soil biogeochemical assessment to understand the principles governing microbial community assembly during decomposition of mouse and human corpses on different soil substrates. We find a suite of bacterial and fungal groups that contribute to nitrogen cycling and a reproducible network of decomposers that emerge on predictable time scales. Our results show that this decomposer community is derived primarily from bulk soil, but key decomposers are ubiquitous in low abundance. Soil type was not a dominant factor driving community development, and the process of decomposition is sufficiently reproducible to offer new opportunities for forensic investigations. Copyright © 2016, American Association for the Advancement of Science.

Nursing and the barriers to sustainable health care: a literature review.

PubMed

Griggs, Chloe; Fernandez, Ana; Callanan, Margie

2017-12-14

global warming poses a serious threat to human health, yet healthcare organisations and staff have been relatively slow to engage with sustainable healthcare practices. This review of the literature seeks to frame what is already known about nurses and their views on global warming and sustainable health care. 11 primary research articles were sourced from a search of five mainstream databases. These articles were subject to a basic thematic analysis. six themes were identified: sustainability, endemic blindness to global issues, environmental numbness, social norms, priority assigned to sustainability, and psychology of responsibility and blame. from the literature reviewed, there are a number of social, cultural and psychological barriers that have led to widespread inaction. This article recommends further research to understand the psychological barriers in more depth as this is a poorly understood area.

Characterization of Nipah virus infection in a model of human airway epithelial cells cultured at an air-liquid interface.

PubMed

Escaffre, Olivier; Borisevich, Viktoriya; Vergara, Leoncio A; Wen, Julie W; Long, Dan; Rockx, Barry

2016-05-01

Nipah virus (NiV) is an emerging paramyxovirus that can cause lethal respiratory illness in humans. No vaccine/therapeutic is currently licensed for humans. Human-to-human transmission was previously reported during outbreaks and NiV could be isolated from respiratory secretions, but the proportion of cases in Malaysia exhibiting respiratory symptoms was significantly lower than that in Bangladesh. Previously, we showed that primary human basal respiratory epithelial cells are susceptible to both NiV-Malaysia (M) and -Bangladesh (B) strains causing robust pro-inflammatory responses. However, the cells of the human respiratory epithelium that NiV targets are unknown and their role in NiV transmission and NiV-related lung pathogenesis is still poorly understood. Here, we characterized NiV infection of the human respiratory epithelium using a model of the human tracheal/bronchial (B-ALI) and small airway (S-ALI) epithelium cultured at an air-liquid interface. We show that NiV-M and NiV-B infect ciliated and secretory cells in B/S-ALI, and that infection of S-ALI, but not B-ALI, results in disruption of the epithelium integrity and host responses recruiting human immune cells. Interestingly, NiV-B replicated more efficiently in B-ALI than did NiV-M. These results suggest that the human tracheal/bronchial epithelium is favourable to NiV replication and shedding, while inducing a limited host response. Our data suggest that the small airways epithelium is prone to inflammation and lesions as well as constituting a point of virus entry into the pulmonary vasculature. The use of relevant models of the human respiratory tract, such as B/S-ALI, is critical for understanding NiV-related lung pathogenesis and identifying the underlying mechanisms allowing human-to-human transmission.

Microbial host interactions and impaired wound healing in mice and humans: defining a role for BD14 and NOD2.

PubMed

Williams, Helen; Campbell, Laura; Crompton, Rachel A; Singh, Gurdeep; McHugh, Brian J; Davidson, Donald J; McBain, Andrew J; Cruickshank, Sheena M; Hardman, Matthew J

2018-04-30

Chronic wounds cause significant patient morbidity and mortality. A key factor in their etiology is microbial infection, yet skin host-microbiota interactions during wound repair remain poorly understood. Microbiome profiles of non-infected human chronic wounds are associated with subsequent healing outcome. Furthermore, poor clinical healing outcome was associated with increased local expression of the pattern recognition receptor NOD2. To investigate NOD2 function in the context of cutaneous healing, we treated mice with the NOD2 ligand muramyl dipeptide (MDP) and analyzed wound repair parameters and expression of anti-microbial peptides. MDP treatment of littermate controls significantly delayed wound repair associated with reduced re-epithelialization, heightened inflammation and upregulation of murine β-Defensins (mBD) 1, 3 and particularly 14. We postulated that although BD14 might impact on local skin microbial communities it may further impact other healing parameters. Indeed, exogenously administered mBD14 directly delayed mouse primary keratinocyte scratch wound closure in vitro. To further explore the role of mBD14 in wound repair, we employed Defb14 -/- mice, and showed they had a global delay in healing in vivo, associated with alterations in wound microbiota. Taken together these studies suggest a key role for NOD2-mediated regulation of local skin microbiota which in turn impacts on chronic wound etiology. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers.

PubMed

Bradford, James R; Wappett, Mark; Beran, Garry; Logie, Armelle; Delpuech, Oona; Brown, Henry; Boros, Joanna; Camp, Nicola J; McEwen, Robert; Mazzola, Anne Marie; D'Cruz, Celina; Barry, Simon T

2016-04-12

The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment.In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery.

JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer

PubMed Central

Song, Wenqiang; Ma, Yufang; Wang, Jialiang; Brantley-Sieders, Dana; Chen, Jin

2014-01-01

Recent genome-wide analyses in human lung cancer revealed that EPHA2 receptor tyrosine kinase is overexpressed in non-small cell lung cancer (NSCLC), and high levels of EPHA2 correlate with poor clinical outcome. However, the mechanistic basis for EPHA2-mediated tumor promotion in lung cancer remains poorly understood. Here we show that the JNK/c-JUN signaling mediates EPHA2-dependent tumor cell proliferation and motility. A screen of phospho-kinase arrays revealed a decrease in phospho-c-JUN levels in EPHA2 knockdown cells. Knockdown of EPHA2 inhibited p-JNK and p-c-JUN levels in approximately 50% of NSCLC lines tested. Treatment of parental cells with SP600125, a JNK inhibitor, recapitulated defects in EPHA2-deficient tumor cells; whereas constitutively activated JNK mutants were sufficient to rescue phenotypes. Knockdown of EPHA2 also inhibited tumor formation and progression in xenograft animal models in vivo. Furthermore, we investigated the role of EPHA2 in cancer stem-like cells. RNAi-mediated depletion of EPHA2 in multiple NSCLC lines decreased the ALDH positive cancer stem-like population and tumor spheroid formation in suspension. Depletion of EPHA2 in sorted ALDH positive populations markedly inhibited tumorigenicity in nude mice. Furthermore, analysis of a human lung cancer tissue microarray revealed a significant, positive association between EPHA2 and ALDH expression, indicating an important role for EPHA2 in human lung cancer stem-like cells. Collectively, these studies revealed a critical role of JNK signaling in EPHA2-dependent lung cancer cell proliferation and motility and a role for EPHA2 in cancer stem-like cell function, providing evidence for EPHA2 as a potential therapeutic target in NSCLC. PMID:24607842

Transmission Risks of Schistosomiasis Japonica: Extraction from Back-propagation Artificial Neural Network and Logistic Regression Model

PubMed Central

Xu, Jun-Fang; Xu, Jing; Li, Shi-Zhu; Jia, Tia-Wu; Huang, Xi-Bao; Zhang, Hua-Ming; Chen, Mei; Yang, Guo-Jing; Gao, Shu-Jing; Wang, Qing-Yun; Zhou, Xiao-Nong

2013-01-01

Background The transmission of schistosomiasis japonica in a local setting is still poorly understood in the lake regions of the People's Republic of China (P. R. China), and its transmission patterns are closely related to human, social and economic factors. Methodology/Principal Findings We aimed to apply the integrated approach of artificial neural network (ANN) and logistic regression model in assessment of transmission risks of Schistosoma japonicum with epidemiological data collected from 2339 villagers from 1247 households in six villages of Jiangling County, P.R. China. By using the back-propagation (BP) of the ANN model, 16 factors out of 27 factors were screened, and the top five factors ranked by the absolute value of mean impact value (MIV) were mainly related to human behavior, i.e. integration of water contact history and infection history, family with past infection, history of water contact, infection history, and infection times. The top five factors screened by the logistic regression model were mainly related to the social economics, i.e. village level, economic conditions of family, age group, education level, and infection times. The risk of human infection with S. japonicum is higher in the population who are at age 15 or younger, or with lower education, or with the higher infection rate of the village, or with poor family, and in the population with more than one time to be infected. Conclusion/Significance Both BP artificial neural network and logistic regression model established in a small scale suggested that individual behavior and socioeconomic status are the most important risk factors in the transmission of schistosomiasis japonica. It was reviewed that the young population (≤15) in higher-risk areas was the main target to be intervened for the disease transmission control. PMID:23556015

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

PubMed Central

Kodama, Takahiro; Newberg, Justin Y.; Kodama, Michiko; Rangel, Roberto; Yoshihara, Kosuke; Tien, Jean C.; Parsons, Pamela H.; Wu, Hao; Finegold, Milton J.; Copeland, Neal G.; Jenkins, Nancy A.

2016-01-01

Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMT-TFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, nonreceptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets. PMID:27247392

Prolactin regulates transcription of the ion uptake Na+/Cl- cotransporter (ncc) gene in zebrafish gill

USGS Publications Warehouse

Breves, Jason P.; Serizier, Sandy B.; Goffin, Vincent; McCormick, Stephen D.; Karlstrom, Rolf O.

2013-01-01

Prolactin (PRL) is a well-known regulator of ion and water transport within osmoregulatory tissues across vertebrate species, yet how PRL acts on some of its target tissues remains poorly understood. Using zebrafish as a model, we show that ionocytes in the gill directly respond to systemic PRL to regulate mechanisms of ion uptake. Ion-poor conditions led to increases in the expression of PRL receptor (prlra), Na+/Cl− cotransporter (ncc; slc12a10.2), Na+/H+ exchanger (nhe3b; slc9a3.2), and epithelial Ca2+ channel (ecac; trpv6) transcripts within the gill. Intraperitoneal injection of ovine PRL (oPRL) increased ncc and prlra transcripts, but did not affect nhe3b or ecac. Consistent with direct PRL action in the gill, addition of oPRL to cultured gill filaments stimulated ncc in a concentration-dependent manner, an effect blocked by a pure human PRL receptor antagonist (Δ1-9-G129R-hPRL). These results suggest that PRL signaling through PRL receptors in the gill regulates the expression of ncc, thereby linking this pituitary hormone with an effector of Cl− uptake in zebrafish for the first time.

Plexin-B2 promotes invasive growth of malignant glioma

PubMed Central

Pingle, Sandeep C.; Kesari, Santosh; Wang, Huaien; Yong, Raymund L.; Zou, Hongyan; Friedel, Roland H.

2015-01-01

Invasive growth is a major determinant of the high lethality of malignant gliomas. Plexin-B2, an axon guidance receptor important for mediating neural progenitor cell migration during development, is upregulated in gliomas, but its function therein remains poorly understood. Combining bioinformatic analyses, immunoblotting and immunohistochemistry of patient samples, we demonstrate that Plexin-B2 is consistently upregulated in all types of human gliomas and that its expression levels correlate with glioma grade and poor survival. Activation of Plexin-B2 by Sema4C ligand in glioblastoma cells induced actin-based cytoskeletal dynamics and invasive migration in vitro. This proinvasive effect was associated with activation of the cell motility mediators RhoA and Rac1. Furthermore, costimulation of Plexin-B2 and the receptor tyrosine kinase Met led to synergistic Met phosphorylation. In intracranial glioblastoma transplants, Plexin-B2 knockdown hindered invasive growth and perivascular spreading, and resulted in decreased tumor vascularity. Our results demonstrate that Plexin-B2 promotes glioma invasion and vascularization, and they identify Plexin-B2 as a potential novel prognostic marker for glioma malignancy. Targeting the Plexin-B2 pathway may represent a novel therapeutic approach to curtail invasive growth of glioblastoma. PMID:25762646

Blaming the helpers: the marginalization of teachers and parents of the urban poor.

PubMed

Farber, B A; Azar, S T

1999-10-01

The nature and origins of the current tendency toward disparaging parents and teachers of the urban poor are examined. It is suggested that the influence of parents and teachers must be understood in the context of multiple intervening variables. Several explanations are offered for the phenomenon of blame, including the fact that women constitute the great majority of teachers and are often the primary agents of parenting.

PHYTOASSESSMENT OF ESTUARINE SEDIMENTS

EPA Science Inventory

Most sediment quality assessments and quality guidelines are based on the laboratory response of single animal species and benthic animal community composition. The role of plants in this hazard assessment process is poorly understood despite the fact that plant-dominated habitat...

FACTORS INFLUENCING LIGHT-INDUCED MORTALITY OF ENTEROCOCCI IN SEDIMENT SUSPENSIONS

EPA Science Inventory

Contamination of recreational waters by pathogenic microorganisms occurs through complex, poorly understood interactions involving variable microbial sources, hydrodynamic transport, arid microbial fate processes. Fecal indicator bacteria such as enterococci have been used to ass...

Plantation management intensity affects belowground carbon and nitrogen storage in northern California

Treesearch

K. J. McFarlane; S. H. Schoenholtz; R. F. Powers

2009-01-01

Belowground C and N storage is important in maintaining forestproductivity and to CO2 sequestration. How these pools respondto management is poorly understood. We investigated effectsof repeated applications of complete fertilizer and competing...

Predictive Models of Liver Cancer

EPA Science Inventory

Predictive models of chemical-induced liver cancer face the challenge of bridging causative molecular mechanisms to adverse clinical outcomes. The latent sequence of intervening events from chemical insult to toxicity are poorly understood because they span multiple levels of bio...

What Can Plasticity Contribute to Insect Responses to Climate Change?

PubMed

Sgrò, Carla M; Terblanche, John S; Hoffmann, Ary A

2016-01-01

Plastic responses figure prominently in discussions on insect adaptation to climate change. Here we review the different types of plastic responses and whether they contribute much to adaptation. Under climate change, plastic responses involving diapause are often critical for population persistence, but key diapause responses under dry and hot conditions remain poorly understood. Climate variability can impose large fitness costs on insects showing diapause and other life cycle responses, threatening population persistence. In response to stressful climatic conditions, insects also undergo ontogenetic changes including hardening and acclimation. Environmental conditions experienced across developmental stages or by prior generations can influence hardening and acclimation, although evidence for the latter remains weak. Costs and constraints influence patterns of plasticity across insect clades, but they are poorly understood within field contexts. Plastic responses and their evolution should be considered when predicting vulnerability to climate change-but meaningful empirical data lag behind theory.

Activity-Induced Remodeling of Olfactory Bulb Microcircuits Revealed by Monosynaptic Tracing

PubMed Central

Arenkiel, Benjamin R.; Hasegawa, Hiroshi; Yi, Jason J.; Larsen, Rylan S.; Wallace, Michael L.; Philpot, Benjamin D.; Wang, Fan; Ehlers, Michael D.

2011-01-01

The continued addition of new neurons to mature olfactory circuits represents a remarkable mode of cellular and structural brain plasticity. However, the anatomical configuration of newly established circuits, the types and numbers of neurons that form new synaptic connections, and the effect of sensory experience on synaptic connectivity in the olfactory bulb remain poorly understood. Using in vivo electroporation and monosynaptic tracing, we show that postnatal-born granule cells form synaptic connections with centrifugal inputs and mitral/tufted cells in the mouse olfactory bulb. In addition, newly born granule cells receive extensive input from local inhibitory short axon cells, a poorly understood cell population. The connectivity of short axon cells shows clustered organization, and their synaptic input onto newborn granule cells dramatically and selectively expands with odor stimulation. Our findings suggest that sensory experience promotes the synaptic integration of new neurons into cell type-specific olfactory circuits. PMID:22216277

The Multifactorial Epidemiology of Blackwater Fever.

PubMed

Shanks, G Dennis

2017-12-01

Blackwater fever is a massive hemolytic event usually occurring in the context of repeated falciparum malaria infections and intermittent quinine use. Its etiology is poorly understood, and it is rarely seen today. Historical epidemiological observations from the 20th century demonstrated variable patterns in prisoners in Andaman Islands, refugees in Macedonia, canal workers in Panama, expatriates in Rhodesia, and Second World War soldiers. Rates of blackwater fever per 1,000 malaria cases varied over two orders of magnitude. Islands, such as the Andaman Islands and New Guinea, had lower blackwater fever rates than continental areas. During the Second World War, blackwater fever rates in British soldiers in West Africa and Australian soldiers in New Guinea differed by a factor of 40 despite similar treatment regimens and falciparum malaria transmission risks. Blackwater fever is a complex interaction between host erythrocyte, falciparum malaria, and antimalarial drugs which remains poorly understood.

Biannual birth pulses allow filoviruses to persist in bat populations

PubMed Central

Hayman, David T. S.

2015-01-01

Filoviruses Ebolavirus (EBOV) and Marburgvirus (MARV) cause haemorrhagic fevers with high mortality rates, posing significant threats to public health. To understand transmission into human populations, filovirus dynamics within reservoir host populations must be understood. Studies have directly linked filoviruses to bats, but the mechanisms allowing viral persistence within bat populations are poorly understood. Theory suggests seasonal birthing may decrease the probability of pathogen persistence within populations, but data suggest MARV may persist within colonies of seasonally breeding Egyptian fruit bats, Rousettus aegyptiacus. I synthesize available filovirus and bat data in a stochastic compartmental model to explore fundamental questions relating to filovirus ecology: can filoviruses persist within isolated bat colonies; do critical community sizes exist; and how do host–pathogen relationships affect spillover transmission potential? Synchronous annual breeding and shorter incubation periods did not allow filovirus persistence, whereas bi-annual breeding and longer incubation periods, such as reported for Egyptian fruit bats and EBOV in experimental studies, allowed persistence in colony sizes often found in nature. Serological data support the findings, with bats from species with two annual birth pulses more likely to be seropositive (odds ratio (OR) 4.4, 95% confidence interval (CI) 2.5–8.7) than those with one, suggesting that biannual birthing is necessary for filovirus persistence. PMID:25673678

Why Leading Consumer Product Companies Develop Proactive Chemical Management Strategies.

PubMed

Scruggs, Caroline E; Van Buren, Harry J

2016-05-01

Scholars have studied the various pressures that companies face related to socially responsible behavior when stakeholders know the particular social issues under consideration. Many have examined social responsibility in the context of environmental responsibility and the general approaches companies take regarding environmental management. The issue of currently unregulated, but potentially hazardous, chemicals in consumer products is not well understood by the general public, but a number of proactive consumer product companies have voluntarily adopted strategies to minimize use of such chemicals. These companies are exceeding regulatory requirements by restricting from their products chemicals that could harm human or environmental health, despite the fact that these actions are costly. They do not usually advertise the details of their strategies to end consumers. This article uses interviews with senior environmental directors of 20 multinational consumer product companies to investigate why these companies engage in voluntary chemicals management. The authors conclude that the most significant reasons are to achieve a competitive advantage and stay ahead of regulations, manage relationships and maintain legitimacy with stakeholders, and put managerial values into practice. Many of the characteristics related to the case of chemicals management are extendable to other areas of stakeholder management in which risks to stakeholders are either unknown or poorly understood.

Why Leading Consumer Product Companies Develop Proactive Chemical Management Strategies

PubMed Central

Scruggs, Caroline E.; Van Buren, Harry J.

2014-01-01

Scholars have studied the various pressures that companies face related to socially responsible behavior when stakeholders know the particular social issues under consideration. Many have examined social responsibility in the context of environmental responsibility and the general approaches companies take regarding environmental management. The issue of currently unregulated, but potentially hazardous, chemicals in consumer products is not well understood by the general public, but a number of proactive consumer product companies have voluntarily adopted strategies to minimize use of such chemicals. These companies are exceeding regulatory requirements by restricting from their products chemicals that could harm human or environmental health, despite the fact that these actions are costly. They do not usually advertise the details of their strategies to end consumers. This article uses interviews with senior environmental directors of 20 multinational consumer product companies to investigate why these companies engage in voluntary chemicals management. The authors conclude that the most significant reasons are to achieve a competitive advantage and stay ahead of regulations, manage relationships and maintain legitimacy with stakeholders, and put managerial values into practice. Many of the characteristics related to the case of chemicals management are extendable to other areas of stakeholder management in which risks to stakeholders are either unknown or poorly understood. PMID:27471326

Inhibition of Type 1 Cytokine–mediated Inflammation by a Soluble CD30 Homologue Encoded by Ectromelia (Mousepox) Virus

PubMed Central

Saraiva, Margarida; Smith, Philip; Fallon, Padraic G.; Alcami, Antonio

2002-01-01

CD30 is up-regulated in several human diseases and viral infections but its role in immune regulation is poorly understood. Here, we report the expression of a functional soluble CD30 homologue, viral CD30 (vCD30), encoded by ectromelia (mousepox) virus, a poxvirus that causes a severe disease related to human smallpox. We show that vCD30 is a 12-kD secreted protein that not only binds CD30L with high affinity and prevents its interaction with CD30, but it also induces reverse signaling in cells expressing CD30L. vCD30 blocked the generation of interferon γ–producing cells in vitro and was a potent inhibitor of T helper cell (Th)1- but not Th2-mediated inflammation in vivo. The finding of a CD30 homologue encoded by ectromelia virus suggests a role for CD30 in antiviral defense. Characterization of the immunological properties of vCD30 has uncovered a role of CD30–CD30L interactions in the generation of inflammatory responses. PMID:12235215

Murine Models of Heart Failure with Preserved Ejection Fraction: a “Fishing Expedition”

PubMed Central

Valero-Muñoz, Maria; Backman, Warren; Sam, Flora

2017-01-01

Summary Heart failure with preserved ejection fraction (HFpEF) is characterized by signs and symptoms of HF in the presence of a normal left ventricular (LV) ejection fraction (EF). Despite accounting for up to 50% of all clinical presentations of HF, the mechanisms implicated in HFpEF are poorly understood, thus precluding effective therapy. The pathophysiological heterogeneity in the HFpEF phenotype also contributes to this disease and likely to the absence of evidence-based therapies. Limited access to human samples and imperfect animal models that completely recapitulate the human HFpEF phenotype have impeded our understanding of the mechanistic underpinnings that exist in this disease. Aging and comorbidities such as atrial fibrillation, hypertension, diabetes and obesity, pulmonary hypertension and renal dysfunction are highly associated with HFpEF. Yet, the relationship and contribution between them remains ill-defined. This review discusses some of the distinctive clinical features of HFpEF in association with these comorbidities and highlights the advantages and disadvantage of commonly used murine models, used to study the HFpEF phenotype. PMID:29333506

Differentiation of human SH-SY5Y neuroblastoma cells by all-trans retinoic acid activates the interleukin-18 system.

PubMed

Sallmon, Hannes; Hoene, Victoria; Weber, Sven C; Dame, Christof

2010-02-01

The clinical prognosis of children with high-stage neuroblastoma is still poor. Therapeutic approaches include surgery and cellular differentiation by retinoic acid, but also experimental interleukin-based immune modulation. However, the molecular mechanisms of all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells are incompletely understood. Herein, we examined the effect of ATRA on the activity of the interleukin-18 (IL-18) system in human SH-SY5Y neuroblastoma cells. It is shown that SH-SY5Y cells express IL-18 receptor (IL-18R) and the secreted antagonist IL-18-binding protein (IL-18BP), but no IL-18. SH-SY5Y cells are highly sensitive to ATRA treatment and react by cellular differentiation from a neuroblastic toward a more neuronal phenotype. This was associated with induction of IL-18 and reduction of IL-18BP expression, while IL-18R expression remained stable. Thereby, we identified the IL-18 system as a novel target of ATRA in neuroblastoma cells that might contribute to the therapeutic properties of retinoids in treatment of neuroblastoma.

Personality and morphological traits affect pigeon survival from raptor attacks.

PubMed

Santos, Carlos D; Cramer, Julia F; Pârâu, Liviu G; Miranda, Ana C; Wikelski, Martin; Dechmann, Dina K N

2015-10-22

Personality traits have recently been shown to impact fitness in different animal species, potentially making them similarly relevant drivers as morphological and life history traits along the evolutionary pathways of organisms. Predation is a major force of natural selection through its deterministic effects on individual survival, but how predation pressure has helped to shape personality trait selection, especially in free-ranging animals, remains poorly understood. We used high-precision GPS tracking to follow whole flocks of homing pigeons (Columba livia) with known personalities and morphology during homing flights where they were severely predated by raptors. This allowed us to determine how the personality and morphology traits of pigeons may affect their risk of being predated by raptors. Our survival model showed that individual pigeons, which were more tolerant to human approach, slower to escape from a confined environment, more resistant to human handling, with larger tarsi, and with lighter plumage, were more likely to be predated by raptors. We provide rare empirical evidence that the personality of prey influences their risk of being predated under free-ranging circumstances.