Criminal Acts against Civil Aviation: 1989

DTIC Science & Technology

1989-01-01

Aviation Security maintains records of aircraft hijackings, bombing attacks, and other significant criminal acts against civil aviation worldwide. These records include actual and attempted hijackings: explosions aboard aircraft, at airports, and at airline offices; and other selected criminal acts against civil aviation. These offenses represent serious threats to the safety of civil aviation and, in those incidents involving U.S. air carriers or facilities outside the United States, are often intended as symbolic attacks against the United States. This edition summarizes

Coxiella burnetii Lipopolysaccharide: What Do We Know?

PubMed Central

Abnave, Prasad; Muracciole, Xavier; Ghigo, Eric

2017-01-01

A small gram-negative bacterium, Coxiella burnetii (C. burnetii), is responsible for a zoonosis called Q fever. C. burnetii is an intracellular bacterium that can survive inside microbicidal cells like monocytes and macrophages by hijacking several functions of the immune system. Among several virulence factors, the lipopolysaccharide (LPS) of C. burnetii is one of the major factors involved in this immune hijacking because of its atypical composition and structure. Thus, the aim of this mini-review is to summarize the repressive effects of C. burnetii LPS on the antibacterial immunity of cells. PMID:29168790

Hijacked organic, limited local, faulty fair trade: what's a radical to eat?

PubMed

Engler, Mark

2012-01-01

Organic farming has been hijacked by big business. Local food can have a larger carbon footprint than products shipped in from overseas. Fair trade doesn't address the real concerns of farmers in the global South. As the food movement has moved from the countercultural fringe to become a mainstream phenomenon, organic, local, and fair trade advocates have been beset by criticism from overt foes and erstwhile allies alike. Now that Starbucks advertises fair trade coffee and Kraft owns Boca soy burgers, it's fair to ask, "What's a radical to eat?"

Pan-cancer analysis of somatic copy number alterations implicates IRS4 and IGF2 in enhancer hijacking

PubMed Central

Weischenfeldt, Joachim; Dubash, Taronish; Drainas, Alexandros P.; Mardin, Balca R.; Chen, Yuanyuan; Stütz, Adrian M.; Waszak, Sebastian M.; Bosco, Graziella; Halvorsen, Ann Rita; Raeder, Benjamin; Efthymiopoulos, Theocharis; Erkek, Serap; Siegl, Christine; Brenner, Hermann; Brustugun, Odd Terje; Dieter, Sebastian M.; Northcott, Paul A.; Petersen, Iver; Pfister, Stefan M.; Schneider, Martin; Solberg, Steinar K.; Thunissen, Erik; Weichert, Wilko; Zichner, Thomas; Thomas, Roman; Peifer, Martin; Helland, Aslaug; Ball, Claudia R.; Jechlinger, Martin; Sotillo, Rocio; Glimm, Hanno; Korbel, Jan O.

2018-01-01

Extensive prior research has focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearranging cis-regulatory elements remains unclear. Here, we present a framework for inferring cancer-related gene overexpression resulting from cis-regulatory element reorganization (e.g., enhancer hijacking), by integrating SCNAs, gene expression data, and information on chromatin interaction domains. Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer associates with recurrent deletions in cis, and present evidence supporting a tumor-promoting role. We additionally pursued cancer type-specific analyses, uncovering IGF2 as a target for enhancer hijacking in colorectal cancer. IGF2-containing tandem duplications result in the de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, which mediates high-level gene activation. Our framework enables systematic inference of cis-regulatory element rearrangements mediating dysregulation in cancer. PMID:27869826

Pathogens: raft hijackers.

PubMed

Mañes, Santos; del Real, Gustavo; Martínez-A, Carlos

2003-07-01

Throughout evolution, organisms have developed immune-surveillance networks to protect themselves from potential pathogens. At the cellular level, the signalling events that regulate these defensive responses take place in membrane rafts--dynamic microdomains that are enriched in cholesterol and glycosphingolipids--that facilitate many protein-protein and lipid-protein interactions at the cell surface. Pathogens have evolved many strategies to ensure their own survival and to evade the host immune system, in some cases by hijacking rafts. However, understanding the means by which pathogens exploit rafts might lead to new therapeutic strategies to prevent or alleviate certain infectious diseases, such as those caused by HIV-1 or Ebola virus.

Hijacking of the mismatch repair system to cause CAG expansion and cell death in neurodegenerative disease.

PubMed

McMurray, Cynthia T

2008-07-01

Mammalian cells have evolved sophisticated DNA repair systems to correct mispaired or damaged bases and extrahelical loops. Emerging evidence suggests that, in some cases, the normal DNA repair machinery is "hijacked" to become a causative factor in mutation and disease, rather than act as a safeguard of genomic integrity. In this review, we consider two cases in which active MMR leads to mutation or to cell death. There may be similar mechanisms by which uncoupling of normal MMR recognition from downstream repair allows triplet expansions underlying human neurodegenerative disease, or cell death in response to chemical lesion.

Bacterial pathogen manipulation of host membrane trafficking.

PubMed

Asrat, Seblewongel; de Jesús, Dennise A; Hempstead, Andrew D; Ramabhadran, Vinay; Isberg, Ralph R

2014-01-01

Pathogens use a vast number of strategies to alter host membrane dynamics. Targeting the host membrane machinery is important for the survival and pathogenesis of several extracellular, vacuolar, and cytosolic bacteria. Membrane manipulation promotes bacterial replication while suppressing host responses, allowing the bacterium to thrive in a hostile environment. This review provides a comprehensive summary of various strategies used by both extracellular and intracellular bacteria to hijack host membrane trafficking machinery. We start with mechanisms used by bacteria to alter the plasma membrane, delve into the hijacking of various vesicle trafficking pathways, and conclude by summarizing bacterial adaptation to host immune responses. Understanding bacterial manipulation of host membrane trafficking provides insights into bacterial pathogenesis and uncovers the molecular mechanisms behind various processes within a eukaryotic cell.

A specialized fungal parasite (Massospora cicadina) hijacks the sexual signals of periodical cicadas (Hemiptera: Cicadidae: Magicicada).

PubMed

Cooley, John R; Marshall, David C; Hill, Kathy B R

2018-01-23

Male periodical cicadas (Magicicada spp.) infected with conidiospore-producing ("Stage I") infections of the entomopathogenic fungus Massospora cicadina exhibit precisely timed wing-flick signaling behavior normally seen only in sexually receptive female cicadas. Male wing-flicks attract copulation attempts from conspecific males in the chorus; close contact apparently spreads the infective conidiospores. In contrast, males with "Stage II" infections that produce resting spores that wait for the next cicada generation do not produce female-specific signals. We propose that these complex fungus-induced behavioral changes, which resemble apparently independently derived changes in other cicada-Massospora systems, represent a fungus "extended phenotype" that hijacks cicadas, turning them into vehicles for fungus transmission at the expense of the cicadas' own interests.

The psychology of nutrition messages.

PubMed

Schofield, Heather; Mullainathan, Sendhil

2008-01-01

The purpose of this paper is to explore consumer thinking about nutrition decisions and how firms can use consumers' awareness of the links between nutrients and health generated by public health messages to market products, including ones, which have little nutritional value. We approach this issue by tracking the development of public health messages based on scientific research, dissemination of those messages in the popular press, and use of nutrition claims in food advertisements to assess whether firms are timing the use of nutrition claims to take advantage of heuristic-based decision-making. Our findings suggest that the timing of the development of nutrition information, its dissemination in the press, and use in advertising accords well with a heuristic processing model in which firms take advantage of associations between nutrient information and health in their advertisements. However, the demonstrated relationships may not be causal. Further research will be needed to provide stronger and more comprehensive evidence regarding the proposed message hijacking process. If the message hijacking framework is borne out: (1) simple overall health rating scales could significantly improve consumer decision-making, (2) the impact of misleading advertisements could be mitigated by encouraging a multidimensional view of nutrition, and (3) more intensive regulation of product labeling could limit the impact of hijacked messages. Overall, this paper considers a novel hypothesis about the impact of public health messages on nutrition and health.

14 CFR 121.417 - Crewmember emergency training.

Code of Federal Regulations, 2010 CFR

2010-01-01

... in cabin areas including all galleys, service centers, lifts, lavatories and movie screens; (iii.... (iv) [Reserved] (v) Hijacking and other unusual situations. (4) Review and discussion of previous...

Maritime security report

DOT National Transportation Integrated Search

1996-04-01

The first article in this report deals with the rising theft and in-transit hijacking of entire containers and trailers in port cities and adjacent areas in the United States. Cargo thefts are occurring most frequently in Florida, California, New Yor...

Nuclear Proteins Hijacked by Mammalian Cytoplasmic Plus Strand RNA Viruses

PubMed Central

Lloyd, Richard E.

2015-01-01

Plus strand RNA viruses that replicate in the cytoplasm face challenges in supporting the numerous biosynthetic functions required for replication and propagation. Most of these viruses are genetically simple and rely heavily on co-opting cellular proteins, particularly cellular RNA-binding proteins, into new roles for support of virus infection at the level of virus-specific translation, and building RNA replication complexes. In the course of infectious cycles many nuclear-cytoplasmic shuttling proteins of mostly nuclear distribution are detained in the cytoplasm by viruses and re-purposed for their own gain. Many mammalian viruses hijack a common group of the same factors. This review summarizes recent gains in our knowledge of how cytoplasmic RNA viruses use these co-opted host nuclear factors in new functional roles supporting virus translation and virus RNA replication and common themes employed between different virus groups. PMID:25818028

Terrorist Attacks Put Academic Freedom to the Test.

ERIC Educational Resources Information Center

Wilson, Robin; Cox, Ana Marie

2001-01-01

Explores how, in the aftermath of the airplane hijackings and deaths at New York's World Trade Center and the Pentagon, academic freedom may be under threat. Provides examples of student or administrative action against professors offering different viewpoints. (EV)

Accountability Overboard

ERIC Educational Resources Information Center

Chieppo, Charles D.; Gass, James T.

2009-01-01

This article reports that special interest groups opposed to charter schools and high-stakes testing have hijacked Massachusetts's once-independent board of education and stand poised to water down the Massachusetts Comprehensive Assessment System (MCAS) tests and the accountability system they support. President Barack Obama and Massachusetts…

Traveling Policies: Hijacked in Central Asia

ERIC Educational Resources Information Center

Silova, Iveta

2005-01-01

Since the collapse of the Soviet Union, Central Asian education reform discourses have become increasingly similar to distinctive Western policy discourses traveling globally across national boundaries. Tracing the trajectory of "traveling policies" in Central Asia, this article discusses the way Western education discourses have been…

A Selective Chronology of Terrorist and Counter-Terrorist Incidents.

ERIC Educational Resources Information Center

Totten, Sam

1986-01-01

Beginning with the July 22, 1966, Palestinian hijacking of an El Al airliner and ending with the April 5, 1986, bombing raid on Libya by the United States, this chronology details 56 terrorist events which were covered in the world press. (JDH)

HIV-1 Vpr Induces the Degradation of ZIP and sZIP, Adaptors of the NuRD Chromatin Remodeling Complex, by Hijacking DCAF1/VprBP

PubMed Central

Maudet, Claire; Sourisce, Adèle; Dragin, Loïc; Lahouassa, Hichem; Rain, Jean-Christophe; Bouaziz, Serge; Ramirez, Bertha Cécilia; Margottin-Goguet, Florence

2013-01-01

The Vpr protein from type 1 and type 2 Human Immunodeficiency Viruses (HIV-1 and HIV-2) is thought to inactivate several host proteins through the hijacking of the DCAF1 adaptor of the Cul4A ubiquitin ligase. Here, we identified two transcriptional regulators, ZIP and sZIP, as Vpr-binding proteins degraded in the presence of Vpr. ZIP and sZIP have been shown to act through the recruitment of the NuRD chromatin remodeling complex. Strikingly, chromatin is the only cellular fraction where Vpr is present together with Cul4A ubiquitin ligase subunits. Components of the NuRD complex and exogenous ZIP and sZIP were also associated with this fraction. Several lines of evidence indicate that Vpr induces ZIP and sZIP degradation by hijacking DCAF1: (i) Vpr induced a drastic decrease of exogenously expressed ZIP and sZIP in a dose-dependent manner, (ii) this decrease relied on the proteasome activity, (iii) ZIP or sZIP degradation was impaired in the presence of a DCAF1-binding deficient Vpr mutant or when DCAF1 expression was silenced. Vpr-mediated ZIP and sZIP degradation did not correlate with the growth-related Vpr activities, namely G2 arrest and G2 arrest-independent cytotoxicity. Nonetheless, infection with HIV-1 viruses expressing Vpr led to the degradation of the two proteins. Altogether our results highlight the existence of two host transcription factors inactivated by Vpr. The role of Vpr-mediated ZIP and sZIP degradation in the HIV-1 replication cycle remains to be deciphered. PMID:24116224

Task force on deterrence of air piracy : final report.

DOT National Transportation Integrated Search

1978-11-01

In February 1969, as the frequency of hijacking of U.S. air carrier aircraft was rising to an all-time high, the Federal Aviation Administration established a multi-disciplinary Task Force on Deterrence of Air Piracy. The work of the Task Force in de...

Hijacked: Co-option of host behavior by entomophthoralean fungi

USDA-ARS?s Scientific Manuscript database

Over 700 species of fungi are known to infect and cause disease in insects and other arthropods. The majority of insect pathogenic fungi are classified in the phyla Entomophthoromycotina and Ascomycotina, and many are ecologically important in regulating insect populations. To summarize fungal-inse...

Ecological Identity in Education: Subverting the Neoliberal Self

ERIC Educational Resources Information Center

Kretz, Lisa

2014-01-01

The neoliberal ideology that is hijacking educational institutions entails an atomistic, individualistic, and Western vision of self. Students are understood as competitive, economic, homogenous entities. Interpreted as information stockpiles, students collect the data necessary for the regurgitation that enables assuming their role in the…

Hijacking common mycorrhizal networks for herbivore-induced defence signal transfer between tomato plants

PubMed Central

Song, Yuan Yuan; Ye, Mao; Li, Chuanyou; He, Xinhua; Zhu-Salzman, Keyan; Wang, Rui Long; Su, Yi Juan; Luo, Shi Ming; Zeng, Ren Sen

2014-01-01

Common mycorrhizal networks (CMNs) link multiple plants together. We hypothesized that CMNs can serve as an underground conduit for transferring herbivore-induced defence signals. We established CMN between two tomato plants in pots with mycorrhizal fungus Funneliformis mosseae, challenged a ‘donor' plant with caterpillar Spodoptera litura, and investigated defence responses and insect resistance in neighbouring CMN-connected ‘receiver' plants. After CMN establishment caterpillar infestation on ‘donor' plant led to increased insect resistance and activities of putative defensive enzymes, induction of defence-related genes and activation of jasmonate (JA) pathway in the ‘receiver' plant. However, use of a JA biosynthesis defective mutant spr2 as ‘donor' plants resulted in no induction of defence responses and no change in insect resistance in ‘receiver' plants, suggesting that JA signalling is required for CMN-mediated interplant communication. These results indicate that plants are able to hijack CMNs for herbivore-induced defence signal transfer and interplant defence communication. PMID:24468912

Privileged Electrophile Sensors: A Resource for Covalent Drug Development.

PubMed

Long, Marcus John Curtis; Aye, Yimon

2017-07-20

This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles. The latest data suggest that innate electrophile sensing-which enables rapid reaction with an endogenous signaling electrophile-is a quintessential resource for the development of covalent drugs. For instance, based on recent work documenting isoform-specific electrophile sensing, isozyme non-specific drugs may be converted to isozyme-specific analogs by hijacking privileged first-responder electrophile-sensing cysteines. Because this approach targets functionally relevant cysteines, we can simultaneously harness previously untapped moonlighting roles of enzymes linked to redox sensing. Copyright © 2017 Elsevier Ltd. All rights reserved.

Executive Summary

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

Thomas, James J.; Cook, Kristin A.

2005-05-09

Motivation Our country faces profound challenges that must be addressed in order to ensure our continued freedom and security. As the September 11, 2001, attacks on the Pentagon and World Trade Center illustrate, threats to the United States are present within our borders. On that day, after at least 20 months of planning and preparation, nineteen terrorists hijacked four airliners at three different airports in a coordinated attack. The hijackers crashed two planes into the World Trade Center’s twin towers and one plane into the Pentagon. The fourth plane, intended to attack another U.S. landmark, crashed in a field inmore » Pennsylvania. 2973 people lost their lives as a result of this attack. As the attack unfolded, government agencies and emergency response personnel had to respond in real time to situations for which policies and procedures did not exist. They were forced to assess situations and make decisions under extreme pressure, often without having critical information that would help them save additional lives. [National Commission on Terrorist Attacks, 2004]« less

Legitimation, Performativity and the Tyranny of a "Hijacked" Word

ERIC Educational Resources Information Center

Clapham, Andrew; Vickers, Rob; Eldridge, Jo

2016-01-01

Outstanding education is a high-level policy narrative in England rehearsed by school leaders, politicians, policy-makers and inspectors alike. The "legitimacy" of knowledge, performativity and discourse-based analysis are mobilised to examine outstanding. The paper explores how informants in the English state secondary education sector…

Piracy off the Horn of Africa

DTIC Science & Technology

2010-04-19

mandate followed months of renewed pirate activity in the region, including the November 2009 seizure of the MV Maran Centaurus , an Greek-flagged...Sirius Star, MV De Xin Hai, MV Maran Centaurus , and the April 2010 hijacking of the MT Samho Dream illustrate the threat piracy can pose to

International Air Transport and Federal Policy

NASA Technical Reports Server (NTRS)

Binder, R. H.

1972-01-01

The Federal policy which establishes guidelines for future U.S. participation in the international air transportation industry is discussed. The policy issues discussed include the following: (1) aircraft hijacking, both foreign and domestic, (2) relationship of scheduled services and charter services, (3) capacity problems, and (4) rate regulation.

Public Science and Participatory Policy Development: Reclaiming Policy as a Democratic Project

ERIC Educational Resources Information Center

Fine, Michelle; Ayala, Jennifer; Zaal, Mayida

2012-01-01

People witness today in the US what might be considered a "generous hijacking" of educational policy. Policy debates on charters, vouchers, for profit schools, testing and evaluation companies, and "education reform" reveal a triple privatization of educational policy. Varied enactments of educational privatization dot the…

On the Job With Emotional Intelligence

DTIC Science & Technology

2013-04-01

stimulates the amygdala , referred to as an “ amygdala hijack ,” a term coined by Daniel Coleman in his 1996 book Emotional Intelligence, the emotion is...because they stimulate the amygdala , an area of the brain responsible for intense emotional reac- tions. The amygdala is responsible for the “fight or

Psychologically Correct Race Baiting?

ERIC Educational Resources Information Center

Thomas, Kenneth R.; Wubbolding, Robert E.; Jackson, Morris L.

2005-01-01

It is commonplace these days for those with axes to grind to hijack the organs of professional associations with diatribes on pet issues. When the American Psychological Association bestowed one of its most prestigious awards recently, the recipient launched into vitriol about past and continuing mistreatment of minorities to a degree that moved…

The ZeroAccess Auto-Clicking and Search-Hijacking Click Fraud Modules

DTIC Science & Technology

2013-12-16

payloads and instead began distributing Bitcoin miners and click fraud modules.3 From a technical perspective, the primary click fraud malware used in...this era operated in the indiscriminate “auto-clicking” fashion we describe in Section 5. Alongside the click fraud and Bitcoin payloads, ZeroAccess

Somalia: Current Conditions and Prospects for a Lasting Peace

DTIC Science & Technology

2011-04-20

hijacked. In 2009, the Ukrainian-owned ship, MV Faina, which was carrying 33 T-72 tanks and other weapons and a Japanese -owned ship, MV Chemstar, were...characterized as extremist and jihadist. The ICU was accused of shutting down cinemas and prohibiting women from working. Some of these measures were

The hijacking of a receptor kinase-driven pathway by a wheat fungal pathogen leads to disease

USDA-ARS?s Scientific Manuscript database

Necrotrophic pathogens live and feed on dying tissue, but their interactions with plants are not well understood compared to biotrophic and hemibiotrophic pathogens. Here, we report the positional cloning of the wheat gene, Snn1, a member of the wall-associated kinase class of receptors, which are ...

Semiannual Report to Congress on the Effectiveness of the Civil Aviation Security Program.

DTIC Science & Technology

1985-11-07

hijackings since 1973 during any comparable 6-month period. (See Exhibits 1, 2, and 3) Air carrier and airport security measures required by the FAA have...enforcement support for airline passenger boarding and airport security measures. The passengers, who are the principal beneficiaries of the security program

Ebola Virus Uses Clathrin-Mediated Endocytosis as an Entry Pathway

DTIC Science & Technology

2010-01-01

enter cells ( Veiga and Cossart, 2005). The large size of the Listeria, which extends to 2 μm (Giardini and Theriot, 2001), suggests that clathrin coated...Weibull, C., Everitt, E., 1991. Infectious entry pathway of adenovirus type 2. J. Virol. 65 (11), 6061–6070. Veiga , E., Cossart, P., 2005. Listeria hijacks

Emerging tuberculosis pathogen hijacks social communication behavior in the group-living banded mongoose (Mungos mungo)

USDA-ARS?s Scientific Manuscript database

Mycobacterium mungi, a novel M. tuberculosis complex pathogen (MtbC), has emerged in wild banded mongoose (Mungos mungo) in Northern Botswana, causing significant mortality. Unlike other members of the MtbC, M. mungi is not transmitted through a primary aerosol route. Rather, pathogen invasion occur...

The End of Public Schools? The Corporate Reform Agenda to Privatize Education

ERIC Educational Resources Information Center

Hursh, David

2017-01-01

In this speech, Hursh shows how public education in the United States is undergoing profound changes. Education policy has been hijacked by the unelected and unaccountable corporate reformers who aspire to overhaul the education system through a corporate model of privatization and market competition. They aim to privatize education through…

HIV-1 Nef hijacks clathrin coats by stabilizing AP-1:Arf1 polygons.

PubMed

Shen, Qing-Tao; Ren, Xuefeng; Zhang, Rui; Lee, Il-Hyung; Hurley, James H

2015-10-23

The lentiviruses HIV and simian immunodeficiency virus (SIV) subvert intracellular membrane traffic as part of their replication cycle. The lentiviral Nef protein helps viruses evade innate and adaptive immune defenses by hijacking the adaptor protein 1 (AP-1) and AP-2 clathrin adaptors. We found that HIV-1 Nef and the guanosine triphosphatase Arf1 induced trimerization and activation of AP-1. Here we report the cryo-electron microscopy structures of the Nef- and Arf1-bound AP-1 trimer in the active and inactive states. A central nucleus of three Arf1 molecules organizes the trimers. We combined the open trimer with a known dimer structure and thus predicted a hexagonal assembly with inner and outer faces that bind the membranes and clathrin, respectively. Hexagons were directly visualized and the model validated by reconstituting clathrin cage assembly. Arf1 and Nef thus play interconnected roles in allosteric activation, cargo recruitment, and coat assembly, revealing an unexpectedly intricate organization of the inner AP-1 layer of the clathrin coat. Copyright © 2015, American Association for the Advancement of Science.

Chlamydia Hijacks ARF GTPases To Coordinate Microtubule Posttranslational Modifications and Golgi Complex Positioning

PubMed Central

Wesolowski, Jordan; Weber, Mary M.; Nawrotek, Agata; Dooley, Cheryl A.; Calderon, Mike; St. Croix, Claudette M.; Hackstadt, Ted; Cherfils, Jacqueline

2017-01-01

ABSTRACT The intracellular bacterium Chlamydia trachomatis develops in a parasitic compartment called the inclusion. Posttranslationally modified microtubules encase the inclusion, controlling the positioning of Golgi complex fragments around the inclusion. The molecular mechanisms by which Chlamydia coopts the host cytoskeleton and the Golgi complex to sustain its infectious compartment are unknown. Here, using a genetically modified Chlamydia strain, we discovered that both posttranslationally modified microtubules and Golgi complex positioning around the inclusion are controlled by the chlamydial inclusion protein CT813/CTL0184/InaC and host ARF GTPases. CT813 recruits ARF1 and ARF4 to the inclusion membrane, where they induce posttranslationally modified microtubules. Similarly, both ARF isoforms are required for the repositioning of Golgi complex fragments around the inclusion. We demonstrate that CT813 directly recruits ARF GTPases on the inclusion membrane and plays a pivotal role in their activation. Together, these results reveal that Chlamydia uses CT813 to hijack ARF GTPases to couple posttranslationally modified microtubules and Golgi complex repositioning at the inclusion. PMID:28465429

The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome.

PubMed

Chung, Lawton K; Park, Yong Hwan; Zheng, Yueting; Brodsky, Igor E; Hearing, Patrick; Kastner, Daniel L; Chae, Jae Jin; Bliska, James B

2016-09-14

Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation; however, the underlying molecular mechanism is largely unknown. Here we show that YopM specifically restricts the pyrin inflammasome, which is triggered by the RhoA-inactivating enzymatic activities of YopE and YopT, in Y. pseudotuberculosis-infected macrophages. The attenuation of a yopM mutant is fully reversed in pyrin knockout mice, demonstrating that YopM inhibits pyrin to promote virulence. Mechanistically, YopM recruits and activates the host kinases PRK1 and PRK2 to negatively regulate pyrin by phosphorylation. These results show how a virulence factor can hijack host kinases to inhibit effector-triggered pyrin inflammasome activation. Copyright © 2016 Elsevier Inc. All rights reserved.

Rabies Virus Hijacks and Accelerates the p75NTR Retrograde Axonal Transport Machinery

PubMed Central

Gluska, Shani; Zahavi, Eitan Erez; Chein, Michael; Gradus, Tal; Bauer, Anja; Finke, Stefan; Perlson, Eran

2014-01-01

Rabies virus (RABV) is a neurotropic virus that depends on long distance axonal transport in order to reach the central nervous system (CNS). The strategy RABV uses to hijack the cellular transport machinery is still not clear. It is thought that RABV interacts with membrane receptors in order to internalize and exploit the endosomal trafficking pathway, yet this has never been demonstrated directly. The p75 Nerve Growth Factor (NGF) receptor (p75NTR) binds RABV Glycoprotein (RABV-G) with high affinity. However, as p75NTR is not essential for RABV infection, the specific role of this interaction remains in question. Here we used live cell imaging to track RABV entry at nerve terminals and studied its retrograde transport along the axon with and without the p75NTR receptor. First, we found that NGF, an endogenous p75NTR ligand, and RABV, are localized in corresponding domains along nerve tips. RABV and NGF were internalized at similar time frames, suggesting comparable entry machineries. Next, we demonstrated that RABV could internalize together with p75NTR. Characterizing RABV retrograde movement along the axon, we showed the virus is transported in acidic compartments, mostly with p75NTR. Interestingly, RABV is transported faster than NGF, suggesting that RABV not only hijacks the transport machinery but can also manipulate it. Co-transport of RABV and NGF identified two modes of transport, slow and fast, that may represent a differential control of the trafficking machinery by RABV. Finally, we determined that p75NTR-dependent transport of RABV is faster and more directed than p75NTR-independent RABV transport. This fast route to the neuronal cell body is characterized by both an increase in instantaneous velocities and fewer, shorter stops en route. Hence, RABV may employ p75NTR-dependent transport as a fast mechanism to facilitate movement to the CNS. PMID:25165859

Chlamydia Hijacks ARF GTPases To Coordinate Microtubule Posttranslational Modifications and Golgi Complex Positioning.

PubMed

Wesolowski, Jordan; Weber, Mary M; Nawrotek, Agata; Dooley, Cheryl A; Calderon, Mike; St Croix, Claudette M; Hackstadt, Ted; Cherfils, Jacqueline; Paumet, Fabienne

2017-05-02

The intracellular bacterium Chlamydia trachomatis develops in a parasitic compartment called the inclusion. Posttranslationally modified microtubules encase the inclusion, controlling the positioning of Golgi complex fragments around the inclusion. The molecular mechanisms by which Chlamydia coopts the host cytoskeleton and the Golgi complex to sustain its infectious compartment are unknown. Here, using a genetically modified Chlamydia strain, we discovered that both posttranslationally modified microtubules and Golgi complex positioning around the inclusion are controlled by the chlamydial inclusion protein CT813/CTL0184/InaC and host ARF GTPases. CT813 recruits ARF1 and ARF4 to the inclusion membrane, where they induce posttranslationally modified microtubules. Similarly, both ARF isoforms are required for the repositioning of Golgi complex fragments around the inclusion. We demonstrate that CT813 directly recruits ARF GTPases on the inclusion membrane and plays a pivotal role in their activation. Together, these results reveal that Chlamydia uses CT813 to hijack ARF GTPases to couple posttranslationally modified microtubules and Golgi complex repositioning at the inclusion. IMPORTANCE Chlamydia trachomatis is an important cause of morbidity and a significant economic burden in the world. However, how Chlamydia develops its intracellular compartment, the so-called inclusion, is poorly understood. Using genetically engineered Chlamydia mutants, we discovered that the effector protein CT813 recruits and activates host ADP-ribosylation factor 1 (ARF1) and ARF4 to regulate microtubules. In this context, CT813 acts as a molecular platform that induces the posttranslational modification of microtubules around the inclusion. These cages are then used to reposition the Golgi complex during infection and promote the development of the inclusion. This study provides the first evidence that ARF1 and ARF4 play critical roles in controlling posttranslationally modified microtubules around the inclusion and that Chlamydia trachomatis hijacks this novel function of ARF to reposition the Golgi complex. Copyright © 2017 Wesolowski et al.

Host transcription factor Speckled 110 kDa (Sp110), a nuclear body protein, is hijacked by hepatitis B virus protein X for viral persistence.

PubMed

Sengupta, Isha; Das, Dipanwita; Singh, Shivaram Prasad; Chakravarty, Runu; Das, Chandrima

2017-12-15

Promyelocytic leukemia nuclear bodies (PML-NB) are sub-nuclear organelles that are the hub of numerous proteins. DNA/RNA viruses often hijack the cellular factors resident in PML-NBs to promote their proliferation in host cells. Hepatitis B virus (HBV), belonging to Hepadnaviridae family, remains undetected in early infection as it does not induce the innate immune response and is known to be the cause of several hepatic diseases leading to cirrhosis and hepatocellular carcinoma. The association of PML-NB proteins and HBV is being addressed in a number of recent studies. Here, we report that the PML-NB protein Speckled 110 kDa (Sp110) is SUMO1-modified and undergoes a deSUMOylation-driven release from the PML-NB in the presence of HBV. Intriguingly, Sp110 knockdown significantly reduced viral DNA load in the culture supernatant by activation of the type I interferon-response pathway. Furthermore, we found that Sp110 differentially regulates several direct target genes of hepatitis B virus protein X (HBx), a viral co-factor. Subsequently, we identified Sp110 as a novel interactor of HBx and found this association to be essential for the exit of Sp110 from the PML-NB during HBV infection and HBx recruitment on the promoter of these genes. HBx, in turn, modulates the recruitment of its associated transcription cofactors p300/HDAC1 to these co-regulated genes, thereby altering the host gene expression program in favor of viral persistence. Thus, we report a mechanism by which HBV can evade host immune response by hijacking the PML-NB protein Sp110, and therefore, we propose it to be a novel target for antiviral therapy. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Colicin Killing: Foiled Cell Defense and Hijacked Cell Functions

NASA Astrophysics Data System (ADS)

de Zamaroczy, Miklos; Chauleau, Mathieu

The study of bacteriocins, notably those produced by E. coli (and named colicins), was initiated in 1925 by Gratia, who first discovered "un remarquable exemple d'antagonisme entre deux souches de colibacilles". Since this innovating observation, the production of toxic exoproteins has been widely reported in all major lineages of Eubacteria and in Archaebacteria. Bacteriocins belong to the most abundant and most diverse group of these bacterial defense systems. Paradoxically, these antimicrobial cytotoxins are actually powerful weapons in the intense battle for bacterial survival. They are also biotechnologically useful since several bacteriocins are used as preservatives in the food industry or as antibiotics or as potential antitumor agents in human health care. Most colicins kill bacteria in one of two ways. The first type is those that form pores in the phospholipid bilayer of the inner membrane. They are active immediately after their translocation across the outer membrane. The translocation pathway requires generally either the BtuB receptor and the Tol (OmpF/TolABQR) complex, or the FepA, FhuA, or Cir receptor and the Ton (TonB/ExbBD) system. The second type of colicins encodes specific endonuclease activities that target DNA, rRNA, or tRNAs in the cytoplasm. To be active, these colicins require translocation across both the outer and inner membranes. The molecular mechanisms implicated in the complex cascade of interactions, required for the transfers of colicin molecules from the extracellular medium through the different "cellular compartments" (outer membrane, periplasm, inner membrane, and cytoplasm), are still incompletely understood. It is clear, however, that the colicins "hijack" specific cellular functions to facilitate access to their target. In this chapter, following a general presentation of colicin biology, we describe, compare, and update several of the concepts related to colicin toxicity and discuss recent, often unexpected findings, which help to advance our understanding of the molecular events governing colicin import. In particular, our review includes the following: (1) Structural data on the tripartite interaction of a colicin with the outer membrane receptor and the translocation machinery, (2) Comparison of the normal cellular functions of the Tol and Ton systems of the inner membrane with their "hijacked" roles during colicin import, (3) An analysis of the interaction of a nuclease-type colicin with its cognate immunity protein in the context of the immunity of producer cells, and of the dissociation of this complex in the context of the attack of the colicin on target cells, (4) Information on the endoproteolytic cleavage, which presumably accompanies the penetration of nuclease-type colicins into the cytoplasm. The new data presented here provides further insight into cellular functions "hijacked" or "borrowed" by colicins to permit their entry into target cells.

Adversary modeling: an analysis of criminal activities analogous to potential threats to nuclear safeguard systems

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

Heineke, J.M.

1978-12-20

This study examines and analyzes several classes of incidents in which decision makers are confronted with adversaries. The classes are analogous to adversaries in a material control system in a nuclear facility. Both internal threats (bank frauds and embezzlements) and external threats (aircraft hijackings and hostage-type terrorist events were analyzed. (DLC)

Asparagine and Glutamine: Co-conspirators Fueling Metastasis.

PubMed

Luo, Ming; Brooks, Michael; Wicha, Max S

2018-05-01

Cancer cells frequently hijack normal metabolic pathways to promote their growth and metastasis. Two recent papers by Knott et al. (2018) and Pavlova et al. (2018) demonstrate that asparagine and glutamine work in concert to drive tumor growth and metastasis through modulation of cell survival, growth, and EMT regulatory pathways. Copyright © 2018. Published by Elsevier Inc.

Imagining No Child Left Behind Freed from Neoliberal Hijackers

ERIC Educational Resources Information Center

Matusov, Eugene

2011-01-01

As a sociocultural educator and scholar, I have always been ambivalent about No Child Left Behind's slogan. I like its democratic ideal of "education without failure," but I do not like the current educational policies guided by a neoliberal ideology. This article begins a discussion about what a No Student Left Behind educational practice might…

Ethics from Web 1.0 to Web 2.0: Standing outside the Box

ERIC Educational Resources Information Center

Harris, Frances Jacobson

2009-01-01

In today's schools and library media centers, emotion-laden concerns about new modes of information and communication technology can hijack librarians' attention, even taking center stage. Something about the online revolution and, more recently, the advent of Web 2.0 tools and their ability to create connections among users, as well as between…

Envisioning an Alternative to the Neoliberalization of Education in the Global South: The Aga Khan's Philosophies of Education

ERIC Educational Resources Information Center

Khoja-Moolji, Shenila S.

2017-01-01

Studies in education over the past decade highlight the hijacking of educational agendas by neoliberal rationalities and logics. I illustrate these processes in relation to transnational campaigns for girls' education, where the purpose of "education" is reduced to producing wage-based labor and an accumulation of skills that enhance…

"Beyond Ground Zero": The Futures of Critical Thought after 9/11

ERIC Educational Resources Information Center

Espiritu, Karen; Moore, Donald G.

2008-01-01

In the wake of the September 11, 2001, attacks on the Pentagon and World Trade Center, and amid sweeping patriotic declarations that the suicide hijackers had waged a war on America as well as democracy, the energetic response by public intellectuals, academics, philosophers, and theorists has been to ask, what "America," what "democracy," what…

In Athena’s Camp; Preparing for a Conflict in the Information Age

DTIC Science & Technology

1997-01-01

capital, as man remains the purest, richest information-hurling system. In the words of pulp cinema icon, John Rambo, "the mind is the greatest...tion camp guards shortly after World War II; the crash of a hijacked Malaysian passen- ger plane in 1977; the arson attack at an Aba’dan movie theater

Kan Na! Authentic Chinese Reading. Lessons for Intermediate to Advanced Self-Study. [CD-ROM].

ERIC Educational Resources Information Center

Fleming, Stephen; Hiple, David; Ning, Cynthia

This compact disc offers several lessons in Chinese, including a photo feature from a Chinese newspaper, the service directory from a Chinese hotel room, a pamphlet for travelers from Taiwan, a family letter, an introduction to Chinese cuisine, an article about a hijacking, a letter of agreement between institutions, an odyssey of a teenaged boy,…

Effectiveness of the Civil Aviation Security Program.

DTIC Science & Technology

1977-10-31

searches. Perhaps the best evidence of the effectiveness of airline and airport security measures is the number of hijackings and related crimes...revision of the regulation that established basic airport security requirements is currently underway. One of the more significant revisions under study... airport security procedures cannot be determined with certainty. Nowever, the number of firearms detected at passenger screening points under suspicious

Effectiveness of the Civil Aviation Security Program.

DTIC Science & Technology

1977-04-05

diversions. Perhaps the best evidence of the effectiveness of airline and airport security measures is the number of hijackings and related crimes prevented...airports. Consideration is being given to include a provision in the airport security regulation which would prohibit the introduction of...Security Program. A complete revision of the regulation that established basic airport security requirements is currently underway. One of the more

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

Clements, Abraham Anthony

EPOXY is a LLVM base compiler that applies security protections to bare-metal programs on ARM Cortex-M series micro-controllers. This includes privilege overlaying, wherein operations requiring privileged execution are identified and only these operations execute in privileged mode. It also applies code integrity, control-flow hijacking defenses, stack protections, and fine-grained randomization schemes. All of its protections work within the constraints of bare-metal systems.

The "Socially Just School" and Critical Pedagogies in Communities "Put at a Disadvantage"

ERIC Educational Resources Information Center

Smyth, John

2012-01-01

Public schools around the world have been hijacked and deformed beyond recognition by the forces of the economy over the past three decades. This paper provides an analysis and a way out of this miasma around the notion of the socially just school. While not another prescription, this orientation is argued to be the most hopeful possibility for…

The Origins of the Transformation of the Defense Language Program

ERIC Educational Resources Information Center

Raugh, Harold E., Jr.

2006-01-01

The horrific events of 11 September 2001, when four hijacked jetliners crashed into and collapsed the twin-towered World Trade Center in New York, slammed into the Pentagon, and nose-dived into a field in rural Pennsylvania (ostensibly on a mission to destroy the U.S. Capitol or the White House), have been indelibly etched into the nation's…

US Counter-Islamic State Strategy: It Could Be Worse

DTIC Science & Technology

2017-03-31

to achieve US political objectives. US Policy Towards Islamic State Modern Islamic terrorism , defined as groups professing Islamic motivations...networks, these extremist organizations adopted terrorism strategies to achieve their political goals.4 Bombing, kidnappings, hijackings and shootings...fueled by US enmity, and focused on striking the West outside of the Middle East. These efforts manifested themselves as the terror attacks on

Congress Investigates: Pearl Harbor and 9/11 Congressional Hearing Exhibits

ERIC Educational Resources Information Center

Blackerby, Christine

2011-01-01

On the morning of December 7, 1941, Japanese bombers staged a surprise attack on U.S. military forces at Pearl Harbor in Hawaii. Sixty years after the attack on Pearl Harbor, the United States was attacked again. On the morning of September 11, 2001, four commercial airplanes hijacked by 19 terrorists killed nearly 3,000 people when they crashed…

Using a Personal Device to Strengthen Password Authentication from an Untrusted Computer

NASA Astrophysics Data System (ADS)

Mannan, Mohammad; van Oorschot, P. C.

Keylogging and phishing attacks can extract user identity and sensitive account information for unauthorized access to users' financial accounts. Most existing or proposed solutions are vulnerable to session hijacking attacks. We propose a simple approach to counter these attacks, which cryptographically separates a user's long-term secret input from (typically untrusted) client PCs; a client PC performs most computations but has access only to temporary secrets. The user's long-term secret (typically short and low-entropy) is input through an independent personal trusted device such as a cellphone. The personal device provides a user's long-term secrets to a client PC only after encrypting the secrets using a pre-installed, "correct" public key of a remote service (the intended recipient of the secrets). The proposed protocol (MP-Auth) realizes such an approach, and is intended to safeguard passwords from keyloggers, other malware (including rootkits), phishing attacks and pharming, as well as to provide transaction security to foil session hijacking. We report on a prototype implementation of MP-Auth, and provide a comparison of web authentication techniques that use an additional factor of authentication (e.g. a cellphone, PDA or hardware token).

Hijacking T cell differentiation: new insights in TLX function in T-ALL.

PubMed

King, Bryan; Ntziachristos, Panagiotis; Aifantis, Iannis

2012-04-17

TLX1 and TLX3 are two closely-related homeobox transcriptional repressors frequently misexpressed and translocated in T cell acute lymphoblastic leukemia (T-ALL). In this issue of Cancer Cell, Dadi et al. provide new insights into how these factors are recruited by ETS-1 to the TCRα enhancer and actively repress differentiation. Copyright © 2012 Elsevier Inc. All rights reserved.

Effectiveness of the Civil Aviation Security Program.

DTIC Science & Technology

1981-04-15

on item were processed through the screening system daily. The airline and airport security measures developed continue to provide increased safety...United States or Puerto Rico. None of these 16 hijackings resulted from insufficient airport security measures or a breakdown in the FAA-approved airport ... airport security programs is conducted at the Transportation Safety Institute in Oklahoma City, Oklahoma. The course provides in-depth coverage of civil

What Practices in Airport Security Should the United States Implement at Commercial Airports in Light of the Events of September 11, 2001?

DTIC Science & Technology

2002-06-01

NAVAL POSTGRADUATE SCHOOL Monterey, California THESIS WHAT PRACTICES IN AIRPORT SECURITY SHOULD THE UNITED STATES IMPLEMENT AT...COVERED Master’s Thesis 4. TITLE AND SUBTITLE What Practices in Airport Security Should the United States Implement at Commercial...complacency and conflicts of interest. 14. SUBJECT TERMS Airport Security , Aviation Security Systems, Terrorism, Hijacking

The Reading Glitch: How the Culture Wars Have Hijacked Reading Instruction--And What We Can Do about It

ERIC Educational Resources Information Center

Sherman, Lee; Ramsey, Betsy

2006-01-01

Reading disability and illiteracy are among the most pressing educational issues facing the United States today. At least 40 percent of America's fourth-graders are unable to read at grade level and a similar proportion of adults read at the lowest two levels of prose literacy. Here, the authors present an unflinching examination of the science…

E's Are Good: Standards of Quality in Public Administration as Reflected in Discourse on Canadian Public Policy Design

ERIC Educational Resources Information Center

Baker, Dana Lee; Miller, Audrey Anna; Bratton, Todd

2015-01-01

Promoting understanding of quality in the context of good governance can be a challenging classroom exercise not only because of the potential for hijacking politicization of the discussion, but also because of the variety of ways in which public sector goals can be defined, even in the context of a single policy. Standards of quality in the…

Imagining How to Break the Co-Optation of a Consensus. A Response to "Imagining No Child Left Behind Freed from Neoliberal Hijackers"

ERIC Educational Resources Information Center

Varenne, Herve

2011-01-01

Given that I share, mostly, Eugene Matusov's passionate concerns, picking on his vocabulary might appear pedantic. However, the issues involved in labeling political movements and, even more, political practices, can be fundamental and address the very grounds on which social analysis must stand. Briefly, I am concerned with the label…

Hermit crabs, humans and crowded house markets.

PubMed

Barnes, David K A

2002-12-01

There is a complex and dynamic interrelationhip between hermit crabs, humans and the coastal environment. Hermit crab homes (shells) are often hard to come by, but humans are helping out by piling middens of shells and rubbish on beachers. Hermit crabs are useful to humans as fishing bait, pets and living wasted disposal systems, and so useful to other animals that they may even be hijacked.

Accountability to Whom? Testing and Social Justice. A Response to "Imagining No Child Left Behind Freed from Neoliberal Hijackers"

ERIC Educational Resources Information Center

Kritt, David W.

2011-01-01

In response to Eugene Matusov's article in this journal, Kritt addresses assumptions of the large-scale testing central to NCLB. Discussion of studies of urban kindergarten children that examine cognitive variability, including the assertion of ability, focuses on how this affects the student as a learner, as well as as a teacher. In contrast,…

Soldier Data Tag Study Effort.

DTIC Science & Technology

1985-06-10

interested in protecting it. The tag itself is difficult--though not impossible--to counterfeit . Also, it (’• iii 71 -, potentially improves the data...attacks during the design, manufacture, and distribution processes, counterfeiting , unauthorized access/alteration of tag data, and use of the tag to...45 3.3.2 Hijacking of SOT System Shipments, or Large- Scale Counterfeit of SOT Systems ....................... 46 3.3.3 Unauthorized Alteration

Effectiveness of the Civil Aviation Security Program.

DTIC Science & Technology

1975-10-06

Results of the passenger screening procedures continue to reflect the success and effec- tiveness of airline and airport security programs. During the...airline and airport security programs. While it is impossible to estimate accurately just how many hijackings and related crimes were prevented, the...attempts might have occurred during 1974 and as many as 25 during the first 6 months of 1975, if current airline and airport security programs had not

Should We Turn the Robots Loose?

DTIC Science & Technology

2010-05-02

interference. Potential sources of electromagnetic interference include everyday signals such as cell phones and Wifi , intentional friendly jamming of IED...might even attempt to hack or hijack our robotic warriors. Our current enemies have proven to be very adaptable and have developed simple counters to our...demonstrates the ease with which robot command and control might be hacked . It is reasonable to suspect that a future threat with a more robust

A bill to close the loophole that allowed the 9/11 hijackers to obtain credit cards from United States banks that financed their terrorist activities, to ensure that illegal immigrants cannot obtain credit cards to evade United States immigration laws, and for other purposes.

THOMAS, 111th Congress

Sen. Vitter, David [R-LA

2009-01-06

Senate - 01/06/2009 Read twice and referred to the Committee on Banking, Housing, and Urban Affairs. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

A bill to close the loophole that allowed the 9/11 hijackers to obtain credit cards from United States banks that financed their terrorist activities, to ensure that illegal immigrants cannot obtain credit cards to evade United States immigration laws, and for other purposes.

THOMAS, 112th Congress

Sen. Vitter, David [R-LA

2011-01-25

Senate - 01/25/2011 Read twice and referred to the Committee on Banking, Housing, and Urban Affairs. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

Genesis: A Framework for Achieving Software Component Diversity

DTIC Science & Technology

2007-01-01

correctly—the initial filters develop to fix the Hotmail vulnerability could be circumvented by using alternate character encodings4. Hence, we focus on...Remotely Exploitable Cross-Site Scripting in Hotmail and Yahoo, (March 2004); http://www.greymagic.com/security/advisories/gm005-mc/. 4...EyeonSecurity, Microsoft Passport Account Hijack Attack: Hacking Hotmail and More, Hacker’s Digest. 5. Y.-W. Huang et al., Web Application Security Assessment by

T-dominance: Prioritized Defense Deployment for BYOD Security (Post Print)

DTIC Science & Technology

2013-10-01

infrastructure. Employees’ demand/ satisfaction , decreased IT acquisition and support cost, and increased use of cloud/virtualization technologies in...example, a report [8] on hijacking hotel Wi-Fi hotspots for drive-by malware attacks on laptops comes close to what we have in mind; practical man-in...obtaining unwarranted privilege, are often ignored for convenience, or circumvented for customization by the users. Rootkits, like iOS Jailbreak5, are

How to Recognize and Avoid Potential, Possible, or Probable Predatory Open-Access Publishers, Standalone, and Hijacked Journals.

PubMed

Danevska, Lenche; Spiroski, Mirko; Donev, Doncho; Pop-Jordanova, Nada; Polenakovic, Momir

2016-11-01

The Internet has enabled an easy method to search through the vast majority of publications and has improved the impact of scholarly journals. However, it can also pose threats to the quality of published articles. New publishers and journals have emerged so-called open-access potential, possible, or probable predatory publishers and journals, and so-called hijacked journals. It was our aim to increase the awareness and warn scholars, especially young researchers, how to recognize these journals and how to avoid submission of their papers to these journals. Review and critical analysis of the relevant published literature, Internet sources and personal experience, thoughts, and observations of the authors. The web blog of Jeffrey Beall, University of Colorado, was greatly consulted. Jeffrey Beall is a Denver academic librarian who regularly maintains two lists: the first one, of potential, possible, or probable predatory publishers and the second one, of potential, possible, or probable predatory standalone journals. Aspects related to this topic presented by other authors have been discussed as well. Academics should bear in mind how to differentiate between trustworthy and reliable journals and predatory ones, considering: publication ethics, peer-review process, international academic standards, indexing and abstracting, preservation in digital repositories, metrics, sustainability, etc.

Where in the Cell Are You? Probing HIV-1 Host Interactions through Advanced Imaging Techniques

PubMed Central

Dirk, Brennan S.; Van Nynatten, Logan R.; Dikeakos, Jimmy D.

2016-01-01

Viruses must continuously evolve to hijack the host cell machinery in order to successfully replicate and orchestrate key interactions that support their persistence. The type-1 human immunodeficiency virus (HIV-1) is a prime example of viral persistence within the host, having plagued the human population for decades. In recent years, advances in cellular imaging and molecular biology have aided the elucidation of key steps mediating the HIV-1 lifecycle and viral pathogenesis. Super-resolution imaging techniques such as stimulated emission depletion (STED) and photoactivation and localization microscopy (PALM) have been instrumental in studying viral assembly and release through both cell–cell transmission and cell–free viral transmission. Moreover, powerful methods such as Forster resonance energy transfer (FRET) and bimolecular fluorescence complementation (BiFC) have shed light on the protein-protein interactions HIV-1 engages within the host to hijack the cellular machinery. Specific advancements in live cell imaging in combination with the use of multicolor viral particles have become indispensable to unravelling the dynamic nature of these virus-host interactions. In the current review, we outline novel imaging methods that have been used to study the HIV-1 lifecycle and highlight advancements in the cell culture models developed to enhance our understanding of the HIV-1 lifecycle. PMID:27775563

Divergent discourse between protests and counter-protests: #BlackLivesMatter and #AllLivesMatter.

PubMed

Gallagher, Ryan J; Reagan, Andrew J; Danforth, Christopher M; Dodds, Peter Sheridan

2018-01-01

Since the shooting of Black teenager Michael Brown by White police officer Darren Wilson in Ferguson, Missouri, the protest hashtag #BlackLivesMatter has amplified critiques of extrajudicial killings of Black Americans. In response to #BlackLivesMatter, other Twitter users have adopted #AllLivesMatter, a counter-protest hashtag whose content argues that equal attention should be given to all lives regardless of race. Through a multi-level analysis of over 860,000 tweets, we study how these protests and counter-protests diverge by quantifying aspects of their discourse. We find that #AllLivesMatter facilitates opposition between #BlackLivesMatter and hashtags such as #PoliceLivesMatter and #BlueLivesMatter in such a way that historically echoes the tension between Black protesters and law enforcement. In addition, we show that a significant portion of #AllLivesMatter use stems from hijacking by #BlackLivesMatter advocates. Beyond simply injecting #AllLivesMatter with #BlackLivesMatter content, these hijackers use the hashtag to directly confront the counter-protest notion of "All lives matter." Our findings suggest that Black Lives Matter movement was able to grow, exhibit diverse conversations, and avoid derailment on social media by making discussion of counter-protest opinions a central topic of #AllLivesMatter, rather than the movement itself.

Cerberus to Mind: Media as Sentinel in the Fight against Terrorism

DTIC Science & Technology

2006-05-01

splits. First, unfiltered signals arrive directly at the amygdala . The amygdala , as the evolutionary and memory-induced warehouse of fear, makes a...and detailed evaluation. The cortically-processed sensory inputs then arrive at the amygdala (with a time detail relative to the direct inputs from...the victims themselves.[4] Terror and the Media Democratic nations must try to find ways to starve the terrorist and the hijacker of the oxygen of

Test and Evaluation Plan for the Explosive Device Detection Baseline (EDDB) Study

DTIC Science & Technology

1995-08-01

of civil aviation security has changed from hijackings to methods of countering bombings. This shift has markedly increased the need for improvements...to detect an environmental event or signal. SDT is a mathematical representation of human performance in deciding whether or not a signal is present...1970; Macmillan & Creelman , 1990; Snodgrass & Corwin, 1988). The chief difference between the measure c and its parametric alternative P3 lies in the

U.S. Navy Capstone Strategies and Concepts (1981-1990): Strategy, Policy, Concept, and Vision Documents

DTIC Science & Technology

2011-12-01

Contra Affair (1988) USS Iowa (BB-61) turret explosion, investigation (1989) US Naval Academy sexual harassment scandal (1989)  Female midshipman...down (1981); Grenada intervention (1983), Lebanon intervention (1982-3); Med hijacker force-down (1985); US assistance to Central American anti...LTG Colin Powell USA Reaction to disastrous USMC intervention in Lebanon (1983)  Forces for Unified Commands memorandum (Feb 1987)  JCS Pub 26

Reflecting on Changing Practices, Contexts and Identities. Proceedings of the Annual Meeting of the Standing Conference on University Teaching and Research in the Education of Adults--SCUTREA (24th, Hull, England, United Kingdom, July 12-14, 1994).

ERIC Educational Resources Information Center

Armstrong, Paul, Ed.; And Others

The following papers are included: "Valuing Change and Changing Values" (Armstrong); "Raybouldism, Russell, and New Reality" (Benn, Fieldhouse); "The Move to Self-Assessment" (Boud); "Hijacking Experience and Delivering Competence" (Bryant); "The Professional Development Model of APEL [Assessment of Prior Experiential Learning]--Some Problems of…

Comparative Profiling of Ubiquitin Proteasome System Interplay with Influenza A Virus PB2 Polymerase Protein Recapitulating Virus Evolution in Humans.

PubMed

Biquand, Elise; Poirson, Juline; Karim, Marwah; Declercq, Marion; Malausse, Nicolas; Cassonnet, Patricia; Barbezange, Cyril; Straub, Marie-Laure; Jones, Louis; Munier, Sandie; Naffakh, Nadia; van der Werf, Sylvie; Jacob, Yves; Masson, Murielle; Demeret, Caroline

2017-01-01

The optimized exploitation of cell resources is one cornerstone of a successful infection. Differential mapping of host-pathogen protein-protein interactions (PPIs) on the basis of comparative interactomics of multiple strains is an effective strategy to highlight correlations between host proteome hijacking and biological or pathogenic traits. Here, we developed an interactomic pipeline to deliver high-confidence comparative maps of PPIs between a given pathogen and the human ubiquitin proteasome system (UPS). This subarray of the human proteome represents a range of essential cellular functions and promiscuous targets for many viruses. The screening pipeline was applied to the influenza A virus (IAV) PB2 polymerase proteins of five strains representing different levels of virulence in humans. An extensive PB2-UPS interplay has been detected that recapitulates the evolution of IAVs in humans. Functional validation with several IAV strains, including the seasonal H1N1 pdm09 and H3N2 viruses, confirmed the biological relevance of most identified UPS factors and revealed strain-independent and strain-specific effects of UPS factor invalidation on IAV infection. This strategy is applicable to proteins from any other virus or pathogen, providing a valuable resource with which to explore the UPS-pathogen interplay and its relationship with pathogenicity. IMPORTANCE Influenza A viruses (IAVs) are responsible for mild-to-severe seasonal respiratory illness of public health concern worldwide, and the risk of avian strain outbreaks in humans is a constant threat. Elucidating the requisites of IAV adaptation to humans is thus of prime importance. In this study, we explored how PB2 replication proteins of IAV strains with different levels of virulence in humans hijack a major protein modification pathway of the human host cell, the ubiquitin proteasome system (UPS). We found that the PB2 protein engages in an extended interplay with the UPS that evolved along with the virus's adaptation to humans. This suggests that UPS hijacking underlies the efficient infection of humans and can be used as an indicator for evaluation of the potential of avian IAVs to infect humans. Several UPS factors were found to be necessary for infection with circulating IAV strains, pointing to potential targets for therapeutic approaches.

Coercion, Cash-Crops and Culture: From Insurgency to Proto-State in Asia’s Opium Belt

DTIC Science & Technology

2008-06-01

were rapidly hijacked by greed due to the war economy of Southeast Asia (hot and cold), and enabling influences of both the Chinese and the Americans...until it finally disintegrated in the late 1980s. Surrenders, splits, and betrayals continued to occur within and between the various ethnic... tablets (methamphetamine) are thought to be shipped from Burma across the border to Thailand, corresponding to about twenty tons of methamphetamine

Send In The Drones! Are Remotely Piloted Aircraft Changing America’s Threshold For Turning To Violence

DTIC Science & Technology

2011-12-01

sides attempted to deliver explosive-laden unmanned balloons to the enemy. The Japanese revived this technique during World War II, when Japanese forces...attempted to send similar balloons across the Atlantic to cause destruction in the United States. 3 As aircraft technology developed, so did the...taken hostage following a failed hijacking attempt. The objective was to free the American captive and it was a success. 55 2005-2011, Pakistan

Archaeology Hijacked: Addressing the Historical Misappropriations of Maritime and Underwater Archaeology

NASA Astrophysics Data System (ADS)

Gately, Iain; Benjamin, Jonathan

2017-09-01

As a discipline that has grown up in the eyes of the camera, maritime and underwater archaeology has struggled historically to distinguish itself from early misrepresentations of it as adventure-seeking, treasure hunting and underwater salvage as popularized in the 1950s and 1960s. Though many professional archaeologists have successfully moved forward from this history through broader theoretical engagement and the development of the discipline within anthropology, public perception of archaeology under water has not advanced in stride. Central to this issue is the portrayal of underwater archaeology within popular culture and the representational structures from the 1950s and 1960s persistently used to introduce the profession to the public, through the consumption of popular books and especially television. This article explores representations of maritime and underwater archaeology to examine how the discipline has been consumed by the public, both methodologically and theoretically, through media. In order to interrogate this, we first examine maritime and underwater archaeology as a combined sub-discipline of archaeology and consider how it has been defined historically and in contemporary professional practice. Finally, we consider how practitioners can take a proactive approach to portray their work and convey archaeological media to the public. In this respect, we aim to advance the theoretical discussion in a way so as to reduce further cases whereby archaeology is accidentally misappropriated or deliberately hijacked.

TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I.

PubMed

van den Boomen, Dick J H; Timms, Richard T; Grice, Guinevere L; Stagg, Helen R; Skødt, Karsten; Dougan, Gordon; Nathan, James A; Lehner, Paul J

2014-08-05

The US11 gene product of human cytomegalovirus promotes viral immune evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. US11 initiates dislocation of newly translocated MHC I from the ER to the cytosol for proteasome-mediated degradation. Despite the critical role for ubiquitin in this degradation pathway, the responsible E3 ligase is unknown. In a forward genetic screen for host ERAD components hijacked by US11 in near-haploid KBM7 cells, we identified TMEM129, an uncharacterized polytopic membrane protein. TMEM129 is essential and rate-limiting for US11-mediated MHC-I degradation and acts as a novel ER resident E3 ubiquitin ligase. TMEM129 contains an unusual cysteine-only RING with intrinsic E3 ligase activity and is recruited to US11 via Derlin-1. Together with its E2 conjugase Ube2J2, TMEM129 is responsible for the ubiquitination, dislocation, and subsequent degradation of US11-associated MHC-I. US11 engages two degradation pathways: a Derlin-1/TMEM129-dependent pathway required for MHC-I degradation and a SEL1L/HRD1-dependent pathway required for "free" US11 degradation. Our data show that TMEM129 is a novel ERAD E3 ligase and the central component of a novel mammalian ERAD complex.

Divergent discourse between protests and counter-protests: #BlackLivesMatter and #AllLivesMatter

PubMed Central

Reagan, Andrew J.; Danforth, Christopher M.; Dodds, Peter Sheridan

2018-01-01

Since the shooting of Black teenager Michael Brown by White police officer Darren Wilson in Ferguson, Missouri, the protest hashtag #BlackLivesMatter has amplified critiques of extrajudicial killings of Black Americans. In response to #BlackLivesMatter, other Twitter users have adopted #AllLivesMatter, a counter-protest hashtag whose content argues that equal attention should be given to all lives regardless of race. Through a multi-level analysis of over 860,000 tweets, we study how these protests and counter-protests diverge by quantifying aspects of their discourse. We find that #AllLivesMatter facilitates opposition between #BlackLivesMatter and hashtags such as #PoliceLivesMatter and #BlueLivesMatter in such a way that historically echoes the tension between Black protesters and law enforcement. In addition, we show that a significant portion of #AllLivesMatter use stems from hijacking by #BlackLivesMatter advocates. Beyond simply injecting #AllLivesMatter with #BlackLivesMatter content, these hijackers use the hashtag to directly confront the counter-protest notion of “All lives matter.” Our findings suggest that Black Lives Matter movement was able to grow, exhibit diverse conversations, and avoid derailment on social media by making discussion of counter-protest opinions a central topic of #AllLivesMatter, rather than the movement itself. PMID:29668754

Optogenetic Excitation of Central Amygdala Amplifies and Narrows Incentive Motivation to Pursue One Reward Above Another

PubMed Central

Warlow, Shelley M.; Berridge, Kent C.

2014-01-01

Choosing one reward above another is important for achieving adaptive life goals. Yet hijacked into excessive intensity in disorders such as addiction, single-minded pursuit becomes maladaptive. Here, we report that optogenetic channelrhodopsin stimulation of neurons in central nucleus of amygdala (CeA), paired with earning a particular sucrose reward in rats, amplified and narrowed incentive motivation to that single reward target. Therefore, CeA rats chose and intensely pursued only the laser-paired sucrose reward while ignoring an equally good sucrose alternative. In contrast, reward-paired stimulation of basolateral amygdala did not hijack choice. In a separate measure of incentive motivation, CeA stimulation also increased the progressive ratio breakpoint or level of effort exerted to obtain sucrose reward. However, CeA stimulation by itself failed to support behavioral self-stimulation in the absence of any paired external food reward, suggesting that CeA photo-excitation specifically transformed the value of its external reward (rather than adding an internal reinforcement state). Nor did CeA stimulation by itself induce any aversive state that motivated escape. Finally, CeA stimulation also failed to enhance ‘liking’ reactions elicited by sucrose taste and did not simply increase the general motivation to eat. This pattern suggests that CeA photo-excitation specifically enhances and narrows incentive motivation to pursue an associated external reward at the expense of another comparable reward. PMID:25505310

Momentum harvesting techniques for solar system travel

NASA Technical Reports Server (NTRS)

Willoughby, Alan J.

1990-01-01

Astronomers are lately estimating there are 400,000 Earth visiting asteroids larger than 100 meters in diameter. These asteroids are accessible sources of building materials, propellants, oxygen, water, and minerals which also constitute a huge momentum reserve, potentially usable for travel throughout the solar system. To use this momentum, these stealthy objects must be tracked and the extraction of the momentum wanted must be learned. Momentum harvesting by momentum transfer from asteroid to spacecraft, and by using the momentum of the extraterrestrial material to help deliver itself to the destination are discussed. A net and tether concept is the suggested means of asteroid capture, the basic momentum exchange process. The energy damping characteristics of the tether will determine the velocity mismatch that can be tolerated, and hence the amount of momentum that can be harvested per capture. As it plays out of its reel, drag on the tether steadily accelerates the spacecraft. A variety of concepts for riding and using the asteroid after capture are discussed. The hitchhiker uses momentum transfer only. The beachcomber, the caveman, the swinger, the prospector, and the rock wrecker also take advantage of raw asteroidal materials. The chemist and the hijacker go further, they process the asteroid into propellant. Or, an 'asteroid railway system' could evolve with each hijacked asteroid becoming a scheduled train. Travelers could board the space railway system assured that water, oxygen, and propellants await them.

Assessing the Efficacy of Capital Punishment in the War on Terror through the Lenses of History, Law and Theory

DTIC Science & Technology

2009-05-21

hijacking aircraft, committing genocide, and engaging in certain wartime activities are considered universal crimes.54 Israel v. Eichmann is an... Eichmann and return him to Israel for trial. This is an example of an irregular option to extradition, but it did not disqualify Israel’s right to try...Adolf Eichmann . The advent of global terrorism has gained enough attention in the United Nations and other international organizations that it falls

Hijacking User Uploads to Online Persistent Data Repositories for Covert Data Exfiltration

DTIC Science & Technology

2010-09-01

Detecting LSB Steganography in Color, and Gray-scale Images . Multimedia, IEEE, 8(4):22 –28, Oct.-Dec. 2001. [Fli10] Flickr. Camera finder...in images is known as Least Significant Bit ( LSB ) manipulation. This technique requires an individual to alter each pixel in an image just slightly...the human eye. It is this property of images that LSB manipulation relies on. When a user creates a piece of data they wish to hide in an image , they

Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches.

PubMed

Hira, Vashendriya V V; Van Noorden, Cornelis J F; Carraway, Hetty E; Maciejewski, Jaroslaw P; Molenaar, Remco J

2017-08-01

Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Xanthomonas TAL effectors hijack host basal transcription factor IIA α and γ subunits for invasion.

PubMed

Ma, Ling; Wang, Qiang; Yuan, Meng; Zou, Tingting; Yin, Ping; Wang, Shiping

2018-02-05

The Xanthomonas genus includes Gram-negative plant-pathogenic bacteria, which infect a broad range of crops and wild plant species, cause symptoms with leaf blights, streaks, spots, stripes, necrosis, wilt, cankers and gummosis on leaves, stems and fruits in a wide variety of plants via injecting their effector proteins into the host cell during infection. Among these virulent effectors, transcription activator-like effectors (TALEs) interact with the γ subunit of host transcription factor IIA (TFIIAγ) to activate the transcription of host disease susceptibility genes. Functional TFIIA is a ternary complex comprising α, β and γ subunits. However, whether TALEs recruit TFIIAα, TFIIAβ, or both remains unknown. The underlying molecular mechanisms by which TALEs mediate host susceptibility gene activation require full elucidation. Here, we show that TALEs interact with the α+γ binary subcomplex but not the α+β+γ ternary complex of rice TFIIA (holo-OsTFIIA). The transcription factor binding (TFB) regions of TALEs, which are highly conserved in Xanthomonas species, have a dominant role in these interactions. Furthermore, the interaction between TALEs and the α+γ complex exhibits robust DNA binding activity in vitro. These results collectively demonstrate that TALE-carrying pathogens hijack the host basal transcription factors TFIIAα and TFIIAγ, but not TFIIAβ, to enhance host susceptibility during pathogen infection. The uncovered mechanism widens new insights on host-microbe interaction and provide an applicable strategy to breed high-resistance crop varieties. Copyright © 2018 Elsevier Inc. All rights reserved.

World commercial aircraft accidents. Second edition, 1946--1992

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

Kimura, C.Y.

1993-01-01

This report is a compilation of all accidents world-wide involving aircraft in commercial service which resulted in the loss of the airframe or one or more fatality, or both. This information has been gathered in order to present a complete inventory of commercial aircraft accidents. Events involving military action, sabotage, terrorist bombings, hijackings, suicides, and industrial ground accidents are included within this list. Included are: accidents involving world commercial jet aircraft, world commercial turboprop aircraft, world commercial pistonprop aircraft with four or more engines and world commercial pistonprop aircraft with two or three engines from 1946 to 1992. Each accidentmore » is presented with information in the following categories: date of the accident, airline and its flight numbers, type of flight, type of aircraft, aircraft registration number, construction number/manufacturers serial number, aircraft damage, accident flight phase, accident location, number of fatalities, number of occupants, cause, remarks, or description (brief) of the accident, and finally references used. The sixth chapter presents a summary of the world commercial aircraft accidents by major aircraft class (e.g. jet, turboprop, and pistonprop) and by flight phase. The seventh chapter presents several special studies including a list of world commercial aircraft accidents for all aircraft types with 100 or more fatalities in order of decreasing number of fatalities, a list of collision accidents involving commercial aircrafts, and a list of world commercial aircraft accidents for all aircraft types involving military action, sabotage, terrorist bombings, and hijackings.« less

World commercial aircraft accidents

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

Kimura, C.Y.

1993-01-01

This report is a compilation of all accidents world-wide involving aircraft in commercial service which resulted in the loss of the airframe or one or more fatality, or both. This information has been gathered in order to present a complete inventory of commercial aircraft accidents. Events involving military action, sabotage, terrorist bombings, hijackings, suicides, and industrial ground accidents are included within this list. Included are: accidents involving world commercial jet aircraft, world commercial turboprop aircraft, world commercial pistonprop aircraft with four or more engines and world commercial pistonprop aircraft with two or three engines from 1946 to 1992. Each accidentmore » is presented with information in the following categories: date of the accident, airline and its flight numbers, type of flight, type of aircraft, aircraft registration number, construction number/manufacturers serial number, aircraft damage, accident flight phase, accident location, number of fatalities, number of occupants, cause, remarks, or description (brief) of the accident, and finally references used. The sixth chapter presents a summary of the world commercial aircraft accidents by major aircraft class (e.g. jet, turboprop, and pistonprop) and by flight phase. The seventh chapter presents several special studies including a list of world commercial aircraft accidents for all aircraft types with 100 or more fatalities in order of decreasing number of fatalities, a list of collision accidents involving commercial aircrafts, and a list of world commercial aircraft accidents for all aircraft types involving military action, sabotage, terrorist bombings, and hijackings.« less

Optogenetic excitation of central amygdala amplifies and narrows incentive motivation to pursue one reward above another.

PubMed

Robinson, Mike J F; Warlow, Shelley M; Berridge, Kent C

2014-12-10

Choosing one reward above another is important for achieving adaptive life goals. Yet hijacked into excessive intensity in disorders such as addiction, single-minded pursuit becomes maladaptive. Here, we report that optogenetic channelrhodopsin stimulation of neurons in central nucleus of amygdala (CeA), paired with earning a particular sucrose reward in rats, amplified and narrowed incentive motivation to that single reward target. Therefore, CeA rats chose and intensely pursued only the laser-paired sucrose reward while ignoring an equally good sucrose alternative. In contrast, reward-paired stimulation of basolateral amygdala did not hijack choice. In a separate measure of incentive motivation, CeA stimulation also increased the progressive ratio breakpoint or level of effort exerted to obtain sucrose reward. However, CeA stimulation by itself failed to support behavioral self-stimulation in the absence of any paired external food reward, suggesting that CeA photo-excitation specifically transformed the value of its external reward (rather than adding an internal reinforcement state). Nor did CeA stimulation by itself induce any aversive state that motivated escape. Finally, CeA stimulation also failed to enhance 'liking' reactions elicited by sucrose taste and did not simply increase the general motivation to eat. This pattern suggests that CeA photo-excitation specifically enhances and narrows incentive motivation to pursue an associated external reward at the expense of another comparable reward. Copyright © 2014 the authors 0270-6474/14/3416567-14$15.00/0.

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

PubMed Central

Hou, Shangmei; Kumar, Anil; Xu, Zaikun; Airo, Adriana M.; Stryapunina, Iryna; Wong, Cheung Pang; Branton, William; Tchesnokov, Egor; Götte, Matthias; Power, Christopher

2017-01-01

ABSTRACT Zika virus (ZIKV), a member of the Flaviviridae family, has recently emerged as an important human pathogen with increasing economic and health impact worldwide. Because of its teratogenic nature and association with the serious neurological condition Guillain-Barré syndrome, a tremendous amount of effort has focused on understanding ZIKV pathogenesis. To gain further insights into ZIKV interaction with host cells, we investigated how this pathogen affects stress response pathways. While ZIKV infection induces stress signaling that leads to phosphorylation of eIF2α and cellular translational arrest, stress granule (SG) formation was inhibited. Further analysis revealed that the viral proteins NS3 and NS4A are linked to translational repression, whereas expression of the capsid protein, NS3/NS2B-3, and NS4A interfered with SG formation. Some, but not all, flavivirus capsid proteins also blocked SG assembly, indicating differential interactions between flaviviruses and SG biogenesis pathways. Depletion of the SG components G3BP1, TIAR, and Caprin-1, but not TIA-1, reduced ZIKV replication. Both G3BP1 and Caprin-1 formed complexes with capsid, whereas viral genomic RNA stably interacted with G3BP1 during ZIKV infection. Taken together, these results are consistent with a scenario in which ZIKV uses multiple viral components to hijack key SG proteins to benefit viral replication. IMPORTANCE There is a pressing need to understand ZIKV pathogenesis in order to advance the development of vaccines and therapeutics. The cellular stress response constitutes one of the first lines of defense against viral infection; therefore, understanding how ZIKV evades this antiviral system will provide key insights into ZIKV biology and potentially pathogenesis. Here, we show that ZIKV induces the stress response through activation of the UPR (unfolded protein response) and PKR (protein kinase R), leading to host translational arrest, a process likely mediated by the viral proteins NS3 and NS4A. Despite the activation of translational shutoff, formation of SG is strongly inhibited by the virus. Specifically, ZIKV hijacks the core SG proteins G3BP1, TIAR, and Caprin-1 to facilitate viral replication, resulting in impaired SG assembly. This process is potentially facilitated by the interactions of the viral RNA with G3BP1 as well as the viral capsid protein with G3BP1 and Caprin-1. Interestingly, expression of capsid proteins from several other flaviviruses also inhibited SG formation. Taken together, the present study provides novel insights into how ZIKV modulates cellular stress response pathways during replication. PMID:28592527

Surfing pathogens and the lessons learned for actin polymerization.

PubMed

Frischknecht, F; Way, M

2001-01-01

A number of unrelated bacterial species as well as vaccinia virus (ab)use the process of actin polymerization to facilitate and enhance their infection cycle. Studies into the mechanism by which these pathogens hijack and control the actin cytoskeleton have provided many interesting insights into the regulation of actin polymerization in migrating cells. This review focuses on what we have learnt from the actin-based motilities of Listeria, Shigella and vaccinia and discusses what we would still like to learn from our nasty friends, including enteropathogenic Escherichia coli and Rickettsia

The Effective Use of U.S. Coast Guard Security Zones in Countering Unlawful Transnational Protests at Sea

DTIC Science & Technology

2009-01-01

Clinton’s Cuba Policy, August 1994," Presidential Studies Quarterly 28, no. 1, Winter 1998, 215. 24 The Sinking ofthe ൕ de Marzo " Tugboat on 13 July...seeking to bring attention to their cause with extreme measures.23 The sinking ofTREZE DE MARZO became an incident on which to focus future protests...Before the mass migration and subsequent agreement of 1994, Cuban migrants hijacked the Cuban tug TREZE DE MARZO on July 11, 1994 in an attempt to escape

Host Factors in Ebola Infection.

PubMed

Rasmussen, Angela L

2016-08-31

Ebola virus (EBOV) emerged in West Africa in 2014 to devastating effect, and demonstrated that infection can cause a broad range of severe disease manifestations. As the virus itself was genetically similar to other Zaire ebolaviruses, the spectrum of pathology likely resulted from variable responses to infection in a large and genetically diverse population. This review comprehensively summarizes current knowledge of the host response to EBOV infection, including pathways hijacked by the virus to facilitate replication, host processes that contribute directly to pathogenesis, and host-pathogen interactions involved in subverting or antagonizing host antiviral immunity.

Pilus hijacking by a bacterial coaggregation factor critical for oral biofilm development.

PubMed

Reardon-Robinson, Melissa E; Wu, Chenggang; Mishra, Arunima; Chang, Chungyu; Bier, Naomi; Das, Asis; Ton-That, Hung

2014-03-11

The formation of dental plaque, a highly complex biofilm that causes gingivitis and periodontitis, requires specific adherence among many oral microbes, including the coaggregation of Actinomyces oris with Streptococcus oralis that helps to seed biofilm development. Here, we report the discovery of a key coaggregation factor for this process. This protein, which we named coaggregation factor A (CafA), is one of 14 cell surface proteins with the LPXTG motif predicted in A. oris MG1, whose function was hitherto unknown. By systematic mutagenesis of each of these genes and phenotypic characterization, we found that the Actinomyces/Streptococcus coaggregation is only abolished by deletion of cafA. Subsequent biochemical and cytological experiments revealed that CafA constitutes the tip of a unique form of the type 2 fimbria long known for its role in coaggregation. The direct and predominant role of CafA in adherence is evident from the fact that CafA or an antibody against CafA inhibits coaggregation, whereas the shaft protein FimA or a polyclonal antibody against FimA has no effect. Remarkably, FimA polymerization was blocked by deletion of genes for both CafA and FimB, the previously described tip protein of the type 2 fimbria. Together, these results indicate that some surface proteins not linked to a pilus gene cluster in Gram-positive bacteria may hijack the pilus. These unique tip proteins displayed on a common pilus shaft may serve distinct physiological functions. Furthermore, the pilus shaft assembly in Gram-positive bacteria may require a tip, as is true for certain Gram-negative bacterial pili.

Smart white-light dazzler

NASA Astrophysics Data System (ADS)

Upton, Timothy D.; Ludman, Jacques E.; Watt, David W.

2004-09-01

The Smart, White-Light Dazzler (SWLD) is a nonlethal weapon designed to aim and deliver a dazzling and disabling light flash of maximum eye-safe energy to a selected target. The two key features of the SWLD technology are its self-aiming and power-adjusting capabilities; optical barriers, such as dark glasses, rifle scopes, binoculars, etc., and iris aperture, whether the eyes are light or dark adapted, are automatically taken into account by using a low-power infrared (IR) laser to probe and return a glint from the eye(s) of the target. Using the retro-reflected glint the dazzle pulse is adjusted and directed to arrive at the target with maximum allowable nonlethal energy at any range from 1 m to 100 m. The collateral risk of this technology is very small. If the weapon is misaimed dramatically, the returned glint may come from an unintended person who will then be dazzled. Although this person will be incapacitated for 2-3 minutes, he will suffer no long-term effects. We assume all persons in dangerous situations would rather be accidentally, temporarily dazzled than suffer more serious consequences. The SWLD adds an important tool to the spectrum of nonlethal responses available for use by military and law enforcement personnel. Applications include dispersing persons in crowd control and disabling terrorists in hijacking situations. The dazzle process may be repeated, choosing the next most susceptible target until a crowd is subdued. One important application in counter-terrorism is onboard planes where a pilot can fire a SWLD through a cockpit-door window and dazzle a hijacker with no damage to passengers.

The non-canonical roles of clathrin and actin in pathogen internalization, egress and spread.

PubMed

Humphries, Ashley C; Way, Michael

2013-08-01

The role of clathrin in pathogen entry has received much attention and has highlighted the adaptability of clathrin during internalization. Recent studies have now uncovered additional roles for clathrin and have put the spotlight on its role in pathogen spread. Here, we discuss the manipulation of clathrin by pathogens, with specific attention to the processes that occur at the plasma membrane. In the majority of cases, both clathrin and the actin cytoskeleton are hijacked, so we also examine the interplay between these two systems and their role during pathogen internalization, egress and spread.

America’s War on Terror: Islamic Jihadist Ideologue or Radical Hijacker of Islam - Will the Real Enemy Please Step Forward

DTIC Science & Technology

2009-04-01

linchpins for the acceptance of the premise that American strategy for the War on Terror must not/cannot separate the religion, Islam, from those that...should such be in relation to America’s war on terror; and, how does it aid in the refinement of focus of American counter efforts? In response to the...53 Zartman, ACSC Blue Course Book, p. 102 54 Scheuer, ACSC Blue Course Book, p. 126 55 Ibid, p. 132 56 Clausewitz, On War , pp. 88‐89 57 JP 1 ‐02

Hypermedicalization in White Noise.

PubMed

Benson, Josef

2015-09-01

The Nazis hijacked Germany's medical establishment and appropriated medical language to hegemonize their ideology. In White Noise, shifting medical information stifles the public into docility. In Nazi Germany the primacy of language and medical authority magnified the importance of academic doctors. The muddling of identities caused complex insecurities and the need for psychological doubles. In White Noise, Professor Gladney is driven by professional insecurities to enact a double in Murray. Through the manipulation of language and medical overreach the U.S., exemplified in the novel White Noise, has become a hypermedicalized society where the spirit of the Hippocratic Oath has eroded.

Space and energy. [space systems for energy generation, distribution and control

NASA Technical Reports Server (NTRS)

Bekey, I.

1976-01-01

Potential contributions of space to energy-related activities are discussed. Advanced concepts presented include worldwide energy distribution to substation-sized users using low-altitude space reflectors; powering large numbers of large aircraft worldwide using laser beams reflected from space mirror complexes; providing night illumination via sunlight-reflecting space mirrors; fine-scale power programming and monitoring in transmission networks by monitoring millions of network points from space; prevention of undetected hijacking of nuclear reactor fuels by space tracking of signals from tagging transmitters on all such materials; and disposal of nuclear power plant radioactive wastes in space.

Technology transfer in New York City - The NASA/NYC Applications Project.

NASA Technical Reports Server (NTRS)

Karen, A.; Orrick, D.; Anuskiewicz, T.

1973-01-01

New York City faces many varied and complex problems ranging from truck hijacking to graffiti. In answer to a request from NYC officials NASA is sponsoring the efforts of a project aimed at applying aerospace-derived solutions to a series of city technical problems. An immediate result has been a pilot experiment to improve security in the City's schools. Other problem areas for NASA review have been selected from the Fire, Police and Air Resources Departments. The Project offers a significant example of a viable approach to the crucial process of bridging the communications gap between urban officials and technologists.

Conflict between co-occurring manipulative parasites? An experimental study of the joint influence of two acanthocephalan parasites on the behaviour of Gammarus pulex.

PubMed

Cezilly, F; Gregoire, A; Bertin, A

2000-06-01

When two parasite species are manipulators and have different definitive hosts, there is a potential for conflict between them. Selection may then exist for either avoiding hosts infected with conflicting parasites, or for hijacking, i.e. competitive processes to gain control of the intermediate host. The evidence for both phenomena depends largely on the study of the relative competitive abilities of parasites within their common intermediate host. We studied the effects of simultaneous infection by a fish acanthocephalan parasite, Pomphorhynchus laevis, and a bird acanthocephalan parasite, Polymorphus minutus, on the behaviour of their common intermediate host, the amphipod Gammarus pulex. We compared the reaction to light and vertical distribution of individuals infected with both parasites to those of individuals harbouring a single parasite species and uninfected ones under controlled conditions. Compared to uninfected gammarids that were photophobic and tended to remain at the bottom of the water column, P. laevis-infected gammarids were attracted to light, whereas P. minutus-infected individuals showed a modified vertical distribution and were swimming closer to the water surface. The effects of both P. laevis and P. minutus appeared to be dependent only on their presence, not on their intensity. Depending on the behavioural trait under study, however, the outcome of the antagonism between P. laevis and P. minutus differed. The vertical distribution of gammarids harbouring both parasites was half-way between those of P. laevis- and P. minutus-infected individuals, whereas P. laevis was able to induce altered reaction to light even in the presence of P. minutus. We discuss our results in relation to the occurrence of active avoidance or hijacking between conflicting manipulative parasites and provide some recommendations for future research.

A Critical Role of Glutamine and Asparagine γ-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus

PubMed Central

Zhu, Ying; Li, Tingting; Ramos da Silva, Suzane; Lee, Jae-Jin; Lu, Chun; Eoh, Hyungjin; Jung, Jae U.

2017-01-01

ABSTRACT While glutamine is a nonessential amino acid that can be synthesized from glucose, some cancer cells primarily depend on glutamine for their growth, proliferation, and survival. Numerous types of cancer also depend on asparagine for cell proliferation. The underlying mechanisms of the glutamine and asparagine requirement in cancer cells in different contexts remain unclear. In this study, we show that the oncogenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV) accelerates the glutamine metabolism of glucose-independent proliferation of cancer cells by upregulating the expression of numerous critical enzymes, including glutaminase 2 (GLS2), glutamate dehydrogenase 1 (GLUD1), and glutamic-oxaloacetic transaminase 2 (GOT2), to support cell proliferation. Surprisingly, cell crisis is rescued only completely by supplementation with asparagine but minimally by supplementation with α-ketoglutarate, aspartate, or glutamate upon glutamine deprivation, implying an essential role of γ-nitrogen in glutamine and asparagine for cell proliferation. Specifically, glutamine and asparagine provide the critical γ-nitrogen for purine and pyrimidine biosynthesis, as knockdown of four rate-limiting enzymes in the pathways, including carbamoylphosphate synthetase 2 (CAD), phosphoribosyl pyrophosphate amidotransferase (PPAT), and phosphoribosyl pyrophosphate synthetases 1 and 2 (PRPS1 and PRPS2, respectively), suppresses cell proliferation. These findings indicate that glutamine and asparagine are shunted to the biosynthesis of nucleotides and nonessential amino acids from the tricarboxylic acid (TCA) cycle to support the anabolic proliferation of KSHV-transformed cells. Our results illustrate a novel mechanism by which an oncogenic virus hijacks a metabolic pathway for cell proliferation and imply potential therapeutic applications in specific types of cancer that depend on this pathway. PMID:28811348

Momentum harvesting techniques for solar system travel

NASA Technical Reports Server (NTRS)

Willoughby, Alan J.

1991-01-01

Astronomers are lately estimating there are 400,000 earth visiting asteroids larger than 100 meters in diameter. These asteroids are uniquely accessible sources of building materials, propellants, oxygen, water, and minerals. They also constitute a huge momentum reserve, potentially usable for travel throughout the solar system. To use this momentum, these stealthy objects must be tracked and the ability to extract the desired momentum obtained. Momentum harvesting by momentum transfer from asteroid to spacecraft, and by using the momentum of the extraterrestrial material to help deliver itself to its destination is discussed. The purpose is neither to quantify nor justify the momentum exchange processes, but to stimulate collective imaginations with some intriguing possibilities which emerge when momentum as well as material is considered. A net and tether concept is the suggested means of asteroid capture, the basic momentum exchange process. The energy damping characteristics of the tether determines the velocity mismatch that can be tolerated, and hence the amount of momentum that can be harvested per capture. As the tether plays out of its reel, drag on the tether steadily accelerates the spacecraft and dilutes, in time, the would-be collision. A variety of concepts for riding and using asteroids after capture are introduced. The hitchhiker uses momentum transfer only. The beachcomber, the caveman, the swinger, the prospector, and the rock wrecker also take advantage of raw asteroid materials. The chemist and the hijacker go further, they process the asteroid into propellants. Or, an asteroid railway system could be constructed with each hijacked asteroid becoming a scheduled train. Travelers could board this space railway system assured that water, oxygen propellants, and shielding await them. Austere space travel could give way to comforts, with a speed and economy impossible without nature's gift of earth visiting asteroids.

Monitoring HPV-16 E7 phosphorylation events

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

Nogueira, Marcela O.; Hošek, Tomáš; Calçada, Eduar

HPV-16 E7 is one of the key proteins that, by interfering with the host metabolism through many protein-protein interactions, hijacks cell regulation and contributes to malignancy. Here we report the high resolution investigation of the CR3 region of HPV-16 E7, both as an isolated domain and in the full-length protein. This opens the way to the atomic level study of the many interactions in which HPV-16 E7 is involved. Along these lines we show here the effect of one of the key post-translational modifications of HPV-16 E7, the phosphorylation by casein kinase II.

Label-free integrative pharmacology on-target of drugs at the β2-adrenergic receptor

NASA Astrophysics Data System (ADS)

Ferrie, Ann M.; Sun, Haiyan; Fang, Ye

2011-07-01

We describe a label-free integrative pharmacology on-target (iPOT) method to assess the pharmacology of drugs at the β2-adrenergic receptor. This method combines dynamic mass redistribution (DMR) assays using an array of probe molecule-hijacked cells with similarity analysis. The whole cell DMR assays track cell system-based, ligand-directed, and kinetics-dependent biased activities of the drugs, and translates their on-target pharmacology into numerical descriptors which are subject to similarity analysis. We demonstrate that the approach establishes an effective link between the label-free pharmacology and in vivo therapeutic indications of drugs.

U.S. Navy Crisis Response Activity, 1946-1989: Preliminary Report

DTIC Science & Technology

1989-11-29

177 La Belle Disco , Libya 4/10/86 6 A6 2 N N Y N 178 Pakistan Hijacking Sep-86 1 A6 1 N N N N 179 Persian Gulf Ops Jan-87 579 A7 2 Y Y Y Y 180...operations as no hostages were released. 177 La Belle Disco , Libya 4/10/86 6 A6 2 N N Y N On 5 April, the La Belle Discotheque in the Federal Republic of...naval units were damaged or sunk; and, on 3 July 1988, in the midst of a surface engagement, CG-49 Vincennes shot down an Iran Air Airbus , killing all

Importin-α7 Is Involved in the Formation of Ebola Virus Inclusion Bodies but Is Not Essential for Pathogenicity in Mice

PubMed Central

Gabriel, Gülsah; Feldmann, Friederike; Reimer, Rudolph; Thiele, Swantje; Fischer, Meike; Hartmann, Enno; Bader, Michael; Ebihara, Hideki; Hoenen, Thomas; Feldmann, Heinz

2015-01-01

Ebola virus (EBOV) protein 24 antagonizes the host interferon (IFN) response by hijacking select nuclear importin-α isoforms. Thereby, it blocks STAT1-mediated IFN-α/β and IFN-γ synthesis. However, owing to the lack of importin-α knockout animal models in the past, their role in EBOV pathogenesis remained largely unknown. Here, we demonstrate that importin-α7 is involved in the formation of EBOV inclusion bodies and replication. However, deletion of the gene encoding importin-α7 was not sufficient to increase survival rates among mice infected with EBOV. PMID:26185094

[What makes a parasite "transforming"? Insights into cancer from the agents of an exotic pathology, Theileria spp].

PubMed

Cheeseman, K M; Weitzman, J B

2017-02-01

Theileria are obligate eukaryotic intracellular parasites of cattle. The diseases they cause, Tropical theileriosis and East Coast Fever, cause huge economic loss in East African, Mediterranean and central and South-East Asian countries. These apicomplexan parasites are the only intracellular eukaryotic parasites known to transform their host cell and represent a unique model to study host-parasite interactions and mechanisms of cancer onset.Here, we review how Theileria parasites induce transformation of their leukocyte host cell and discuss similarities with tumorigenesis. We describe how genomic innovation, epigenetic changes and hijacking of signal transductions enable a eukaryotic parasite to transform its host cell.

Environmental Regulation of Yersinia Pathophysiology

PubMed Central

Chen, Shiyun; Thompson, Karl M.; Francis, Matthew S.

2016-01-01

Hallmarks of Yersinia pathogenesis include the ability to form biofilms on surfaces, the ability to establish close contact with eukaryotic target cells and the ability to hijack eukaryotic cell signaling and take over control of strategic cellular processes. Many of these virulence traits are already well-described. However, of equal importance is knowledge of both confined and global regulatory networks that collaborate together to dictate spatial and temporal control of virulence gene expression. This review has the purpose to incorporate historical observations with new discoveries to provide molecular insight into how some of these regulatory mechanisms respond rapidly to environmental flux to govern tight control of virulence gene expression by pathogenic Yersinia. PMID:26973818

Deaths in World Trade Center terrorist attacks--New York City, 2001.

PubMed

2002-09-11

On September 11, 2001, terrorists flew two hijacked airplanes into the World Trade Center (WTC) in lower Manhattan in New York City (NYC), destroying both towers of the WTC. This report presents preliminary vital statistics on the deaths caused by the terrorist attacks and describes the procedures developed by the New York City Department of Health and Mental Hygiene (NYCDOHMH) to issue death certificates in response to the attacks. These data underscore the need for legal mechanisms to expedite the issuance of death certificates in the absence of human remains and the need for vital registration systems that can be relocated in case of emergency.

Actin- and myosin-driven movement of viruses along filopodia precedes their entry into cells.

PubMed

Lehmann, Maik J; Sherer, Nathan M; Marks, Carolyn B; Pypaert, Marc; Mothes, Walther

2005-07-18

Viruses have often been observed in association with the dense microvilli of polarized epithelia as well as the filopodia of nonpolarized cells, yet whether interactions with these structures contribute to infection has remained unknown. Here we show that virus binding to filopodia induces a rapid and highly ordered lateral movement, "surfing" toward the cell body before cell entry. Virus cell surfing along filopodia is mediated by the underlying actin cytoskeleton and depends on functional myosin II. Any disruption of virus cell surfing significantly reduces viral infection. Our results reveal another example of viruses hijacking host machineries for efficient infection by using the inherent ability of filopodia to transport ligands to the cell body.

Can hi-jacking hypoxia inhibit extracellular vesicles in cancer?

PubMed

Lowry, Michelle C; O'Driscoll, Lorraine

2018-06-01

Increasing evidence indicates that extracellular vesicles (EVs) are key players in undesirable cell-cell communication in cancer. However, the release of EVs is not unique to cancer cells; normal cells release EVs to perform physiological roles. Thus, selective inhibition of EV release from cancer cells is desirable. Hypoxia contributes to tumour development and aggressiveness. EV quantities and thus undesirable communications are substantially increased in hypoxia. Targeting hypoxia could selectively inhibit EV release from tumour cells without disturbing physiologically relevant EVs. The unfavourable association between hypoxia and EV release is evident in multiple tumour types; therefore, targeting hypoxia could have a broad therapeutic benefit. Copyright © 2018 Elsevier Ltd. All rights reserved.

Dysfunctions at human intestinal barrier by water-borne protozoan parasites: lessons from cultured human fully differentiated colon cancer cell lines.

PubMed

Liévin-Le Moal, Vanessa

2013-06-01

Some water-borne protozoan parasites induce diseases through their membrane-associated functional structures and virulence factors that hijack the host cellular molecules and signalling pathways leading to structural and functional lesions in the intestinal barrier. In this Microreview we analyse the insights on the mechanisms of pathogenesis of Entamoeba intestinalis, Giardia and Cryptosporidium observed in the human colon carcinoma fully differentiated colon cancer cell lines, cell subpopulations and clones expressing the structural and functional characteristics of highly specialized fully differentiated epithelial cells lining the intestinal epithelium and mimicking structurally and functionally an intestinal barrier. © 2013 John Wiley & Sons Ltd.

September 11, 2001: then and now.

PubMed

Jameson, John R

2002-01-01

This article, written by a historian, uses the sequential questioning technique to present a selected historical and statistical overview of the tragic events of September 11, 2001, including: the hijackings; the suicide attacks in New York, Washington, D C, and Pennsylvania; background on Osama bin Laden and al-Qaeda; rescue and recovery efforts; and a brief discussion of how the horrors of the day continue to affect the American people a year later. Especially sobering are the dollar costs of the attacks and the projected expenses of U.S. efforts to control the spread of international terrorism (estimated at $640 billion, just through fiscal year 2003). Throughout, the article draws on the experiences of the victims, the rescuers, and the survivors.

Enterococcus faecalis Prophage Dynamics and Contributions to Pathogenic Traits

PubMed Central

Matos, Renata C.; Lapaque, Nicolas; Rigottier-Gois, Lionel; Debarbieux, Laurent; Meylheuc, Thierry; Gonzalez-Zorn, Bruno; Repoila, Francis; Lopes, Maria de Fatima; Serror, Pascale

2013-01-01

Polylysogeny is frequently considered to be the result of an adaptive evolutionary process in which prophages confer fitness and/or virulence factors, thus making them important for evolution of both bacterial populations and infectious diseases. The Enterococcus faecalis V583 isolate belongs to the high-risk clonal complex 2 that is particularly well adapted to the hospital environment. Its genome carries 7 prophage-like elements (V583-pp1 to -pp7), one of which is ubiquitous in the species. In this study, we investigated the activity of the V583 prophages and their contribution to E. faecalis biological traits. We systematically analyzed the ability of each prophage to excise from the bacterial chromosome, to replicate and to package its DNA. We also created a set of E. faecalis isogenic strains that lack from one to all six non-ubiquitous prophages by mimicking natural excision. Our work reveals that prophages of E. faecalis V583 excise from the bacterial chromosome in the presence of a fluoroquinolone, and are able to produce active phage progeny. Intricate interactions between V583 prophages were also unveiled: i) pp7, coined EfCIV583 for E. faecalis chromosomal island of V583, hijacks capsids from helper phage 1, leading to the formation of distinct virions, and ii) pp1, pp3 and pp5 inhibit excision of pp4 and pp6. The hijacking exerted by EfCIV583 on helper phage 1 capsids is the first example of molecular piracy in Gram positive bacteria other than staphylococci. Furthermore, prophages encoding platelet-binding-like proteins were found to be involved in adhesion to human platelets, considered as a first step towards the development of infective endocarditis. Our findings reveal not only a role of E. faecalis V583 prophages in pathogenicity, but also provide an explanation for the correlation between antibiotic usage and E. faecalis success as a nosocomial pathogen, as fluoriquinolone may provoke release of prophages and promote gene dissemination among isolates. PMID:23754962

A host YB-1 ribonucleoprotein complex is hijacked by hepatitis C virus for the control of NS3-dependent particle production.

PubMed

Chatel-Chaix, Laurent; Germain, Marie-Anne; Motorina, Alena; Bonneil, Éric; Thibault, Pierre; Baril, Martin; Lamarre, Daniel

2013-11-01

Hepatitis C virus (HCV) orchestrates the different stages of its life cycle in time and space through the sequential participation of HCV proteins and cellular machineries; hence, these represent tractable molecular host targets for HCV elimination by combination therapies. We recently identified multifunctional Y-box-binding protein 1 (YB-1 or YBX1) as an interacting partner of NS3/4A protein and HCV genomic RNA that negatively regulates the equilibrium between viral translation/replication and particle production. To identify novel host factors that regulate the production of infectious particles, we elucidated the YB-1 interactome in human hepatoma cells by a quantitative mass spectrometry approach. We identified 71 YB-1-associated proteins that included previously reported HCV regulators DDX3, heterogeneous nuclear RNP A1, and ILF2. Of the potential YB-1 interactors, 26 proteins significantly modulated HCV replication in a gene-silencing screening. Following extensive interaction and functional validation, we identified three YB-1 partners, C1QBP, LARP-1, and IGF2BP2, that redistribute to the surface of core-containing lipid droplets in HCV JFH-1-expressing cells, similarly to YB-1 and DDX6. Importantly, knockdown of these proteins stimulated the release and/or egress of HCV particles without affecting virus assembly, suggesting a functional YB-1 protein complex that negatively regulates virus production. Furthermore, a JFH-1 strain with the NS3 Q221L mutation, which promotes virus production, was less sensitive to this negative regulation, suggesting that this HCV-specific YB-1 protein complex modulates an NS3-dependent step in virus production. Overall, our data support a model in which HCV hijacks host cell machinery containing numerous RNA-binding proteins to control the equilibrium between viral RNA replication and NS3-dependent late steps in particle production.

A Host YB-1 Ribonucleoprotein Complex Is Hijacked by Hepatitis C Virus for the Control of NS3-Dependent Particle Production

PubMed Central

Chatel-Chaix, Laurent; Germain, Marie-Anne; Motorina, Alena; Bonneil, Éric; Thibault, Pierre; Baril, Martin

2013-01-01

Hepatitis C virus (HCV) orchestrates the different stages of its life cycle in time and space through the sequential participation of HCV proteins and cellular machineries; hence, these represent tractable molecular host targets for HCV elimination by combination therapies. We recently identified multifunctional Y-box-binding protein 1 (YB-1 or YBX1) as an interacting partner of NS3/4A protein and HCV genomic RNA that negatively regulates the equilibrium between viral translation/replication and particle production. To identify novel host factors that regulate the production of infectious particles, we elucidated the YB-1 interactome in human hepatoma cells by a quantitative mass spectrometry approach. We identified 71 YB-1-associated proteins that included previously reported HCV regulators DDX3, heterogeneous nuclear RNP A1, and ILF2. Of the potential YB-1 interactors, 26 proteins significantly modulated HCV replication in a gene-silencing screening. Following extensive interaction and functional validation, we identified three YB-1 partners, C1QBP, LARP-1, and IGF2BP2, that redistribute to the surface of core-containing lipid droplets in HCV JFH-1-expressing cells, similarly to YB-1 and DDX6. Importantly, knockdown of these proteins stimulated the release and/or egress of HCV particles without affecting virus assembly, suggesting a functional YB-1 protein complex that negatively regulates virus production. Furthermore, a JFH-1 strain with the NS3 Q221L mutation, which promotes virus production, was less sensitive to this negative regulation, suggesting that this HCV-specific YB-1 protein complex modulates an NS3-dependent step in virus production. Overall, our data support a model in which HCV hijacks host cell machinery containing numerous RNA-binding proteins to control the equilibrium between viral RNA replication and NS3-dependent late steps in particle production. PMID:23986595

Imbalanced decision hierarchy in addicts emerging from drug-hijacked dopamine spiraling circuit.

PubMed

Keramati, Mehdi; Gutkin, Boris

2013-01-01

Despite explicitly wanting to quit, long-term addicts find themselves powerless to resist drugs, despite knowing that drug-taking may be a harmful course of action. Such inconsistency between the explicit knowledge of negative consequences and the compulsive behavioral patterns represents a cognitive/behavioral conflict that is a central characteristic of addiction. Neurobiologically, differential cue-induced activity in distinct striatal subregions, as well as the dopamine connectivity spiraling from ventral striatal regions to the dorsal regions, play critical roles in compulsive drug seeking. However, the functional mechanism that integrates these neuropharmacological observations with the above-mentioned cognitive/behavioral conflict is unknown. Here we provide a formal computational explanation for the drug-induced cognitive inconsistency that is apparent in the addicts' "self-described mistake". We show that addictive drugs gradually produce a motivational bias toward drug-seeking at low-level habitual decision processes, despite the low abstract cognitive valuation of this behavior. This pathology emerges within the hierarchical reinforcement learning framework when chronic exposure to the drug pharmacologically produces pathologicaly persistent phasic dopamine signals. Thereby the drug hijacks the dopaminergic spirals that cascade the reinforcement signals down the ventro-dorsal cortico-striatal hierarchy. Neurobiologically, our theory accounts for rapid development of drug cue-elicited dopamine efflux in the ventral striatum and a delayed response in the dorsal striatum. Our theory also shows how this response pattern depends critically on the dopamine spiraling circuitry. Behaviorally, our framework explains gradual insensitivity of drug-seeking to drug-associated punishments, the blocking phenomenon for drug outcomes, and the persistent preference for drugs over natural rewards by addicts. The model suggests testable predictions and beyond that, sets the stage for a view of addiction as a pathology of hierarchical decision-making processes. This view is complementary to the traditional interpretation of addiction as interaction between habitual and goal-directed decision systems.

Rotavirus NSP1 Requires Casein Kinase II-Mediated Phosphorylation for Hijacking of Cullin-RING Ligases.

PubMed

Davis, Kaitlin A; Morelli, Marco; Patton, John T

2017-08-29

The rotavirus nonstructural protein NSP1 repurposes cullin-RING E3 ubiquitin ligases (CRLs) to antagonize innate immune responses. By functioning as substrate adaptors of hijacked CRLs, NSP1 causes ubiquitination and proteasomal degradation of host proteins that are essential for expression of interferon (IFN) and IFN-stimulated gene products. The target of most human and porcine rotaviruses is the β-transducin repeat-containing protein (β-TrCP), a regulator of NF-κB activation. β-TrCP recognizes a phosphorylated degron (DSGΦXS) present in the inhibitor of NF-κB (IκB); phosphorylation of the IκB degron is mediated by IκB kinase (IKK). Because NSP1 contains a C-terminal IκB-like degron (ILD; DSGXS) that recruits β-TrCP, we investigated whether the NSP1 ILD is similarly activated by phosphorylation and whether this modification is required to trigger the incorporation of NSP1 into CRLs. Based on mutagenesis and phosphatase treatment studies, we found that both serine residues of the NSP1 ILD are phosphorylated, a pattern mimicking phosphorylation of IκB. A three-pronged approach using small-molecule inhibitors, small interfering RNAs, and mutagenesis demonstrated that NSP1 phosphorylation is mediated by the constitutively active casein kinase II (CKII), rather than IKK. In coimmunoprecipitation assays, we found that this modification was essential for NSP1 recruitment of β-TrCP and induced changes involving the NSP1 N-terminal RING motif that allowed formation of Cul3-NSP1 complexes. Taken together, our results indicate a highly regulated stepwise process in the formation of NSP1-Cul3 CRLs that is initiated by CKII phosphorylation of NSP1, followed by NSP1 recruitment of β-TrCP and ending with incorporation of the NSP1-β-TrCP complex into the CRL via interactions dependent on the highly conserved NSP1 RING motif. IMPORTANCE Rotavirus is a segmented double-stranded RNA virus that causes severe diarrhea in young children. A primary mechanism used by the virus to inhibit host innate immune responses is to hijack cellular cullin-RING E3 ubiquitin ligases (CRLs) and redirect their targeting activity to the degradation of cellular proteins crucial for interferon expression. This task is accomplished through the rotavirus nonstructural protein NSP1, which incorporates itself into a CRL and serves as a substrate recognition subunit. The substrate recognized by the NSP1 of many human and porcine rotaviruses is β-TrCP, a protein that regulates the transcription factor NF-κB. In this study, we show that formation of NSP1 CRLs is a highly regulated stepwise process initiated by CKII phosphorylation of the β-TrCP recognition motif in NSP1. This modification triggers recruitment of the β-TrCP substrate and induces subsequent changes in a highly conserved NSP1 RING domain that allow anchoring of the NSP1-β-TrCP complex to a cullin scaffold. Copyright © 2017 Davis et al.

Actin- and myosin-driven movement of viruses along filopodia precedes their entry into cells

PubMed Central

Lehmann, Maik J.; Sherer, Nathan M.; Marks, Carolyn B.; Pypaert, Marc; Mothes, Walther

2005-01-01

Viruses have often been observed in association with the dense microvilli of polarized epithelia as well as the filopodia of nonpolarized cells, yet whether interactions with these structures contribute to infection has remained unknown. Here we show that virus binding to filopodia induces a rapid and highly ordered lateral movement, “surfing” toward the cell body before cell entry. Virus cell surfing along filopodia is mediated by the underlying actin cytoskeleton and depends on functional myosin II. Any disruption of virus cell surfing significantly reduces viral infection. Our results reveal another example of viruses hijacking host machineries for efficient infection by using the inherent ability of filopodia to transport ligands to the cell body. PMID:16027225

Ocean sciences after September 11

NASA Astrophysics Data System (ADS)

McPhaden, Michael J.

The terrorist attacks in New York City and Washington D.C. on September 11, 2001 shocked the world with their audacity and destruction. Shortly thereafter, bioterrorists struck through the U.S. postal system. Virtually overnight, major policy shifts took place in the United States that catapulted national security and homeland defense to the top of the political agenda. The consequences were unimaginable just a few months before: an international coalition at war against the Taliban in Afghanistan, major increases in U.S. defense spending, tightened security measures at airports, government facilities, and research laboratories, and a new sense of vulnerability in the post-cold war era. AGU itself was directly affected: three of its members perished in the hijacked planes, or on the ground in New York City.

Emerging therapeutic delivery capabilities and challenges utilizing enzyme/protein packaged bacterial vesicles.

PubMed

Alves, Nathan J; Turner, Kendrick B; Medintz, Igor L; Walper, Scott A

2015-07-01

Nanoparticle-based therapeutics are poised to play a critical role in treating disease. These complex multifunctional drug delivery vehicles provide for the passive and active targeted delivery of numerous small molecule, peptide and protein-derived pharmaceuticals. This article will first discuss some of the current state of the art nanoparticle classes (dendrimers, lipid-based, polymeric and inorganic), highlighting benefits/drawbacks associated with their implementation. We will then discuss an emerging class of nanoparticle therapeutics, bacterial outer membrane vesicles, that can provide many of the nanoparticle benefits while simplifying assembly. Through molecular biology techniques; outer membrane vesicle hijacking potentially allows for stringent control over nanoparticle production allowing for targeted protein packaged nanoparticles to be fully synthesized by bacteria.

Viral Infection at High Magnification: 3D Electron Microscopy Methods to Analyze the Architecture of Infected Cells

PubMed Central

Romero-Brey, Inés; Bartenschlager, Ralf

2015-01-01

As obligate intracellular parasites, viruses need to hijack their cellular hosts and reprogram their machineries in order to replicate their genomes and produce new virions. For the direct visualization of the different steps of a viral life cycle (attachment, entry, replication, assembly and egress) electron microscopy (EM) methods are extremely helpful. While conventional EM has given important information about virus-host cell interactions, the development of three-dimensional EM (3D-EM) approaches provides unprecedented insights into how viruses remodel the intracellular architecture of the host cell. During the last years several 3D-EM methods have been developed. Here we will provide a description of the main approaches and examples of innovative applications. PMID:26633469

The Use of Naval Forces in the Post-War Era: U.S. Navy and U.S. Marine Corps Crisis Response Activity, 1946-1990

DTIC Science & Technology

1991-02-01

their Caribbean coasts to guard against possible infiltration. The patrol force included one CVA ( Shangri - La ), one CVS (Wasp), and eight surface ships. 61...38 Shangri - La CVA-39 Lake Champlain CVA-40 Tarawa CV-41 Midway CVB-42 FD Roosevelt CV-43 Coral Sea CV-59 Forrestal CV-60 Saratoga CV-61 Ranger CV-62...N N 189 La Belle Disco, Libya 4/10/86 6 A6 Y 2 Y Y Y Y N 190 Pakistan Hijacking Sep-86 1 A6 Y 1 N N N N 191 Persian Gulf Ops Jan-87 579 A7 Y 2 Y Y N Y

ILLICIT DOPAMINE TRANSIENTS: RECONCILING ACTIONS OF ABUSED DRUGS

PubMed Central

Covey, Dan P.; Roitman, Mitchell F.; Garris, Paul A.

2014-01-01

Phasic increases in brain dopamine are required for cue-directed reward seeking. While compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyper-activating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyper-activation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural reward and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome. PMID:24656971

Apparatus for stopping a vehicle

DOEpatents

Wattenburg, Willard H [Walnut Creek, CA; McCallen, David B [Livermore, CA

2007-03-20

An apparatus for externally controlling one or more brakes on a vehicle having a pressurized fluid braking system. The apparatus can include a pressurizable vessel that is adapted for fluid-tight coupling to the braking system. Impact to the rear of the vehicle by a pursuit vehicle, shooting a target mounted on the vehicle or sending a signal from a remote control can all result in the fluid pressures in the braking system of the vehicle being modified so that the vehicle is stopped and rendered temporarily inoperable. A control device can also be provided in the driver's compartment of the vehicle for similarly rendering the vehicle inoperable. A driver or hijacker of the vehicle preferably cannot overcome the stopping action from the driver's compartment.

Security Enhancement Using Cache Based Reauthentication in WiMAX Based E-Learning System

PubMed Central

Rajagopal, Chithra; Bhuvaneshwaran, Kalaavathi

2015-01-01

WiMAX networks are the most suitable for E-Learning through their Broadcast and Multicast Services at rural areas. Authentication of users is carried out by AAA server in WiMAX. In E-Learning systems the users must be forced to perform reauthentication to overcome the session hijacking problem. The reauthentication of users introduces frequent delay in the data access which is crucial in delaying sensitive applications such as E-Learning. In order to perform fast reauthentication caching mechanism known as Key Caching Based Authentication scheme is introduced in this paper. Even though the cache mechanism requires extra storage to keep the user credentials, this type of mechanism reduces the 50% of the delay occurring during reauthentication. PMID:26351658

Security Enhancement Using Cache Based Reauthentication in WiMAX Based E-Learning System.

PubMed

Rajagopal, Chithra; Bhuvaneshwaran, Kalaavathi

2015-01-01

WiMAX networks are the most suitable for E-Learning through their Broadcast and Multicast Services at rural areas. Authentication of users is carried out by AAA server in WiMAX. In E-Learning systems the users must be forced to perform reauthentication to overcome the session hijacking problem. The reauthentication of users introduces frequent delay in the data access which is crucial in delaying sensitive applications such as E-Learning. In order to perform fast reauthentication caching mechanism known as Key Caching Based Authentication scheme is introduced in this paper. Even though the cache mechanism requires extra storage to keep the user credentials, this type of mechanism reduces the 50% of the delay occurring during reauthentication.

A review of X-ray explosives detection techniques for checked baggage.

PubMed

Wells, K; Bradley, D A

2012-08-01

In recent times, the security focus for civil aviation has shifted from hijacking in the 1980s, towards deliberate sabotage. X-ray imaging provides a major tool in checked baggage inspection, with various sensitive techniques being brought to bear in determining the form, and density of items within luggage as well as other material dependent parameters. This review first examines the various challenges to X-ray technology in securing a safe system of passenger transportation. An overview is then presented of the various conventional and less conventional approaches that are available to the airline industry, leading to developments in state-of-the-art imaging technology supported by enhanced machine and observer-based decision making principles. Copyright © 2012 Elsevier Ltd. All rights reserved.

A feminist response to Weitzer.

PubMed

Dines, Gail

2012-04-01

In his review of my book Pornland: How Porn has Hijacked our Sexuality, Ronald Weitzer claims that anti-porn feminists are incapable of objective, rigorous research because they operate within the "oppression paradigm," which he defines as "a perspective that depicts all types of sex work as exploitive, violent, and perpetuating gender inequality." (VAW, 2011, 666). This article argues that while anti-porn feminists do indeed see pornography as exploitive, such a position is rooted in the rigorous theories and methods of cultural studies developed by critical media scholars such as Stuart Hall and Antonio Gramsci. Pornland applies a cultural studies approach by exploring how porn images are part of a wider system of sexist representations that legitimize and normalize the economic, political and legal oppression of women.

A CRISPR toolbox to study virus–host interactions

PubMed Central

Puschnik, Andreas S.; Majzoub, Karim; Ooi, Yaw Shin; Carette, Jan E.

2018-01-01

Viruses depend on their hosts to complete their replication cycles; they exploit cellular receptors for entry and hijack cellular functions to replicate their genome, assemble progeny virions and spread. Recently, genome-scale CRISPR–Cas screens have been used to identify host factors that are required for virus replication, including the replication of clinically relevant viruses such as Zika virus, West Nile virus, dengue virus and hepatitis C virus. In this Review, we discuss the technical aspects of genome-scale knockout screens using CRISPR–Cas technology, and we compare these screens with alternative genetic screening technologies. The relative ease of use and reproducibility of CRISPR–Cas make it a powerful tool for probing virus–host interactions and for identifying new antiviral targets. PMID:28420884

Viral Infection at High Magnification: 3D Electron Microscopy Methods to Analyze the Architecture of Infected Cells.

PubMed

Romero-Brey, Inés; Bartenschlager, Ralf

2015-12-03

As obligate intracellular parasites, viruses need to hijack their cellular hosts and reprogram their machineries in order to replicate their genomes and produce new virions. For the direct visualization of the different steps of a viral life cycle (attachment, entry, replication, assembly and egress) electron microscopy (EM) methods are extremely helpful. While conventional EM has given important information about virus-host cell interactions, the development of three-dimensional EM (3D-EM) approaches provides unprecedented insights into how viruses remodel the intracellular architecture of the host cell. During the last years several 3D-EM methods have been developed. Here we will provide a description of the main approaches and examples of innovative applications.

Signals and cues in the evolution of plant-microbe communication.

PubMed

Padje, Anouk Van't; Whiteside, Matthew D; Kiers, E Toby

2016-08-01

Communication has played a key role in organismal evolution. If sender and receiver have a shared interest in propagating reliable information, such as when they are kin relatives, then effective communication can bring large fitness benefits. However, interspecific communication (among different species) is more prone to dishonesty. Over the last decade, plants and their microbial root symbionts have become a model system for studying interspecific molecular crosstalk. However, less is known about the evolutionary stability of plant-microbe communication. What prevents partners from hijacking or manipulating information to their own benefit? Here, we focus on communication between arbuscular mycorrhizal fungi and their host plants. We ask how partners use directed signals to convey specific information, and highlight research on the problem of dishonest signaling. Copyright © 2016 Elsevier Ltd. All rights reserved.

Illicit dopamine transients: reconciling actions of abused drugs.

PubMed

Covey, Dan P; Roitman, Mitchell F; Garris, Paul A

2014-04-01

Phasic increases in brain dopamine are required for cue-directed reward seeking. Although compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyperactivating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyperactivation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural rewards and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome. Copyright © 2014 Elsevier Ltd. All rights reserved.

Leishmania hijacking of the macrophage intracellular compartments.

PubMed

Liévin-Le Moal, Vanessa; Loiseau, Philippe M

2016-02-01

Leishmania spp., transmitted to humans by the bite of the sandfly vector, are responsible for the three major forms of leishmaniasis, cutaneous, diffuse mucocutaneous and visceral. Leishmania spp. interact with membrane receptors of neutrophils and macrophages. In macrophages, the parasite is internalized within a parasitophorous vacuole and engages in a particular intracellular lifestyle in which the flagellated, motile Leishmania promastigote metacyclic form differentiates into non-motile, metacyclic amastigote form. This phenomenon is induced by Leishmania-triggered events leading to the fusion of the parasitophorous vacuole with vesicular members of the host cell endocytic pathway including recycling endosomes, late endosomes and the endoplasmic reticulum. Maturation of the parasitophorous vacuole leads to the intracellular proliferation of the Leishmania amastigote forms by acquisition of host cell nutrients while escaping host defense responses. © 2015 FEBS.

Bench to Bedside: From the Science to the Practice of Addiction Medicine.

PubMed

Levounis, Petros

2016-03-01

The current understanding of addiction is based on a biopsychosocial model of illness. From a neurobiological perspective, addiction can be seen as the hijacking of the pleasure-reward pathways of the brain with a concomitant weakening of its executive function. The fundamental model has been expanded to include newer concepts such as multiple levels of severity of illness, motivational circuitry, and anti-reward pathways. These neurobiological concepts can explain some of the successes and failures of addiction treatment in the second half of the 20th century and the beginning of the 21st century. Psychosocial interventions (primarily cognitive behavior therapy, mutual help groups, and motivational interviewing) and pharmacological treatments (such as agonists, antagonists, and partial agonists) form the basis of addiction treatment today.

The Salmonella type III secretion system virulence effector forms a new hexameric chaperone assembly for export of effector/chaperone complexes

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

Tsai, Chi -Lin; Burkinshaw, Brianne J.; Strynadka, Natalie C. J.

Bacteria hijack eukaryotic cells by injecting virulence effectors into host cytosol with a type III secretion system (T3SS). Effectors are targeted with their cognate chaperones to hexameric T3SS ATPase at the bacterial membrane's cytosolic face. In this issue of the Journal of Bacteriology, Roblin et al. (P. Roblin, F. Dewitte, V. Villeret, E. G. Biondi, and C. Bompard, J Bacteriol 197:688–698, 2015, http://dx.doi.org/10.1128/JB.02294-14) show that the T3SS chaperone SigE of Salmonella can form hexameric rings rather than dimers when bound to its cognate effector, SopB, implying a novel multimeric association for chaperone/effector complexes with their ATPase.

Nipah virus matrix protein: expert hacker of cellular machines.

PubMed

Watkinson, Ruth E; Lee, Benhur

2016-08-01

Nipah virus (NiV, Henipavirus) is a highly lethal emergent zoonotic paramyxovirus responsible for repeated human outbreaks of encephalitis in South East Asia. There are no approved vaccines or treatments, thus improved understanding of NiV biology is imperative. NiV matrix protein recruits a plethora of cellular machinery to scaffold and coordinate virion budding. Intriguingly, matrix also hijacks cellular trafficking and ubiquitination pathways to facilitate transient nuclear localization. While the biological significance of matrix nuclear localization for an otherwise cytoplasmic virus remains enigmatic, the molecular details have begun to be characterized, and are conserved among matrix proteins from divergent paramyxoviruses. Matrix protein appropriation of cellular machinery will be discussed in terms of its early nuclear targeting and later role in virion assembly. © 2016 Federation of European Biochemical Societies.

Viral Pseudo Enzymes Activate RIG-I via Deamidation to Evade Cytokine Production

PubMed Central

He, Shanping; Zhao, Jun; Song, Shanshan; He, Xiaojing; Minassian, Arlet; Zhou, Yu; Zhang, Junjie; Brulois, Kevin; Wang, Yuqi; Cabo, Jackson; Zandi, Ebrahim; Liang, Chengyu; Jung, Jae U; Zhang, Xuewu; Feng, Pinghui

2015-01-01

SUMMARY RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologues of phosphoribosylformyglycinamide synthase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homologue thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme. PMID:25752576

A Focus on Reward Prediction and the Lateral Habenula: Functional Alterations and the Behavioral Outcomes Induced by Drugs of Abuse.

PubMed

Graziane, Nicholas M; Neumann, Peter A; Dong, Yan

2018-01-01

The lateral habenula (LHb) regulates reward learning and controls the updating of reward-related information. Drugs of abuse have the capacity to hijack the cellular and neurocircuit mechanisms mediating reward learning, forming non-adaptable, compulsive behaviors geared toward obtaining illicit substances. Here, we discuss current findings demonstrating how drugs of abuse alter intrinsic and synaptic LHb neuronal function. Additionally, we discuss evidence for how drug-induced LHb alterations may affect the ability to predict reward, potentially facilitating an addiction-like state. Altogether, we combine ex vivo and in vivo results for an overview of how drugs of abuse alter LHb function and how these functional alterations affect the ability to learn and update behavioral responses to hedonic external stimuli.

The Salmonella type III secretion system virulence effector forms a new hexameric chaperone assembly for export of effector/chaperone complexes

DOE PAGES

Tsai, Chi -Lin; Burkinshaw, Brianne J.; Strynadka, Natalie C. J.; ...

2014-12-08

Bacteria hijack eukaryotic cells by injecting virulence effectors into host cytosol with a type III secretion system (T3SS). Effectors are targeted with their cognate chaperones to hexameric T3SS ATPase at the bacterial membrane's cytosolic face. In this issue of the Journal of Bacteriology, Roblin et al. (P. Roblin, F. Dewitte, V. Villeret, E. G. Biondi, and C. Bompard, J Bacteriol 197:688–698, 2015, http://dx.doi.org/10.1128/JB.02294-14) show that the T3SS chaperone SigE of Salmonella can form hexameric rings rather than dimers when bound to its cognate effector, SopB, implying a novel multimeric association for chaperone/effector complexes with their ATPase.

How pathogens use linear motifs to perturb host cell networks.

PubMed

Via, Allegra; Uyar, Bora; Brun, Christine; Zanzoni, Andreas

2015-01-01

Molecular mimicry is one of the powerful stratagems that pathogens employ to colonise their hosts and take advantage of host cell functions to guarantee their replication and dissemination. In particular, several viruses have evolved the ability to interact with host cell components through protein short linear motifs (SLiMs) that mimic host SLiMs, thus facilitating their internalisation and the manipulation of a wide range of cellular networks. Here we present convincing evidence from the literature that motif mimicry also represents an effective, widespread hijacking strategy in prokaryotic and eukaryotic parasites. Further insights into host motif mimicry would be of great help in the elucidation of the molecular mechanisms behind host cell invasion and the development of anti-infective therapeutic strategies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Importin-α7 Is Involved in the Formation of Ebola Virus Inclusion Bodies but Is Not Essential for Pathogenicity in Mice.

PubMed

Gabriel, Gülsah; Feldmann, Friederike; Reimer, Rudolph; Thiele, Swantje; Fischer, Meike; Hartmann, Enno; Bader, Michael; Ebihara, Hideki; Hoenen, Thomas; Feldmann, Heinz

2015-10-01

Ebola virus (EBOV) protein 24 antagonizes the host interferon (IFN) response by hijacking select nuclear importin-α isoforms. Thereby, it blocks STAT1-mediated IFN-α/β and IFN-γ synthesis. However, owing to the lack of importin-α knockout animal models in the past, their role in EBOV pathogenesis remained largely unknown. Here, we demonstrate that importin-α7 is involved in the formation of EBOV inclusion bodies and replication. However, deletion of the gene encoding importin-α7 was not sufficient to increase survival rates among mice infected with EBOV. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Exploiting an ancient signalling machinery to enjoy a nitrogen fixing symbiosis.

PubMed

Geurts, Rene; Lillo, Alessandra; Bisseling, Ton

2012-08-01

For almost a century now it has been speculated that a transfer of the largely legume-specific symbiosis with nitrogen fixing rhizobium would be profitable in agriculture [1,2]. Up to now such a step has not been achieved, despite intensive research in this era. Novel insights in the underlying signalling networks leading to intracellular accommodation of rhizobium as well as mycorrhizal fungi of the Glomeromycota order show extensive commonalities between both interactions. As mycorrhizae symbiosis can be established basically with most higher plant species it raises questions why is it only in a few taxonomic lineages that the underlying signalling network could be hijacked by rhizobium. Unravelling this will lead to insights that are essential to achieve an old dream. Copyright © 2012. Published by Elsevier Ltd.

Listeria membrane protrusion collapse: Requirement of Cyclophilin A for Listeria cell-to-cell spreading.

PubMed

Dhanda, Aaron S; Lulic, Katarina T; Vogl, A Wayne; Mc Gee, Margaret M; Chiu, Robert H; Guttman, Julian A

2018-05-04

Listeria generate actin-rich tubular protrusions at the plasma membrane that propel the bacteria into neighbouring cells. The precise molecular mechanisms governing the formation of these protrusions remain poorly defined. Here we demonstrate that the PPIase Cyclophilin A (CypA) is hijacked by Listeria at membrane protrusions used for cell-to-cell spreading. CypA localizes within the F-actin of these structures and is crucial for their proper formation, as in cells depleted of CypA, these extended actin-rich structures are mis-shaped and collapsed due to changes within the F-actin network. The lack of structural integrity within the Listeria membrane protrusions hampers the microbes from spreading from CypA null cells. Our results demonstrate a crucial role for CypA during Listeria infections.

Tribute to H. John Caulfield: hijacking of the 'holographic principle' by cosmologists

NASA Astrophysics Data System (ADS)

Roychoudhuri, Chandrasekhar

2013-09-01

I came to know Caulfield as a graduate student while developing suitable techniques to quantitatively evaluate coherence properties of pulsed Ruby and YAG lasers beams during the first decade of their evolutions. We continued our professional acquaintance till 2011 through various yearly conferences. It was at the 2011, 4th biennial conference on, "The nature of light: What are photons?" [1], Caulfield gave a paper on this topic and privately expressed his deep concern that the optical "Holographic Principle" has been hijacked by the cosmologists based upon insufficient understanding of the physical processes behind generation and reconstruction of optical holograms. Unlike our material universe, holographic images do not exist as touchable objects; but the material universe does. Now, in his absence, I have taken the liberty of presenting his views about the holographic principle and extend that to further challenge the prevailing hypothesis that cosmological red shift is purely optical Doppler shift that has led to the postulate that the current universe is expanding rapidly. Rigorously speaking, the core problem is generated when we assign reality to human interpreted information out of experimentally derived data, which can never capture complete behavioral properties of any cosmological object that we try to characterize. In holography, an object is a touch-able reality. Scattered light from an object brings incomplete, but sufficient information about the object to construct a decent hologram. It records phase and amplitude information indirectly as intensity fringes. Further, the reconstructed IMAGE does not represent the original touch-able reality. Besides, the image is further degraded from the insufficient information originally recorded on the hologram. Physical theories should be based upon our need to map physical processes behind the phenomenon under study. Information is a subjective human interpretation of measurable parameters registered by instruments, whose registration fidelities are always less than 100%. We illustrate this point by further criticizing the postulate of "Expanding Universe" by analyzing optical Doppler shift as a function of the two velocities, those of source-atoms and those of detector-atoms, in the coronas of stars in different galaxies with respect to the stationary space, instead of just the relative velocities between all possible pairs of galaxies.

Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1.

PubMed

Ocaña, Oscar H; Córcoles, Rebeca; Fabra, Angels; Moreno-Bueno, Gema; Acloque, Hervé; Vega, Sonia; Barrallo-Gimeno, Alejandro; Cano, Amparo; Nieto, M Angela

2012-12-11

The epithelial-mesenchymal transition (EMT) is required in the embryo for the formation of tissues for which cells originate far from their final destination. Carcinoma cells hijack this program for tumor dissemination. The relevance of the EMT in cancer is still debated because it is unclear how these migratory cells colonize distant tissues to form macrometastases. We show that the homeobox factor Prrx1 is an EMT inducer conferring migratory and invasive properties. The loss of Prrx1 is required for cancer cells to metastasize in vivo, which revert to the epithelial phenotype concomitant with the acquisition of stem cell properties. Thus, unlike the classical EMT transcription factors, Prrx1 uncouples EMT and stemness, and is a biomarker associated with patient survival and lack of metastasis. Copyright © 2012 Elsevier Inc. All rights reserved.

Chromatin reorganisation in Epstein-Barr virus-infected cells and its role in cancer development.

PubMed

West, Michelle J

2017-10-01

The oncogenic Epstein-Barr virus (EBV) growth transforms B cells and drives lymphoma and carcinoma development. The virus encodes four key transcription factors (EBNA2, EBNA3A, EBNA3B and EBNA3C) that hijack host cell factors to bind gene control elements and reprogramme infected B cells. These viral factors predominantly target long-range enhancers to alter the expression of host cell genes that control B cell growth and survival and facilitate virus persistence. Enhancer and super-enhancer binding by these EBNAs results in large-scale reorganisation of three-dimensional enhancer-promoter architecture to drive the overexpression of oncogenes, the silencing of tumour suppressors and the modulation of transcription, cell-cycle progression, migration and adhesion. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Dopamine reward prediction error coding.

PubMed

Schultz, Wolfram

2016-03-01

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards-an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware.

Molecular model of cannabis sensitivity in developing neuronal circuits

PubMed Central

Keimpema, Erik; Mackie, Ken; Harkany, Tibor

2011-01-01

Prenatal cannabis exposure can complicate in utero development of the nervous system. Cannabis impacts the formation and functions of neuronal circuitries by targeting cannabinoid receptors. Endocannabinoid signaling emerges as a signaling cassette to orchestrate neuronal differentiation programs through the precisely timed interaction of endocannabinoid ligands with their cognate cannabinoid receptors. By indiscriminately prolonging the ‘switched-on’ period of cannabinoid receptors, cannabis can hijack endocannabinoid signals to evoke molecular rearrangements, leading to the erroneous wiring of neuronal networks. Here, we formulate a hierarchical network design necessary and sufficient to describe molecular underpinnings of cannabis-induced neural growth defects. We integrate signalosome components deduced from genome- and proteome-wide arrays and candidate analyses to propose a mechanistic hypothesis on how cannabis-induced ectopic cannabinoid receptor activity overrides physiological neurodevelopmental endocannabinoid signals, affecting the timely formation of synapses. PMID:21757242

Wnt Signaling in Normal and Malignant Hematopoiesis

PubMed Central

Lento, William; Congdon, Kendra; Voermans, Carlijn; Kritzik, Marcie; Reya, Tannishtha

2013-01-01

One of the most remarkable characteristics of stem cells is their ability to perpetuate themselves through self-renewal while concomitantly generating differentiated cells. In the hematopoietic system, stem cells balance these mechanisms to maintain steady-state hematopoiesis for the lifetime of the organism, and to effectively regenerate the system following injury. Defects in the proper control of self-renewal and differentiation can be potentially devastating and contribute to the development of malignancies. In this review, we trace the emerging role of Wnt signaling as a critical regulator of distinct aspects of self-renewal and differentiation, its contribution to the maintenance of homeostasis and regeneration, and how the pathway can be hijacked to promote leukemia development. A better understanding of these processes could pave the way to enhancing recovery after injury and to developing better therapeutic approaches for hematologic malignancies. PMID:23378582

Bartonella and Brucella—Weapons and Strategies for Stealth Attack

PubMed Central

Ben-Tekaya, Houchaima; Gorvel, Jean-Pierre; Dehio, Christoph

2013-01-01

Bartonella spp. and Brucella spp. are closely related α-proteobacterial pathogens that by distinct stealth-attack strategies cause chronic infections in mammals including humans. Human infections manifest by a broad spectrum of clinical symptoms, ranging from mild to fatal disease. Both pathogens establish intracellular replication niches and subvert diverse pathways of the host’s immune system. Several virulence factors allow them to adhere to, invade, proliferate, and persist within various host-cell types. In particular, type IV secretion systems (T4SS) represent essential virulence factors that transfer effector proteins tailored to recruit host components and modulate cellular processes to the benefit of the bacterial intruders. This article puts the remarkable features of these two pathogens into perspective, highlighting the mechanisms they use to hijack signaling and trafficking pathways of the host as the basis for their stealthy infection strategies. PMID:23906880

Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production.

PubMed

He, Shanping; Zhao, Jun; Song, Shanshan; He, Xiaojing; Minassian, Arlet; Zhou, Yu; Zhang, Junjie; Brulois, Kevin; Wang, Yuqi; Cabo, Jackson; Zandi, Ebrahim; Liang, Chengyu; Jung, Jae U; Zhang, Xuewu; Feng, Pinghui

2015-04-02

RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here, we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologs of phosphoribosylformylglycinamidine synthetase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homolog thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme. Copyright © 2015 Elsevier Inc. All rights reserved.

Virus-mimetic nanovesicles as a versatile antigen-delivery system

PubMed Central

Zhang, Pengfei; Chen, Yixin; Zeng, Yun; Shen, Chenguang; Li, Rui; Guo, Zhide; Li, Shaowei; Zheng, Qingbing; Chu, Chengchao; Wang, Zhantong; Zheng, Zizheng; Tian, Rui; Ge, Shengxiang; Zhang, Xianzhong; Xia, Ning-Shao; Liu, Gang; Chen, Xiaoyuan

2015-01-01

It is a critically important challenge to rapidly design effective vaccines to reduce the morbidity and mortality of unexpected pandemics. Inspired from the way that most enveloped viruses hijack a host cell membrane and subsequently release by a budding process that requires cell membrane scission, we genetically engineered viral antigen to harbor into cell membrane, then form uniform spherical virus-mimetic nanovesicles (VMVs) that resemble natural virus in size, shape, and specific immunogenicity with the help of surfactants. Incubation of major cell membrane vesicles with surfactants generates a large amount of nano-sized uniform VMVs displaying the native conformational epitopes. With the diverse display of epitopes and viral envelope glycoproteins that can be functionally anchored onto VMVs, we demonstrate VMVs to be straightforward, robust and tunable nanobiotechnology platforms for fabricating antigen delivery systems against a wide range of enveloped viruses. PMID:26504197

Dopamine reward prediction error coding

PubMed Central

Schultz, Wolfram

2016-01-01

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards—an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware. PMID:27069377

Hijacked then lost in translation: the plight of the recombinant host cell in membrane protein structural biology projects.

PubMed

Bill, Roslyn M; von der Haar, Tobias

2015-06-01

Membrane protein structural biology is critically dependent upon the supply of high-quality protein. Over the last few years, the value of crystallising biochemically characterised, recombinant targets that incorporate stabilising mutations has been established. Nonetheless, obtaining sufficient yields of many recombinant membrane proteins is still a major challenge. Solutions are now emerging based on an improved understanding of recombinant host cells; as a 'cell factory' each cell is tasked with managing limited resources to simultaneously balance its own growth demands with those imposed by an expression plasmid. This review examines emerging insights into the role of translation and protein folding in defining high-yielding recombinant membrane protein production in a range of host cells. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Near Real Time Ship Detection Experiments

NASA Astrophysics Data System (ADS)

Brusch, S.; Lehner, S.; Schwarz, E.; Fritz, T.

2010-04-01

A new Near Real Time (NRT) ship detection processor SAINT (SAR AIS Integrated Toolbox) was developed in the framework of the ESA project MARISS. Data are received at DLRs ground segment DLR-BN (Neustrelitz, Germany). Results of the ship detection are available on ftp server within 30 min after the acquisition started. The detectability of ships on Synthetic Aperture Radar (SAR) ERS-2, ENVISAT ASAR and TerraSAR-X (TS-X) images is validated by coastal (live) AIS and space AIS. The monitoring areas chosen for surveillance are the North-, Baltic Sea, and Cape Town. The detectability in respect to environmental parameters like wind field, sea state, currents and changing coastlines due to tidal effects is investigated. In the South Atlantic a tracking experiment of the German research vessel Polarstern has been performed. Issues of piracy in particular in respect to ships hijacked at the Somali coast are discussed. Some examples using high resolution images from TerraSAR-X are given.

Detection and Prevention of Insider Threats in Database Driven Web Services

NASA Astrophysics Data System (ADS)

Chumash, Tzvi; Yao, Danfeng

In this paper, we take the first step to address the gap between the security needs in outsourced hosting services and the protection provided in the current practice. We consider both insider and outsider attacks in the third-party web hosting scenarios. We present SafeWS, a modular solution that is inserted between server side scripts and databases in order to prevent and detect website hijacking and unauthorized access to stored data. To achieve the required security, SafeWS utilizes a combination of lightweight cryptographic integrity and encryption tools, software engineering techniques, and security data management principles. We also describe our implementation of SafeWS and its evaluation. The performance analysis of our prototype shows the overhead introduced by security verification is small. SafeWS will allow business owners to significantly reduce the security risks and vulnerabilities of outsourcing their sensitive customer data to third-party providers.

Access to site-specific Fc-cRGD peptide conjugates through streamlined expressed protein ligation.

PubMed

Frutos, S; Jordan, J B; Bio, M M; Muir, T W; Thiel, O R; Vila-Perelló, M

2016-10-12

An ideal drug should be highly effective, non-toxic and be delivered by a convenient and painless single dose. We are still far from such optimal treatment but peptides, with their high target selectivity and low toxicity profiles, provide a very attractive platform from which to strive towards it. One of the major limitations of peptide drugs is their high clearance rates, which limit dosage regimen options. Conjugation to antibody Fc domains is a viable strategy to improve peptide stability by increasing their hydrodynamic radius and hijacking the Fc recycling pathway. We report the use of a split-intein based semi-synthetic approach to site-specifically conjugate a synthetic integrin binding peptide to an Fc domain. The strategy described here allows conjugating synthetic peptides to Fc domains, which is not possible via genetic methods, fully maintaining the ability of both the Fc domain and the bioactive peptide to interact with their binding partners.

Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes.

PubMed

Abounit, Saïda; Bousset, Luc; Loria, Frida; Zhu, Seng; de Chaumont, Fabrice; Pieri, Laura; Olivo-Marin, Jean-Christophe; Melki, Ronald; Zurzolo, Chiara

2016-10-04

Synucleinopathies such as Parkinson's disease are characterized by the pathological deposition of misfolded α-synuclein aggregates into inclusions throughout the central and peripheral nervous system. Mounting evidence suggests that intercellular propagation of α-synuclein aggregates may contribute to the neuropathology; however, the mechanism by which spread occurs is not fully understood. By using quantitative fluorescence microscopy with co-cultured neurons, here we show that α-synuclein fibrils efficiently transfer from donor to acceptor cells through tunneling nanotubes (TNTs) inside lysosomal vesicles. Following transfer through TNTs, α-synuclein fibrils are able to seed soluble α-synuclein aggregation in the cytosol of acceptor cells. We propose that donor cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. Our findings thus reveal a possible novel role of TNTs and lysosomes in the progression of synucleinopathies. © 2016 The Authors.

Purine synthesis promotes maintenance of brain tumor initiating cells in glioma.

PubMed

Wang, Xiuxing; Yang, Kailin; Xie, Qi; Wu, Qiulian; Mack, Stephen C; Shi, Yu; Kim, Leo J Y; Prager, Briana C; Flavahan, William A; Liu, Xiaojing; Singer, Meromit; Hubert, Christopher G; Miller, Tyler E; Zhou, Wenchao; Huang, Zhi; Fang, Xiaoguang; Regev, Aviv; Suvà, Mario L; Hwang, Tae Hyun; Locasale, Jason W; Bao, Shideng; Rich, Jeremy N

2017-05-01

Brain tumor initiating cells (BTICs), also known as cancer stem cells, hijack high-affinity glucose uptake active normally in neurons to maintain energy demands. Here we link metabolic dysregulation in human BTICs to a nexus between MYC and de novo purine synthesis, mediating glucose-sustained anabolic metabolism. Inhibiting purine synthesis abrogated BTIC growth, self-renewal and in vivo tumor formation by depleting intracellular pools of purine nucleotides, supporting purine synthesis as a potential therapeutic point of fragility. In contrast, differentiated glioma cells were unaffected by the targeting of purine biosynthetic enzymes, suggesting selective dependence of BTICs. MYC coordinated the control of purine synthetic enzymes, supporting its role in metabolic reprogramming. Elevated expression of purine synthetic enzymes correlated with poor prognosis in glioblastoma patients. Collectively, our results suggest that stem-like glioma cells reprogram their metabolism to self-renew and fuel the tumor hierarchy, revealing potential BTIC cancer dependencies amenable to targeted therapy.

The Power of the Picture: How Narrative Film Captures Attention and Disrupts Goal Pursuit.

PubMed

Cohen, Anna-Lisa; Shavalian, Elliot; Rube, Moshe

2015-01-01

Narrative transportation is described as a state of detachment that arises when one becomes immersed in the narrative of a story. Participants viewed either an intact version of an engaging 20 min film, "Bang You're Dead!," (1961) by Alfred Hitchcock (contiguous condition), or a version of the same film with scenes presented out of order (noncontiguous condition). In this latter condition, the individual scenes were intact but were presented out of chronological order. Participants were told a cover story that we were interested in the amount of gun violence depicted in films. Both groups were given the goal to remember to lift their hand every time they heard the word "gun" spoken during the film. Results revealed that participants were significantly less likely to remember to execute their goal in the contiguous condition, presumably because this narrative transported viewers' attention and thereby "hijacked" processing resources away from internal goals.

Communication between filamentous pathogens and plants at the biotrophic interface.

PubMed

Yi, Mihwa; Valent, Barbara

2013-01-01

Fungi and oomycetes that colonize living plant tissue form extensive interfaces with plant cells in which the cytoplasm of the microorganism is closely aligned with the host cytoplasm for an extended distance. In all cases, specialized biotrophic hyphae function to hijack host cellular processes across an interfacial zone consisting of a hyphal plasma membrane, a specialized interfacial matrix, and a plant-derived membrane. The interface is the site of active secretion by both players. This cross talk at the interface determines the winner in adversarial relationships and establishes the partnership in mutualistic relationships. Fungi and oomycetes secrete many specialized effector proteins for controlling the host, and they can stimulate remarkable cellular reorganization even in distant plant cells. Breakthroughs in live-cell imaging of fungal and oomycete encounter sites, including live-cell imaging of pathogens secreting fluorescently labeled effector proteins, have led to recent progress in understanding communication across the interface.

Molecular model of cannabis sensitivity in developing neuronal circuits.

PubMed

Keimpema, Erik; Mackie, Ken; Harkany, Tibor

2011-09-01

Prenatal cannabis exposure can complicate in utero development of the nervous system. Cannabis impacts the formation and functions of neuronal circuitries by targeting cannabinoid receptors. Endocannabinoid signaling emerges as a signaling cassette that orchestrates neuronal differentiation programs through the precisely timed interaction of endocannabinoid ligands with their cognate cannabinoid receptors. By indiscriminately prolonging the 'switched-on' period of cannabinoid receptors, cannabis can hijack endocannabinoid signals to evoke molecular rearrangements, leading to the erroneous wiring of neuronal networks. Here, we formulate a hierarchical network design necessary and sufficient to describe the molecular underpinnings of cannabis-induced neural growth defects. We integrate signalosome components, deduced from genome- and proteome-wide arrays and candidate analyses, to propose a mechanistic hypothesis of how cannabis-induced ectopic cannabinoid receptor activity overrides physiological neurodevelopmental endocannabinoid signals, affecting the timely formation of synapses. Copyright © 2011 Elsevier Ltd. All rights reserved.

Biochemical basis for activation of virulence genes by bile salts in Vibrio parahaemolyticus.

PubMed

Rivera-Cancel, Giomar; Orth, Kim

2017-07-04

Bile salts act as a stressor to bacteria that transit the intestinal tract. Enteric pathogens have hijacked bile as an intestinal signal to regulate virulence factors. We recently demonstrated that Vibrio parahemolyticus senses bile salts via a heterodimeric receptor formed by the periplasmic domains of inner-membrane proteins VtrA and VtrC. Crystal structures of the periplasmic complex reveal that VtrA and VtrC form a β-barrel that binds bile salts in its hydrophobic interior to activate the VtrA cytoplasmic DNA-binding domain. Proteins with the same domain arrangement as VtrA and VtrC are widespread in Vibrio and related bacteria, where they are involved in regulating virulence and other unknown functions. Here we discuss our findings and review current knowledge on VtrA and VtrC homologs. We propose that signaling by these membrane-bound transcription factors can be advantageous for the regulation of membrane and secretory proteins.

Molecular cloning and characterization of a threonine/serine protein kinase lvakt from Litopenaeus vannamei

NASA Astrophysics Data System (ADS)

Ruan, Lingwei; Liu, Rongdiao; Xu, Xun; Shi, Hong

2014-07-01

The phosphatidylinositol 3-kinase (PI3K)-AKT pathway is involved in various cellular functions, including anti-apoptosis, protein synthesis, glucose metabolism and cell cycling. However, the role of the PI3K-AKT pathway in crustaceans remains unclear. In the present study, we cloned and characterized the AKT gene lvakt from Litopenaeus vannamei. The 511-residue LVAKT was highly conserved; contained a PH domain, a catalytic domain and a hydrophobic domain; and was highly expressed in the heart and gills of L. vannamei. We found, using Real-Time Quantitative PCR (Q-PCR) analysis, that lvakt was up-regulated during early white spot syndrome virus (WSSV) infection. Moreover, the PI3K-specific inhibitor, LY294002, reduced viral gene transcription, implying that the PI3K-AKT pathway might be hijacked by WSSV. Our results therefore suggest that LVAKT may play an important role in the shrimp immune response against WSSV.

The devil is in the details: Transposable element analysis of the Tasmanian devil genome.

PubMed

Nilsson, Maria A

2016-01-01

The third marsupial genome was sequenced from the Tasmanian devil ( Sarcophilus harrisii ), a species that currently is driven to extinction by a rare transmissible cancer. The transposable element (TE) landscape of the Tasmanian devil genome revealed that the main driver of retrotransposition the L ong IN terspersed E lement 1 (LINE1) seem to have become inactivated during the past 12 million years. Strangely, the S hort IN terspersed E lements (SINE), that normally hijacks the LINE1 retrotransposition system, became inactive prior to LINE1 at around 30 million years ago. The SINE inactivation was in vitro verified in several species. Here I discuss that the apparent LINE1 inactivation might be caused by a genome assembly artifact. The repetitive fraction of any genome is highly complex to assemble and the observed problems are not unique to the Tasmanian devil genome.

The devil is in the details: Transposable element analysis of the Tasmanian devil genome

PubMed Central

Nilsson, Maria A.

2016-01-01

ABSTRACT The third marsupial genome was sequenced from the Tasmanian devil (Sarcophilus harrisii), a species that currently is driven to extinction by a rare transmissible cancer. The transposable element (TE) landscape of the Tasmanian devil genome revealed that the main driver of retrotransposition the Long INterspersed Element 1 (LINE1) seem to have become inactivated during the past 12 million years. Strangely, the Short INterspersed Elements (SINE), that normally hijacks the LINE1 retrotransposition system, became inactive prior to LINE1 at around 30 million years ago. The SINE inactivation was in vitro verified in several species. Here I discuss that the apparent LINE1 inactivation might be caused by a genome assembly artifact. The repetitive fraction of any genome is highly complex to assemble and the observed problems are not unique to the Tasmanian devil genome. PMID:27066301

Infection, inflammation and host carbohydrates: A Glyco-Evasion Hypothesis

PubMed Central

Kreisman, Lori SC; Cobb, Brian A

2012-01-01

Microbial immune evasion can be achieved through the expression, or mimicry, of host-like carbohydrates on the microbial cell surface to hide from detection. However, disparate reports collectively suggest that evasion could also be accomplished through the modulation of the host glycosylation pathways, a mechanism that we call the “Glyco-Evasion Hypothesis”. Here, we will summarize the evidence in support of this paradigm by reviewing three separate bodies of work present in the literature. We review how infection and inflammation can lead to host glycosylation changes, how host glycosylation changes can increase susceptibility to infection and inflammation and how glycosylation impacts molecular and cellular function. Then, using these data as a foundation, we propose a unifying hypothesis in which microbial products can hijack host glycosylation to manipulate the immune response to the advantage of the pathogen. This model reveals areas of research that we believe could significantly improve our fight against infectious disease. PMID:22492234

Evolutionary scalpels for dissecting tumor ecosystems

PubMed Central

Rosenbloom, Daniel I. S.; Camara, Pablo G.; Chu, Tim; Rabadan, Raul

2017-01-01

Amidst the growing literature on cancer genomics and intratumor heterogeneity, essential principles in evolutionary biology recur time and time again. Here we use these principles to guide the reader through major advances in cancer research, highlighting issues of “hit hard, hit early” treatment strategies, drug resistance, and metastasis. We distinguish between two frameworks for understanding heterogeneous tumors, both of which can inform treatment strategies: (1) The tumor as diverse ecosystem, a Darwinian population of sometimes-competing, sometimes-cooperating cells; (2) The tumor as tightly integrated, self-regulating organ, which may hijack developmental signals to restore functional heterogeneity after treatment. While the first framework dominates literature on cancer evolution, the second framework enjoys support as well. Throughout this review, we illustrate how mathematical models inform understanding of tumor progression and treatment outcomes. Connecting models to genomic data faces computational and technical hurdles, but high-throughput single-cell technologies show promise to clear these hurdles. PMID:27923679

The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy.

PubMed

Sockolosky, Jonathan T; Szoka, Francis C

2015-08-30

Immunoglobulin G (IgG)-based drugs are arguably the most successful class of protein therapeutics due in part to their remarkably long blood circulation. This arises from IgG interaction with the neonatal Fc receptor, FcRn. FcRn is the central regulator of IgG and albumin homeostasis throughout life and is increasingly being recognized as an important player in autoimmune disease, mucosal immunity, and tumor immune surveillance. Various engineering approaches that hijack or disrupt the FcRn-mediated transport pathway have been devised to develop long-lasting and non-invasive protein therapeutics, protein subunit vaccines, and therapeutics for treatment of autoimmune and infectious disease. In this review, we highlight the diverse biological functions of FcRn, emerging therapeutic opportunities, as well as the associated challenges of targeting FcRn for drug delivery and disease therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

AMP kinase promotes glioblastoma bioenergetics and tumour growth.

PubMed

Chhipa, Rishi Raj; Fan, Qiang; Anderson, Jane; Muraleedharan, Ranjithmenon; Huang, Yan; Ciraolo, Georgianne; Chen, Xiaoting; Waclaw, Ronald; Chow, Lionel M; Khuchua, Zaza; Kofron, Matthew; Weirauch, Matthew T; Kendler, Ady; McPherson, Christopher; Ratner, Nancy; Nakano, Ichiro; Dasgupta, Nupur; Komurov, Kakajan; Dasgupta, Biplab

2018-06-18

Stress is integral to tumour evolution, and cancer cell survival depends on stress management. We found that cancer-associated stress chronically activates the bioenergetic sensor AMP kinase (AMPK) and, to survive, tumour cells hijack an AMPK-regulated stress response pathway conserved in normal cells. Analysis of The Cancer Genome Atlas data revealed that AMPK isoforms are highly expressed in the lethal human cancer glioblastoma (GBM). We show that AMPK inhibition reduces viability of patient-derived GBM stem cells (GSCs) and tumours. In stressed (exercised) skeletal muscle, AMPK is activated to cooperate with CREB1 (cAMP response element binding protein-1) and promote glucose metabolism. We demonstrate that oncogenic stress chronically activates AMPK in GSCs that coopt the AMPK-CREB1 pathway to coordinate tumour bioenergetics through the transcription factors HIF1α and GABPA. Finally, we show that adult mice tolerate systemic deletion of AMPK, supporting the use of AMPK pharmacological inhibitors in the treatment of GBM.

Effect of endosomal acidification on small ion transport through the anthrax toxin PA63 channel.

PubMed

Kalu, Nnanya; Alcaraz, Antonio; Yamini, Goli; Momben Abolfath, Sanaz; Lucas, Laura; Kenney, Clare; Aguilella, Vicente M; Nestorovich, Ekaterina M

2017-11-01

Tight regulation of pH is critical for the structure and function of cells and organelles. The pH environment changes dramatically along the endocytic pathway, an internalization transport process that is 'hijacked' by many intracellularly active bacterial exotoxins, including the anthrax toxin. Here, we investigate the role of pH on single-channel properties of the anthrax toxin protective antigen (PA 63 ). Using conductance and current noise analysis, blocker binding, ion selectivity, and poly(ethylene glycol) partitioning measurements, we show that the channel exists in two different open states ('maximum' and 'main') at pH ≥ 5.5, while only a maximum conductance state is detected at pH < 5.5. We describe two substantially distinct patterns of PA 63 conductance dependence on KCl concentration uncovered at pH 6.5 and 4.5. © 2017 Federation of European Biochemical Societies.

Taming power: Generative historical consciousness.

PubMed

Winter, David G

2016-04-01

Power is a necessary dimension of all human enterprises. It can inspire and illuminate, but it can also corrupt, oppress, and destroy. Therefore, taming power has been a central moral and political question for most of human history. Writers, theorists, and researchers have suggested many methods and mechanisms for taming power: through affiliation and love, intellect and reason, responsibility, religion and values, democratic political structures, and separation of powers. Historical examples and social science research suggest that each has some success, but also that each is vulnerable to being hijacked by power itself. I therefore introduce generative historical consciousness (GHC) as a concept and measure that might help to secure the benefits of power while protecting against its outrages and excesses. I conclude by discussing the role that GHC may have played in the peaceful resolution of the Cuban Missile Crisis of 1962. (c) 2016 APA, all rights reserved).

Intervention of Phytohormone Pathways by Pathogen Effectors[OPEN

PubMed Central

Kazan, Kemal; Lyons, Rebecca

2014-01-01

The constant struggle between plants and microbes has driven the evolution of multiple defense strategies in the host as well as offense strategies in the pathogen. To defend themselves from pathogen attack, plants often rely on elaborate signaling networks regulated by phytohormones. In turn, pathogens have adopted innovative strategies to manipulate phytohormone-regulated defenses. Tactics frequently employed by plant pathogens involve hijacking, evading, or disrupting hormone signaling pathways and/or crosstalk. As reviewed here, this is achieved mechanistically via pathogen-derived molecules known as effectors, which target phytohormone receptors, transcriptional activators and repressors, and other components of phytohormone signaling in the host plant. Herbivores and sap-sucking insects employ obligate pathogens such as viruses, phytoplasma, or symbiotic bacteria to intervene with phytohormone-regulated defenses. Overall, an improved understanding of phytohormone intervention strategies employed by pests and pathogens during their interactions with plants will ultimately lead to the development of new crop protection strategies. PMID:24920334

Roles of small RNAs in plant disease resistance.

PubMed

Yang, Li; Huang, Hai

2014-10-01

The interaction between plants and pathogens represents a dynamic competition between a robust immune system and efficient infectious strategies. Plant innate immunity is composed of complex and highly regulated molecular networks, which can be triggered by the perception of either conserved or race-specific pathogenic molecular signatures. Small RNAs are emerging as versatile regulators of plant development, growth and response to biotic and abiotic stresses. They act in different tiers of plant immunity, including the pathogen-associated molecular pattern-triggered and the effector-triggered immunity. On the other hand, pathogens have evolved effector molecules to suppress or hijack the host small RNA pathways. This leads to an arms race between plants and pathogens at the level of small RNA-mediated defense. Here, we review recent advances in small RNA-mediated defense responses and discuss the challenging questions in this area. © 2014 Institute of Botany, Chinese Academy of Sciences.

Epstein-Barr Virus Hijacks DNA Damage Response Transducers to Orchestrate Its Life Cycle.

PubMed

Hau, Pok Man; Tsao, Sai Wah

2017-11-16

The Epstein-Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt's lymphoma, Hodgkin's lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has shown that EBV triggers a DNA damage response (DDR) during primary infection and lytic reactivation. The EBV-encoded viral proteins have been implicated in deregulating the DDR signaling pathways. The consequences of DDR inactivation lead to genomic instability and promote cellular transformation. This review summarizes the current understanding of the relationship between EBV infection and the DDR transducers, including ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), and DNA-PK (DNA-dependent protein kinase), and discusses how EBV manipulates the DDR signaling pathways to complete the replication process of viral DNA during lytic reactivation.

Plant actin cytoskeleton re-modeling by plant parasitic nematodes.

PubMed

Engler, Janice de Almeida; Rodiuc, Natalia; Smertenko, Andrei; Abad, Pierre

2010-03-01

The cytoskeleton is an important component of the plant's defense mechanism against the attack of pathogenic organisms. Plants however, are defenseless against parasitic root-knot and cyst nematodes and respond to the invasion by the development of a special feeding site that supplies the parasite with nutrients required for the completion of its life cycle. Recent studies of nematode invasion under treatment with cytoskeletal drugs and in mutant plants where normal functions of the cytoskeleton have been affected, demonstrate the importance of the cytoskeleton in the establishment of a feeding site and successful nematode reproduction. It appears that in the case of microfilaments, nematodes hijack the intracellular machinery that regulates actin dynamics and modulate the organization and properties of the actin filament network. Intervening with this process reduces the nematode infection efficiency and inhibits its life cycle. This discovery uncovers a new pathway that can be exploited for the protection of plants against nematodes.

At the forefront of thought: the effect of media exposure on airplane typicality.

PubMed

Novick, Laura R

2003-12-01

The terrorist attacks of September 11, 2001 provided a unique opportunity to investigate the causal status of frequency on typicality for one exemplar of a common conceptual category--namely, the typicality of airplane as a member of the category of vehicles. The extensive media coverage following the attacks included numerous references to the hijacked airplanes and to the consequences of suspending air travel to and from the United States for several days. The present study, involving 152 undergraduates, assessed airplane typicality at three time points ranging from 5 h to 1 month after the attacks and then again at 4.5 months after the attacks. Airplane was judged to be a more typical vehicle for 1 month following the attacks, relative to a baseline calculated from data collected yearly for 5 years preceding the attacks. By 4.5 months, however, typicality was back to baseline.

Pancreatic Cancer Metabolism: Breaking It Down to Build It Back Up.

PubMed

Perera, Rushika M; Bardeesy, Nabeel

2015-12-01

How do cancer cells escape tightly controlled regulatory circuits that link their proliferation to extracellular nutrient cues? An emerging theme in cancer biology is the hijacking of normal stress response mechanisms to enable growth even when nutrients are limiting. Pancreatic ductal adenocarcinoma (PDA) is the quintessential aggressive malignancy that thrives in nutrient-poor, hypoxic environments. PDAs overcome these limitations through appropriation of unorthodox strategies for fuel source acquisition and utilization. In addition, the interplay between evolving PDA and whole-body metabolism contributes to disease pathogenesis. Deciphering how these pathways function and integrate with one another can reveal novel angles of therapeutic attack. Alterations in tumor cell and systemic metabolism are central to the biology of pancreatic cancer. Further investigation of these processes will provide important insights into how these tumors develop and grow, and suggest new approaches for its detection, prevention, and treatment. ©2015 American Association for Cancer Research.

ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia.

PubMed

Thirant, Cécile; Ignacimouttou, Cathy; Lopez, Cécile K; Diop, M'Boyba; Le Mouël, Lou; Thiollier, Clarisse; Siret, Aurélie; Dessen, Phillipe; Aid, Zakia; Rivière, Julie; Rameau, Philippe; Lefebvre, Céline; Khaled, Mehdi; Leverger, Guy; Ballerini, Paola; Petit, Arnaud; Raslova, Hana; Carmichael, Catherine L; Kile, Benjamin T; Soler, Eric; Crispino, John D; Wichmann, Christian; Pflumio, Françoise; Schwaller, Jürg; Vainchenker, William; Lobry, Camille; Droin, Nathalie; Bernard, Olivier A; Malinge, Sébastien; Mercher, Thomas

2017-03-13

Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia. Copyright © 2017 Elsevier Inc. All rights reserved.

HTLV-1 Tax plugs and freezes UPF1 helicase leading to nonsense-mediated mRNA decay inhibition.

PubMed

Fiorini, Francesca; Robin, Jean-Philippe; Kanaan, Joanne; Borowiak, Malgorzata; Croquette, Vincent; Le Hir, Hervé; Jalinot, Pierre; Mocquet, Vincent

2018-01-30

Up-Frameshift Suppressor 1 Homolog (UPF1) is a key factor for nonsense-mediated mRNA decay (NMD), a cellular process that can actively degrade mRNAs. Here, we study NMD inhibition during infection by human T-cell lymphotropic virus type I (HTLV-1) and characterise the influence of the retroviral Tax factor on UPF1 activity. Tax interacts with the central helicase core domain of UPF1 and might plug the RNA channel of UPF1, reducing its affinity for nucleic acids. Furthermore, using a single-molecule approach, we show that the sequential interaction of Tax with a RNA-bound UPF1 freezes UPF1: this latter is less sensitive to the presence of ATP and shows translocation defects, highlighting the importance of this feature for NMD. These mechanistic insights reveal how HTLV-1 hijacks the central component of NMD to ensure expression of its own genome.

The Antibiotic CJ-15,801 is an Antimetabolite which Hijacks and then Inhibits CoA Biosynthesis

PubMed Central

van der Westhuyzen, Renier; Hammons, Justin C.; Meier, Jordan L.; Dahesh, Samira; Moolman, Wessel J. A.; Pelly, Stephen C.; Nizet, Victor; Burkart, Michael D.; Strauss, Erick

2012-01-01

SUMMARY The natural product CJ-15,801 is an inhibitor of Staphylococcus aureus, but not other bacteria. Its close structural resemblance to pantothenic acid, the vitamin precursor of coenzyme A (CoA), and its Michael acceptor moiety suggest that it irreversibly inhibits an enzyme involved in CoA biosynthesis or utilization. However, its mode of action and the basis for its specificity have not been elucidated to date. We demonstrate that CJ-15,801 is transformed by the uniquely selective S. aureus pantothenate kinase, the first CoA biosynthetic enzyme, into a substrate for the next enzyme, phosphopantothenoylcysteine synthetase, which is inhibited through formation of a tight-binding structural mimic of its native reaction intermediate. These findings reveal CJ-15,801 as a vitamin biosynthetic pathway antimetabolite with a mechanism similar to that of the sulfonamide antibiotics, and highlight CoA biosynthesis as a viable antimicrobial drug target. PMID:22633408

Novel Evasion Mechanisms of the Classical Complement Pathway

PubMed Central

Garcia, Brandon L.; Zwarthoff, Seline A.; Rooijakkers, Suzan H. M.; Geisbrecht, Brian V.

2016-01-01

Complement is a network of soluble and cell surface-associated proteins which gives rise to a self-amplifying, yet tightly regulated system with fundamental roles in immune surveillance and clearance. Complement becomes activated on the surface of ‘non-self’ cells by one of three initiating mechanisms known as the classical, lectin, or alternative pathways. Evasion of complement function is a hallmark of invasive pathogens and hematophagous organisms. While many complement inhibition strategies hinge on hijacking activities of endogenous complement regulatory proteins, an increasing number of uniquely evolved evasion molecules have been discovered over the past decade. In this review we focus on several recent investigations which have revealed mechanistically distinct inhibitors of the classical pathway. Because the classical pathway is an important and specific mediator of various autoimmune and inflammatory disorders, in-depth knowledge of novel evasion mechanisms could direct future development of therapeutic anti-inflammatory molecules. PMID:27591336

Novel Evasion Mechanisms of the Classical Complement Pathway.

PubMed

Garcia, Brandon L; Zwarthoff, Seline A; Rooijakkers, Suzan H M; Geisbrecht, Brian V

2016-09-15

Complement is a network of soluble and cell surface-associated proteins that gives rise to a self-amplifying, yet tightly regulated system with fundamental roles in immune surveillance and clearance. Complement becomes activated on the surface of nonself cells by one of three initiating mechanisms known as the classical, lectin, and alternative pathways. Evasion of complement function is a hallmark of invasive pathogens and hematophagous organisms. Although many complement-inhibition strategies hinge on hijacking activities of endogenous complement regulatory proteins, an increasing number of uniquely evolved evasion molecules have been discovered over the past decade. In this review, we focus on several recent investigations that revealed mechanistically distinct inhibitors of the classical pathway. Because the classical pathway is an important and specific mediator of various autoimmune and inflammatory disorders, in-depth knowledge of novel evasion mechanisms could direct future development of therapeutic anti-inflammatory molecules. Copyright © 2016 by The American Association of Immunologists, Inc.

The adaptive safety analysis and monitoring system

NASA Astrophysics Data System (ADS)

Tu, Haiying; Allanach, Jeffrey; Singh, Satnam; Pattipati, Krishna R.; Willett, Peter

2004-09-01

The Adaptive Safety Analysis and Monitoring (ASAM) system is a hybrid model-based software tool for assisting intelligence analysts to identify terrorist threats, to predict possible evolution of the terrorist activities, and to suggest strategies for countering terrorism. The ASAM system provides a distributed processing structure for gathering, sharing, understanding, and using information to assess and predict terrorist network states. In combination with counter-terrorist network models, it can also suggest feasible actions to inhibit potential terrorist threats. In this paper, we will introduce the architecture of the ASAM system, and discuss the hybrid modeling approach embedded in it, viz., Hidden Markov Models (HMMs) to detect and provide soft evidence on the states of terrorist network nodes based on partial and imperfect observations, and Bayesian networks (BNs) to integrate soft evidence from multiple HMMs. The functionality of the ASAM system is illustrated by way of application to the Indian Airlines Hijacking, as modeled from open sources.

Structural and Functional Analysis of Cell Wall-anchored Polypeptide Adhesin BspA in Streptococcus agalactiae*

PubMed Central

Rego, Sara; Heal, Timothy J.; Pidwill, Grace R.; Till, Marisa; Robson, Alice; Lamont, Richard J.; Sessions, Richard B.; Jenkinson, Howard F.; Race, Paul R.; Nobbs, Angela H.

2016-01-01

Streptococcus agalactiae (group B Streptococcus, GBS) is the predominant cause of early-onset infectious disease in neonates and is responsible for life-threatening infections in elderly and immunocompromised individuals. Clinical manifestations of GBS infection include sepsis, pneumonia, and meningitis. Here, we describe BspA, a deviant antigen I/II family polypeptide that confers adhesive properties linked to pathogenesis in GBS. Heterologous expression of BspA on the surface of the non-adherent bacterium Lactococcus lactis confers adherence to scavenger receptor gp340, human vaginal epithelium, and to the fungus Candida albicans. Complementary crystallographic and biophysical characterization of BspA reveal a novel β-sandwich adhesion domain and unique asparagine-dependent super-helical stalk. Collectively, these findings establish a new bacterial adhesin structure that has in effect been hijacked by a pathogenic Streptococcus species to provide competitive advantage in human mucosal infections. PMID:27311712

Ambulance snatching: how vulnerable are we?

PubMed

Alves, Donald W; Bissell, Richard A

2003-08-01

Out of concern that ambulances might be targeted for hijack for terrorism purposes, we observed security-related behaviors of a cross-section of ambulance crews and their vehicles in Emergency Department ambulance bays. We sent observers to a convenience sample of trauma and suburban Emergency Department ambulance entrances in several states. We observed 151 total ambulance arrivals. Overall, the average time present was 21.5 min, 23.2% of units were left with the engine running, 26.5% were left open, 90.1% were left unattended, 84.1% were unlocked, and 16.6% had a non-crew visitor in the ambulance bay. Several issues were identified demonstrating potential "attractiveness" to individuals who may wish to disrupt Emergency Medical Services or steal an emergency vehicle. We are concerned that this is the case at the majority of ambulance bays in our country. Emergency services agencies should take steps to train their personnel to secure the ambulance.

Analysis of complex network performance and heuristic node removal strategies

NASA Astrophysics Data System (ADS)

Jahanpour, Ehsan; Chen, Xin

2013-12-01

Removing important nodes from complex networks is a great challenge in fighting against criminal organizations and preventing disease outbreaks. Six network performance metrics, including four new metrics, are applied to quantify networks' diffusion speed, diffusion scale, homogeneity, and diameter. In order to efficiently identify nodes whose removal maximally destroys a network, i.e., minimizes network performance, ten structured heuristic node removal strategies are designed using different node centrality metrics including degree, betweenness, reciprocal closeness, complement-derived closeness, and eigenvector centrality. These strategies are applied to remove nodes from the September 11, 2001 hijackers' network, and their performance are compared to that of a random strategy, which removes randomly selected nodes, and the locally optimal solution (LOS), which removes nodes to minimize network performance at each step. The computational complexity of the 11 strategies and LOS is also analyzed. Results show that the node removal strategies using degree and betweenness centralities are more efficient than other strategies.

Investigation of natural gas theft by magnetic remanence mapping.

PubMed

Dobó, Zsolt; Kovács, Helga; Tóth, Pál; Palotás, Árpád B

2014-12-01

Natural gas theft causes major losses in the energy industry in Hungary. Among the non-technical losses occurring in natural gas networks, fraudulent residential consumption is one of the main factors. Up to 2014, gas meters that are most widely used in residential monitoring are manufactured with ferromagnetic moving components, which makes it possible to alter or disrupt the operation of the meters non-intrusively by placing permanent magnets on the casing of the meters. Magnetic remanence mapping was used to investigate a sample of 80 recalled residential meters and detect potentially fraudulent activity. 10% of the meters were found suspect by magnetic remanence measurement, of which 50% were confirmed to be potentially hijacked by further mechanical investigation. The details of the technique are described in this paper, along with experimental results and the discussion of the analysis of the real-world samples. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Manipulation of ubiquitin/SUMO pathways in human herpesviruses infection.

PubMed

Gan, Jin; Qiao, Niu; Strahan, Roxanne; Zhu, Caixia; Liu, Lei; Verma, Subhash C; Wei, Fang; Cai, Qiliang

2016-11-01

Post-translational modification of proteins with ubiquitin/small ubiquitin-like modifier (SUMO) molecules triggers multiple signaling pathways that are critical for many aspects of cellular physiology. Given that viruses hijack the biosynthetic and degradative systems of their host, it is not surprising that viruses encode proteins to manipulate the host's cellular machinery for ubiquitin/SUMO modification at multiple levels. Infection with a herpesvirus, among the most ubiquitous human DNA viruses, has been linked to many human diseases, including cancers. The interplay between human herpesviruses and the ubiquitylation/SUMOylation modification system has been extensively investigated in the past decade. In this review, we present an overview of recent advances to address how the ubiquitin/SUMO-modified system alters the latency and lytic replication of herpesvirus and how herpesviruses usurp the ubiquitin/SUMO pathways against the host's intrinsic and innate immune response to favor their pathogenesis. Copyright © 2016 John Wiley & Sons, Ltd.

Cellular Signaling Pathways and Posttranslational Modifications Mediated by Nematode Effector Proteins.

PubMed

Hewezi, Tarek

2015-10-01

Plant-parasitic cyst and root-knot nematodes synthesize and secrete a suite of effector proteins into infected host cells and tissues. These effectors are the major virulence determinants mediating the transformation of normal root cells into specialized feeding structures. Compelling evidence indicates that these effectors directly hijack or manipulate refined host physiological processes to promote the successful parasitism of host plants. Here, we provide an update on recent progress in elucidating the molecular functions of nematode effectors. In particular, we emphasize how nematode effectors modify plant cell wall structure, mimic the activity of host proteins, alter auxin signaling, and subvert defense signaling and immune responses. In addition, we discuss the emerging evidence suggesting that nematode effectors target and recruit various components of host posttranslational machinery in order to perturb the host signaling networks required for immunity and to regulate their own activity and subcellular localization. © 2015 American Society of Plant Biologists. All Rights Reserved.

Current topics in HIV-1 pathogenesis: The emergence of deregulated immuno-metabolism in HIV-infected subjects.

PubMed

Dagenais-Lussier, Xavier; Mouna, Aounallah; Routy, Jean-Pierre; Tremblay, Cecile; Sekaly, Rafick-Pierre; El-Far, Mohamed; Grevenynghe, Julien van

2015-12-01

HIV-1 infection results in long-lasting activation of the immune system including elevated production of pro-inflammatory cytokine/chemokines, and bacterial product release from gut into blood and tissue compartments, which are not fully restored by antiretroviral therapies. HIV-1 has also developed numerous strategies via viral regulatory proteins to hijack cell molecular mechanisms to enhance its own replication and dissemination. Here, we reviewed the relationship between viral proteins, immune activation/inflammation, and deregulated metabolism occurring in HIV-1-infected patients that ultimately dampens the protective innate and adaptive arms of immunity. Defining precisely the molecular mechanisms related to deregulated immuno-metabolism during HIV-1 infection could ultimately help in the development of novel clinical approaches to restore proper immune functions in these patients. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

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

Hood, Iris V.; Berger, James M.

Replisome assembly requires the loading of replicative hexameric helicases onto origins by AAA+ ATPases. How loader activity is appropriately controlled remains unclear. Here, we use structural and biochemical analyses to establish how an antimicrobial phage protein interferes with the function of theStaphylococcus aureusreplicative helicase loader, DnaI. The viral protein binds to the loader’s AAA+ ATPase domain, allowing binding of the host replicative helicase but impeding loader self-assembly and ATPase activity. Close inspection of the complex highlights an unexpected locus for the binding of an interdomain linker element in DnaI/DnaC-family proteins. We find that the inhibitor protein is genetically coupled tomore » a phage-encoded homolog of the bacterial helicase loader, which we show binds to the host helicase but not to the inhibitor itself. These findings establish a new approach by which viruses can hijack host replication processes and explain how loader activity is internally regulated to prevent aberrant auto-association.« less

Rice Stripe Tenuivirus Nonstructural Protein 3 Hijacks the 26S Proteasome of the Small Brown Planthopper via Direct Interaction with Regulatory Particle Non-ATPase Subunit 3

PubMed Central

Xu, Yi; Wu, Jianxiang; Fu, Shuai; Li, Chenyang; Zhu, Zeng-Rong

2015-01-01

ABSTRACT The ubiquitin/26S proteasome system plays a vital role in regulating host defenses against pathogens. Previous studies have highlighted different roles for the ubiquitin/26S proteasome in defense during virus infection in both mammals and plants, but their role in the vectors that transmit those viruses is still unclear. In this study, we determined that the 26S proteasome is present in the small brown planthopper (SBPH) (Laodelphgax striatellus) and has components similar to those in plants and mammals. There was an increase in the accumulation of Rice stripe virus (RSV) in the transmitting vector SBPH after disrupting the 26S proteasome, indicating that the SBPH 26S proteasome plays a role in defense against RSV infection by regulating RSV accumulation. Yeast two-hybrid analysis determined that a subunit of the 26S proteasome, named RPN3, could interact with RSV NS3. Transient overexpression of RPN3 had no effect on the RNA silencing suppressor activity of RSV NS3. However, NS3 could inhibit the ability of SBPH rpn3 to complement an rpn3 mutation in yeast. Our findings also indicate that the direct interaction between RPN3 and NS3 was responsible for inhibiting the complementation ability of RPN3. In vivo, we found an accumulation of ubiquitinated protein in SBPH tissues where the RSV titer was high, and silencing of rpn3 resulted in malfunction of the SBPH proteasome-mediated proteolysis. Consequently, viruliferous SBPH in which RPN3 was repressed transmitted the virus more effectively as a result of higher accumulation of RSV. Our results suggest that the RSV NS3 protein is able to hijack the 26S proteasome in SBPH via a direct interaction with the RPN3 subunit to attenuate the host defense response. IMPORTANCE We show, for the first time, that the 26S proteasome components are present in the small brown planthopper and play a role in defense against its vectored plant virus (RSV). In turn, RSV encodes a protein that subverts the SBPH 26S proteasome via direct interaction with the 26S proteasome subunit RPN3. Our results imply that the molecular arms race observed in plant hosts can be extended to the insect vector that transmits those viruses. PMID:25653432

Access to site-specific Fc–cRGD peptide conjugates through streamlined expressed protein ligation†

PubMed Central

Frutos, S.; Jordan, J. B.; Bio, M. M.; Muir, T. W.; Thiel, O. R.; Vila-Perelló, M.

2018-01-01

An ideal drug should be highly effective, non-toxic and be delivered by a convenient and painless single dose. We are still far from such optimal treatment but peptides, with their high target selectivity and low toxicity profiles, provide a very attractive platform from which to strive towards it. One of the major limitations of peptide drugs is their high clearance rates, which limit dosage regimen options. Conjugation to antibody Fc domains is a viable strategy to improve peptide stability by increasing their hydrodynamic radius and hijacking the Fc recycling pathway. We report the use of a split-intein based semi-synthetic approach to site-specifically conjugate a synthetic integrin binding peptide to an Fc domain. The strategy described here allows conjugating synthetic peptides to Fc domains, which is not possible via genetic methods, fully maintaining the ability of both the Fc domain and the bioactive peptide to interact with their binding partners. PMID:27722696

Biochemical basis for activation of virulence genes by bile salts in Vibrio parahaemolyticus

PubMed Central

2017-01-01

ABSTRACT Bile salts act as a stressor to bacteria that transit the intestinal tract. Enteric pathogens have hijacked bile as an intestinal signal to regulate virulence factors. We recently demonstrated that Vibrio parahemolyticus senses bile salts via a heterodimeric receptor formed by the periplasmic domains of inner-membrane proteins VtrA and VtrC. Crystal structures of the periplasmic complex reveal that VtrA and VtrC form a β-barrel that binds bile salts in its hydrophobic interior to activate the VtrA cytoplasmic DNA-binding domain. Proteins with the same domain arrangement as VtrA and VtrC are widespread in Vibrio and related bacteria, where they are involved in regulating virulence and other unknown functions. Here we discuss our findings and review current knowledge on VtrA and VtrC homologs. We propose that signaling by these membrane-bound transcription factors can be advantageous for the regulation of membrane and secretory proteins. PMID:28129014

Privilege and status in an unequal society: shifting the focus of health promotion research to include the maintenance of advantage.

PubMed

Stephens, Christine

2010-10-01

There has been a great deal of social policy and health promotion practice directed toward the inclusion of underprivileged groups with the aim of improving their health. This focus on disadvantaged people and poor communities, to help them empower themselves and improve their lot, often fails because it ignores the role of the broader society. We neglect to note the crucial part that the advantaged play in perpetuating inequalities. Theory and empirical work from sociology and anthropology points to the everyday ways in which privileged people are able to maintain their advantage and even hi-jack the benefits of public health programmes designed to improve the health of the poor. Some examples from these other disciplines suggest ways in which a social psychological perspective can contribute to an understanding of how inequalities and poverty are perpetuated in everyday life. These understandings will inform the effectiveness of social programmes to reduce inequalities.

Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle

PubMed Central

Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R.

2013-01-01

Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses. PMID:23657274

Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle.

PubMed

Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R

2013-01-01

Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses.

A specialist root herbivore exploits defensive metabolites to locate nutritious tissues

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

Erb M.; Babst B.; Robert, C.A.M.

2011-10-01

The most valuable organs of plants are often particularly rich in essential elements, but also very well defended. This creates a dilemma for herbivores that need to maximise energy intake while minimising intoxication. We investigated how the specialist root herbivore Diabrotica virgifera solves this conundrum when feeding on wild and cultivated maize plants. We found that crown roots of maize seedlings were vital for plant development and, in accordance, were rich in nutritious primary metabolites and contained higher amounts of the insecticidal 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) and the phenolic compound chlorogenic acid. The generalist herbivores Diabrotica balteata and Spodoptera littoralis were deterredmore » from feeding on crown roots, whereas the specialist D. virgifera preferred and grew best on these tissues. Using a 1,4-benzoxazin-3-one-deficient maize mutant, we found that D. virgifera is resistant to DIMBOA and other 1,4-benzoxazin-3-ones and that it even hijacks these compounds to optimally forage for nutritious roots.« less

Analysis of Ebola Virus Entry Into Macrophages

PubMed Central

Dahlmann, Franziska; Biedenkopf, Nadine; Babler, Anne; Jahnen-Dechent, Willi; Karsten, Christina B.; Gnirß, Kerstin; Schneider, Heike; Wrensch, Florian; O'Callaghan, Christopher A.; Bertram, Stephanie; Herrler, Georg; Becker, Stephan; Pöhlmann, Stefan; Hofmann-Winkler, Heike

2015-01-01

Ebolaviruses constitute a public health threat, particularly in Central and Western Africa. Host cell factors required for spread of ebolaviruses may serve as targets for antiviral intervention. Lectins, TAM receptor tyrosine kinases (Tyro3, Axl, Mer), T cell immunoglobulin and mucin domain (TIM) proteins, integrins, and Niemann-Pick C1 (NPC1) have been reported to promote entry of ebolaviruses into certain cellular systems. However, the factors used by ebolaviruses to invade macrophages, major viral targets, are poorly defined. Here, we show that mannose-specific lectins, TIM-1 and Axl augment entry into certain cell lines but do not contribute to Ebola virus (EBOV)-glycoprotein (GP)–driven transduction of macrophages. In contrast, expression of Mer, integrin αV, and NPC1 was required for efficient GP-mediated transduction and EBOV infection of macrophages. These results define cellular factors hijacked by EBOV for entry into macrophages and, considering that Mer and integrin αV promote phagocytosis of apoptotic cells, support the concept that EBOV relies on apoptotic mimicry to invade target cells. PMID:25877552

A multi-layered mechanistic modelling approach to understand how effector genes extend beyond phytoplasma to modulate plant hosts, insect vectors and the environment.

PubMed

Tomkins, Melissa; Kliot, Adi; Marée, Athanasius Fm; Hogenhout, Saskia A

2018-03-13

Members of the Candidatus genus Phytoplasma are small bacterial pathogens that hijack their plant hosts via the secretion of virulence proteins (effectors) leading to a fascinating array of plant phenotypes, such as witch's brooms (stem proliferations) and phyllody (retrograde development of flowers into vegetative tissues). Phytoplasma depend on insect vectors for transmission, and interestingly, these insect vectors were found to be (in)directly attracted to plants with these phenotypes. Therefore, phytoplasma effectors appear to reprogram plant development and defence to lure insect vectors, similarly to social engineering malware, which employs tricks to lure people to infected computers and webpages. A multi-layered mechanistic modelling approach will enable a better understanding of how phytoplasma effector-mediated modulations of plant host development and insect vector behaviour contribute to phytoplasma spread, and ultimately to predict the long reach of phytoplasma effector genes. Copyright © 2018. Published by Elsevier Ltd.

Comparative RNAi screening reveals host factors involved in enterovirus infection of polarized endothelial monolayers.

PubMed

Coyne, Carolyn B; Bozym, Rebecca; Morosky, Stefanie A; Hanna, Sheri L; Mukherjee, Amitava; Tudor, Matthew; Kim, Kwang Sik; Cherry, Sara

2011-01-20

Enteroviruses, including coxsackievirus B (CVB) and poliovirus (PV), can access the CNS through the blood brain barrier (BBB) endothelium to cause aseptic meningitis. To identify cellular components required for CVB and PV infection of human brain microvascular endothelial cells, an in vitro BBB model, we performed comparative RNAi screens and identified 117 genes that influenced infection. Whereas a large proportion of genes whose depletion enhanced infection (17 of 22) were broadly antienteroviral, only 46 of the 95 genes whose depletion inhibited infection were required by both CVB and PV and included components of cell signaling pathways such as adenylate cyclases. Downregulation of genes including Rab GTPases, Src tyrosine kinases, and tyrosine phosphatases displayed specificity in their requirement for either CVB or PV infection. These findings highlight the pathways hijacked by enteroviruses for entry and replication in the BBB endothelium, a specialized and clinically relevant cell type for these viruses. Copyright © 2011 Elsevier Inc. All rights reserved.

A Chemical-Genomic Screen of Neglected Antibiotics Reveals Illicit Transport of Kasugamycin and Blasticidin S

DOE PAGES

Shiver, Anthony L.; Osadnik, Hendrik; Kritikos, George; ...

2016-06-29

Fighting antibiotic resistance requires a deeper understanding of the genetic factors that determine the antibiotic susceptibility of bacteria. Here we describe a chemical-genomic screen in Escherichia coli K-12 that was designed to discover new aspects of antibiotic resistance by focusing on a set of 26 antibiotics and other stresses with poorly characterized mode-of-action and determinants of resistance. We show that the screen identifies new resistance determinants for these antibiotics including a common signature from two antimicrobials, kasugamycin and blasticidin S, used to treat crop diseases like rice blast and fire blight. Following this signature, we further investigated the mechanistic basismore » for susceptibility to kasugamycin and blasticidin S in E. coli using both genetic and biochemical approaches. We provide evidence that these compounds hijack an overlapping set of peptide ABC-importers to enter the bacterial cell. As a result, the loss of uptake may be an underappreciated mechanism for the development of kasugamycin resistance in bacterial plant pathogens.« less

The cell surface environment for pathogen recognition and entry.

PubMed

Stow, Jennifer L; Condon, Nicholas D

2016-04-01

The surface of mammalian cells offers an interface between the cell interior and its surrounding milieu. As part of the innate immune system, macrophages have cell surface features optimised for probing and sampling as they patrol our tissues for pathogens, debris or dead cells. Their highly dynamic and constantly moving cell surface has extensions such as lamellipodia, filopodia and dorsal ruffles that help detect pathogens. Dorsal ruffles give rise to macropinosomes for rapid, high volume non-selective fluid sampling, receptor internalisation and plasma membrane turnover. Ruffles can also generate phagocytic cups for the receptor-mediated uptake of pathogens or particles. The membrane lipids, actin cytoskeleton, receptors and signalling proteins that constitute these cell surface domains are discussed. Although the cell surface is designed to counteract pathogens, many bacteria, viruses and other pathogens have evolved to circumvent or hijack these cell structures and their underlying machinery for entry and survival. Nevertheless, these features offer important potential for developing vaccines, drugs and preventative measures to help fight infection.

Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective.

PubMed

Bechara, Antoine

2005-11-01

Here I argue that addicted people become unable to make drug-use choices on the basis of long-term outcome, and I propose a neural framework that explains this myopia for future consequences. I suggest that addiction is the product of an imbalance between two separate, but interacting, neural systems that control decision making: an impulsive, amygdala system for signaling pain or pleasure of immediate prospects, and a reflective, prefrontal cortex system for signaling pain or pleasure of future prospects. After an individual learns social rules, the reflective system controls the impulsive system via several mechanisms. However, this control is not absolute; hyperactivity within the impulsive system can override the reflective system. I propose that drugs can trigger bottom-up, involuntary signals originating from the amygdala that modulate, bias or even hijack the goal-driven cognitive resources that are needed for the normal operation of the reflective system and for exercising the willpower to resist drugs.

Leishmania infantum Modulates Host Macrophage Mitochondrial Metabolism by Hijacking the SIRT1-AMPK Axis

PubMed Central

Moreira, Diana; Rodrigues, Vasco; Abengozar, Maria; Rivas, Luis; Rial, Eduardo; Laforge, Mireille; Li, Xiaoling; Foretz, Marc; Viollet, Benoit; Estaquier, Jérôme; Cordeiro da Silva, Anabela; Silvestre, Ricardo

2015-01-01

Metabolic manipulation of host cells by intracellular pathogens is currently recognized to play an important role in the pathology of infection. Nevertheless, little information is available regarding mitochondrial energy metabolism in Leishmania infected macrophages. Here, we demonstrate that during L. infantum infection, macrophages switch from an early glycolytic metabolism to an oxidative phosphorylation, and this metabolic deviation requires SIRT1 and LKB1/AMPK. SIRT1 or LBK1 deficient macrophages infected with L. infantum failed to activate AMPK and up-regulate its targets such as Slc2a4 and Ppargc1a, which are essential for parasite growth. As a result, impairment of metabolic switch caused by SIRT1 or AMPK deficiency reduces parasite load in vitro and in vivo. Overall, our work demonstrates the importance of SIRT1 and AMPK energetic sensors for parasite intracellular survival and proliferation, highlighting the modulation of these proteins as potential therapeutic targets for the treatment of leishmaniasis. PMID:25738568

AMPK in Pathogens.

PubMed

Mesquita, Inês; Moreira, Diana; Sampaio-Marques, Belém; Laforge, Mireille; Cordeiro-da-Silva, Anabela; Ludovico, Paula; Estaquier, Jérôme; Silvestre, Ricardo

2016-01-01

During host-pathogen interactions, a complex web of events is crucial for the outcome of infection. Pathogen recognition triggers powerful cellular signaling events that is translated into the induction and maintenance of innate and adaptive host immunity against infection. In opposition, pathogens employ active mechanisms to manipulate host cell regulatory pathways toward their proliferation and survival. Among these, subversion of host cell energy metabolism by pathogens is currently recognized to play an important role in microbial growth and persistence. Extensive studies have documented the role of AMP-activated protein kinase (AMPK) signaling, a central cellular hub involved in the regulation of energy homeostasis, in host-pathogen interactions. Here, we highlight the most recent advances detailing how pathogens hijack cellular metabolism by suppressing or increasing the activity of the host energy sensor AMPK. We also address the role of lower eukaryote AMPK orthologues in the adaptive process to the host microenvironment and their contribution for pathogen survival, differentiation, and growth. Finally, we review the effects of pharmacological or genetic AMPK modulation on pathogen growth and persistence.

The Proteome of the Isolated Chlamydia trachomatis Containing Vacuole Reveals a Complex Trafficking Platform Enriched for Retromer Components

PubMed Central

Fischer, Martina; Jehmlich, Nico; Rose, Laura; Koch, Sophia; Laue, Michael; Renard, Bernhard Y.; Schmidt, Frank; Heuer, Dagmar

2015-01-01

Chlamydia trachomatis is an important human pathogen that replicates inside the infected host cell in a unique vacuole, the inclusion. The formation of this intracellular bacterial niche is essential for productive Chlamydia infections. Despite its importance for Chlamydia biology, a holistic view on the protein composition of the inclusion, including its membrane, is currently missing. Here we describe the host cell-derived proteome of isolated C. trachomatis inclusions by quantitative proteomics. Computational analysis indicated that the inclusion is a complex intracellular trafficking platform that interacts with host cells’ antero- and retrograde trafficking pathways. Furthermore, the inclusion is highly enriched for sorting nexins of the SNX-BAR retromer, a complex essential for retrograde trafficking. Functional studies showed that in particular, SNX5 controls the C. trachomatis infection and that retrograde trafficking is essential for infectious progeny formation. In summary, these findings suggest that C. trachomatis hijacks retrograde pathways for effective infection. PMID:26042774

From amoeba to macrophages: exploring the molecular mechanisms of Legionella pneumophila infection in both hosts.

PubMed

Escoll, Pedro; Rolando, Monica; Gomez-Valero, Laura; Buchrieser, Carmen

2013-01-01

Legionella pneumophila is a Gram-negative bacterium and the causative agent of Legionnaires' disease. It replicates within amoeba and infects accidentally human macrophages. Several similarities are seen in the L. pneumophila-infection cycle in both hosts, suggesting that the tools necessary for macrophage infection may have evolved during co-evolution of L. pneumophila and amoeba. The establishment of the Legionella-containing vacuole (LCV) within the host cytoplasm requires the remodeling of the LCV surface and the hijacking of vesicles and organelles. Then L. pneumophila replicates in a safe intracellular niche in amoeba and macrophages. In this review we will summarize the existing knowledge of the L. pneumophila infection cycle in both hosts at the molecular level and compare the factors involved within amoeba and macrophages. This knowledge will be discussed in the light of recent findings from the Acanthamoeba castellanii genome analyses suggesting the existence of a primitive immune-like system in amoeba.

[Parasites and cancer: is there a causal link?

PubMed

Cheeseman, Kevin; Certad, Gabriela; Weitzman, Jonathan B

2016-10-01

Over 20 % of cancers have infectious origins, including well-known examples of microbes such as viruses (HPV, EBV) and bacteria (H. pylori). The contribution of intracellular eukaryotic parasites to cancer etiology is largely unexplored. Epidemiological and clinical reports indicate that eukaryotic protozoan, such as intracellular apicomplexan that cause diseases of medical or economic importance, can be linked to various cancers: Theileria and Cryptosporidium induce host cell transformation while Plasmodium was linked epidemiologically to the "African lymphoma belt" over fifty years ago. These intracellular eukaryotic parasites hijack cellular pathways to manipulate the host cell epigenome, cellular machinery, signaling pathways and epigenetic programs and marks, such as methylation and acetylation, for their own benefit. In doing so, they tinker with the same pathways as those deregulated during cancer onset. Here we discuss how epidemiological evidence linking eukaryotic intracellular parasites to cancer onset are further strengthened by recent mechanistic studies in three apicomplexan parasites. © 2016 médecine/sciences – Inserm.

Current and potential cyber attacks on medical journals; guidelines for improving security.

PubMed

Dadkhah, Mehdi; Seno, Seyed Amin Hosseini; Borchardt, Glenn

2017-03-01

At the moment, scholarly publishing is faced with much academic misconduct and threats such as predatory journals, hijacked journals, phishing, and other scams. In response, we have been discussing this misconduct and trying to increase the awareness of researchers, but it seems that there is a lack of research that presents guidelines for editors to help them protect themselves against these threats. It seems that information security is missing in some parts of scholarly publishing that particularly involves medical journals. In this paper, we explain different types of cyber-attacks that especially threaten editors and academic journals. We then explain the details involved in each type of attack. Finally, we present general guidelines for detection and prevention of the attacks. In some cases, we use small experiments to show that our claim is true. Finally, we conclude the paper with a prioritization of these attacks. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

The influenza fingerprints: NS1 and M1 proteins contribute to specific host cell ultrastructure signatures upon infection by different influenza A viruses

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

Terrier, Olivier; Moules, Vincent; Carron, Coralie

Influenza A are nuclear replicating viruses which hijack host machineries in order to achieve optimal infection. Numerous functional virus-host interactions have now been characterized, but little information has been gathered concerning their link to the virally induced remodeling of the host cellular architecture. In this study, we infected cells with several human and avian influenza viruses and we have analyzed their ultrastructural modifications by using electron and confocal microscopy. We discovered that infections lead to a major and systematic disruption of nucleoli and the formation of a large number of diverse viral structures showing specificity that depended on the subtypemore » origin and genomic composition of viruses. We identified NS1 and M1 proteins as the main actors in the remodeling of the host ultra-structure and our results suggest that each influenza A virus strain could be associated with a specific cellular fingerprint, possibly correlated to the functional properties of their viral components.« less

The antibiotic CJ-15,801 is an antimetabolite that hijacks and then inhibits CoA biosynthesis.

PubMed

van der Westhuyzen, Renier; Hammons, Justin C; Meier, Jordan L; Dahesh, Samira; Moolman, Wessel J A; Pelly, Stephen C; Nizet, Victor; Burkart, Michael D; Strauss, Erick

2012-05-25

The natural product CJ-15,801 is an inhibitor of Staphylococcus aureus, but not other bacteria. Its close structural resemblance to pantothenic acid, the vitamin precursor of coenzyme A (CoA), and its Michael acceptor moiety suggest that it irreversibly inhibits an enzyme involved in CoA biosynthesis or utilization. However, its mode of action and the basis for its specificity have not been elucidated to date. We demonstrate that CJ-15,801 is transformed by the uniquely selective S. aureus pantothenate kinase, the first CoA biosynthetic enzyme, into a substrate for the next enzyme, phosphopantothenoylcysteine synthetase, which is inhibited through formation of a tight-binding structural mimic of its native reaction intermediate. These findings reveal CJ-15,801 as a vitamin biosynthetic pathway antimetabolite with a mechanism similar to that of the sulfonamide antibiotics and highlight CoA biosynthesis as a viable antimicrobial drug target. Copyright © 2012 Elsevier Ltd. All rights reserved.

Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses.

PubMed

Soares, Helena; Lasserre, Rémi; Alcover, Andrés

2013-11-01

Immunological synapses are specialized cell-cell contacts formed between T lymphocytes and antigen-presenting cells. They are induced upon antigen recognition and are crucial for T-cell activation and effector functions. The generation and function of immunological synapses depend on an active T-cell polarization process, which results from a finely orchestrated crosstalk between the antigen receptor signal transduction machinery, the actin and microtubule cytoskeletons, and controlled vesicle traffic. Although we understand how some of these particular events are regulated, we still lack knowledge on how these multiple cellular elements are harmonized to ensure appropriate T-cell responses. We discuss here our view on how T-cell receptor signal transduction initially commands cytoskeletal and vesicle traffic polarization, which in turn sets the immunological synapse molecular design that regulates T-cell activation. We also discuss how the human immunodeficiency virus (HIV-1) hijacks some of these processes impairing immunological synapse generation and function. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections

PubMed Central

El-Aouar Filho, Rachid A.; Nicolas, Aurélie; De Paula Castro, Thiago L.; Deplanche, Martine; De Carvalho Azevedo, Vasco A.; Goossens, Pierre L.; Taieb, Frédéric; Lina, Gerard; Le Loir, Yves; Berkova, Nadia

2017-01-01

Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of actions of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, γ-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating cytotoxin, cytotoxic necrotizing factor, Panton-Valentine leukocidin, phenol soluble modulins, and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host. PMID:28589102

Coupled Activation of Primary Sensory Neurons Contributes to Chronic Pain.

PubMed

Kim, Yu Shin; Anderson, Michael; Park, Kyoungsook; Zheng, Qin; Agarwal, Amit; Gong, Catherine; Saijilafu; Young, LeAnne; He, Shaoqiu; LaVinka, Pamela Colleen; Zhou, Fengquan; Bergles, Dwight; Hanani, Menachem; Guan, Yun; Spray, David C; Dong, Xinzhong

2016-09-07

Primary sensory neurons in the DRG play an essential role in initiating pain by detecting painful stimuli in the periphery. Tissue injury can sensitize DRG neurons, causing heightened pain sensitivity, often leading to chronic pain. Despite the functional importance, how DRG neurons function at a population level is unclear due to the lack of suitable tools. Here we developed an imaging technique that allowed us to simultaneously monitor the activities of >1,600 neurons/DRG in live mice and discovered a striking neuronal coupling phenomenon that adjacent neurons tend to activate together following tissue injury. This coupled activation occurs among various neurons and is mediated by an injury-induced upregulation of gap junctions in glial cells surrounding DRG neurons. Blocking gap junctions attenuated neuronal coupling and mechanical hyperalgesia. Therefore, neuronal coupling represents a new form of neuronal plasticity in the DRG and contributes to pain hypersensitivity by "hijacking" neighboring neurons through gap junctions. Copyright © 2016 Elsevier Inc. All rights reserved.

Tuning cancer fate: the unremitting role of host immunity

PubMed Central

Molon, B.; Viola, A.

2017-01-01

Host immunity plays a central and complex role in dictating tumour progression. Solid tumours are commonly infiltrated by a large number of immune cells that dynamically interact with the surrounding microenvironment. At first, innate and adaptive immune cells successfully cooperate to eradicate microcolonies of transformed cells. Concomitantly, surviving tumour clones start to proliferate and harness immune responses by specifically hijacking anti-tumour effector mechanisms and fostering the accumulation of immunosuppressive immune cell subsets at the tumour site. This pliable interplay between immune and malignant cells is a relentless process that has been concisely organized in three different phases: elimination, equilibrium and escape. In this review, we aim to depict the distinct immune cell subsets and immune-mediated responses characterizing the tumour landscape throughout the three interconnected phases. Importantly, the identification of key immune players and molecules involved in the dynamic crosstalk between tumour and immune system has been crucial for the introduction of reliable prognostic factors and effective therapeutic protocols against cancers. PMID:28404796

Getting the “kill” into “shock and kill”: strategies to eliminate latent HIV

PubMed Central

Kim, Youry; Anderson, Jenny L.; Lewin, Sharon R.

2018-01-01

Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is lifelong. HIV persists during ART due to long lived and proliferating latently infected CD4+ T-cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection. PMID:29324227

A Competitive Stapled Peptide Screen Identifies a Selective Small Molecule that Overcomes MCL-1-dependent Leukemia Cell Survival

PubMed Central

Cohen, Nicole A.; Stewart, Michelle L.; Gavathiotis, Evripidis; Tepper, Jared L.; Bruekner, Susanne R.; Koss, Brian; Opferman, Joseph T.; Walensky, Loren D.

2012-01-01

SUMMARY Cancer cells hijack BCL-2 family survival proteins to suppress the death effectors and thereby enforce an immortal state. This is accomplished biochemically by an anti-apoptotic surface groove that neutralizes the pro-apoptotic BH3 α-helix of death proteins. Anti-apoptotic MCL-1 in particular has emerged as a ubiquitous resistance factor in cancer. Whereas targeting the BCL-2 anti-apoptotic subclass effectively restores the death pathway in BCL-2-dependent cancer, the development of molecules tailored to the binding specificity of MCL-1 has lagged. We previously discovered that a hydrocarbon-stapled MCL-1 BH3 helix is an exquisitely selective MCL-1 antagonist. By deploying this unique reagent in a competitive screen, we identified an MCL-1 inhibitor molecule that selectively targets the BH3-binding groove of MCL-1, neutralizes its biochemical lockhold on apoptosis, and induces caspase activation and leukemia cell death in the specific context of MCL-1 dependence. PMID:22999885

The whole-genome landscape of medulloblastoma subtypes.

PubMed

Northcott, Paul A; Buchhalter, Ivo; Morrissy, A Sorana; Hovestadt, Volker; Weischenfeldt, Joachim; Ehrenberger, Tobias; Gröbner, Susanne; Segura-Wang, Maia; Zichner, Thomas; Rudneva, Vasilisa A; Warnatz, Hans-Jörg; Sidiropoulos, Nikos; Phillips, Aaron H; Schumacher, Steven; Kleinheinz, Kortine; Waszak, Sebastian M; Erkek, Serap; Jones, David T W; Worst, Barbara C; Kool, Marcel; Zapatka, Marc; Jäger, Natalie; Chavez, Lukas; Hutter, Barbara; Bieg, Matthias; Paramasivam, Nagarajan; Heinold, Michael; Gu, Zuguang; Ishaque, Naveed; Jäger-Schmidt, Christina; Imbusch, Charles D; Jugold, Alke; Hübschmann, Daniel; Risch, Thomas; Amstislavskiy, Vyacheslav; Gonzalez, Francisco German Rodriguez; Weber, Ursula D; Wolf, Stephan; Robinson, Giles W; Zhou, Xin; Wu, Gang; Finkelstein, David; Liu, Yanling; Cavalli, Florence M G; Luu, Betty; Ramaswamy, Vijay; Wu, Xiaochong; Koster, Jan; Ryzhova, Marina; Cho, Yoon-Jae; Pomeroy, Scott L; Herold-Mende, Christel; Schuhmann, Martin; Ebinger, Martin; Liau, Linda M; Mora, Jaume; McLendon, Roger E; Jabado, Nada; Kumabe, Toshihiro; Chuah, Eric; Ma, Yussanne; Moore, Richard A; Mungall, Andrew J; Mungall, Karen L; Thiessen, Nina; Tse, Kane; Wong, Tina; Jones, Steven J M; Witt, Olaf; Milde, Till; Von Deimling, Andreas; Capper, David; Korshunov, Andrey; Yaspo, Marie-Laure; Kriwacki, Richard; Gajjar, Amar; Zhang, Jinghui; Beroukhim, Rameen; Fraenkel, Ernest; Korbel, Jan O; Brors, Benedikt; Schlesner, Matthias; Eils, Roland; Marra, Marco A; Pfister, Stefan M; Taylor, Michael D; Lichter, Peter

2017-07-19

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

The mechanisms of neurotoxicity and the selective vulnerability of nervous system sites.

PubMed

Maurer, Laura L; Philbert, Martin A

2015-01-01

The spatial heterogeneity of the structure, function, and cellular composition of the nervous system confers extraordinary complexity and a multiplicity of mechanisms of chemical neurotoxicity. Because of its relatively high metabolic demands and functional dependence on postmitotic neurons, the nervous system is vulnerable to a variety of xenobiotics that affect essential homeostatic mechanisms that support function. Despite protection from the neuroglia and blood-brain barrier, the central nervous system is prone to attack from lipophilic toxicants and those that hijack endogenous transport, receptor, metabolic, and other biochemical systems. The inherent predilection of chemicals for highly conserved biochemical systems confers selective vulnerability of the nervous system to neurotoxicants. This chapter discusses selective vulnerability of the nervous system in the context of neuron-specific decrements (axonopathy, myelinopathy, disruption of neurotransmission), and the degree to which neuronal damage is facilitated or ameliorated by surrounding nonneural cells in both the central and peripheral nervous systems. © 2015 Elsevier B.V. All rights reserved.

A Chemical-Genomic Screen of Neglected Antibiotics Reveals Illicit Transport of Kasugamycin and Blasticidin S

PubMed Central

Shiver, Anthony L.; Kritikos, George; Li, Bo; Krogan, Nevan; Typas, Athanasios

2016-01-01

Fighting antibiotic resistance requires a deeper understanding of the genetic factors that determine the antibiotic susceptibility of bacteria. Here we describe a chemical-genomic screen in Escherichia coli K-12 that was designed to discover new aspects of antibiotic resistance by focusing on a set of 26 antibiotics and other stresses with poorly characterized mode-of-action and determinants of resistance. We show that the screen identifies new resistance determinants for these antibiotics including a common signature from two antimicrobials, kasugamycin and blasticidin S, used to treat crop diseases like rice blast and fire blight. Following this signature, we further investigated the mechanistic basis for susceptibility to kasugamycin and blasticidin S in E. coli using both genetic and biochemical approaches. We provide evidence that these compounds hijack an overlapping set of peptide ABC-importers to enter the bacterial cell. Loss of uptake may be an underappreciated mechanism for the development of kasugamycin resistance in bacterial plant pathogens. PMID:27355376

Production of ω-hydroxy octanoic acid with Escherichia coli.

PubMed

Kirtz, Marko; Klebensberger, Janosch; Otte, Konrad B; Richter, Sven M; Hauer, Bernhard

2016-07-20

The present proof-of-concept study reports the construction of a whole-cell biocatalyst for the de novo production of ω-hydroxy octanoic acid. This was achieved by hijacking the natural fatty acid cycle and subsequent hydroxylation using a specific monooxygenase without the need for the additional feed of alkene-like precursors. For this, we used the model organism Escherichia coli and increased primarily the release of the octanoic acid precursors by overexpressing the plant thioesterase FatB2 from Cuphea hookeriana in a β-oxidation deficient strain, which lead to the production of 2.32mM (8.38mggcww(-1)) octanoic acid in 24h. In order to produce the corresponding ω-hydroxy derivative, we additionally expressed the engineered self-sufficient monooxygenase fusion protein CYP153AMaq(G307A)-CPRBM3 within the octanoic acid producing strain. With this, we finally produced 234μM (0.95mggcww(-1)) ω-hydroxy octanoic acid in a 20h fed-batch set-up. Copyright © 2016 Elsevier B.V. All rights reserved.

Viral infection and human disease - insights from minimotifs

PubMed Central

Kadaveru, Krishna; Vyas, Jay; Schiller, Martin R.

2008-01-01

Short functional peptide motifs cooperate in many molecular functions including protein interactions, protein trafficking, and posttranslational modifications. Viruses exploit these motifs as a principal mechanism for hijacking cells and many motifs are necessary for the viral life-cycle. A virus can accommodate many short motifs in its small genome size providing a plethora of ways for the virus to acquire host molecular machinery. Host enzymes that act on motifs such as kinases, proteases, and lipidation enzymes, as well as protein interaction domains, are commonly mutated in human disease, suggesting that the short peptide motif targets of these enzymes may also be mutated in disease; however, this is not observed. How can we explain why viruses have evolved to be so dependent on motifs, yet these motifs, in general do not seem to be as necessary for human viability? We propose that short motifs are used at the system level. This system architecture allows viruses to exploit a motif, whereas the viability of the host is not affected by mutation of a single motif. PMID:18508672

Profile of pembrolizumab in the treatment of head and neck squamous cell carcinoma: design development and place in therapy

PubMed Central

Haque, Sulsal; Yellu, Mahender; Randhawa, Jaskirat; Hashemi-Sadraei, Nooshin

2017-01-01

Head and neck squamous cell cancer (HNSCC) is the sixth most common malignancy worldwide, and despite advances in cytotoxic, surgical and radiation techniques, outcomes are still poor in those with both locally advanced and metastatic diseases. The need for development of better therapeutics along with a greater understanding of the relationship between the immune system and malignancies has led to a new therapeutic modality, immune modulators, particularly checkpoint inhibitors in HNSCC. It is now well recognized that HNSCC circumvents crucial pathways utilized by the immune system to escape surveillance. These hijacked pathways include impairing tumor antigen presentation machinery and co-opting checkpoint receptors. This understanding has led to the development of monoclonal antibodies targeting checkpoint receptors and has resulted in promising outcomes in HNSCC. This article describes the mechanisms that HNSCC utilizes to escape immune surveillance, clinical impact of checkpoint inhibitors (with a focus on pembrolizumab), ongoing studies, and future directions. PMID:28919706

Escherichia coli K1 utilizes host macropinocytic pathways for invasion of brain microvascular endothelial cells.

PubMed

Loh, Lip Nam; McCarthy, Elizabeth M C; Narang, Priyanka; Khan, Naveed A; Ward, Theresa H

2017-11-01

Eukaryotic cells utilize multiple endocytic pathways for specific uptake of ligands or molecules, and these pathways are commonly hijacked by pathogens to enable host cell invasion. Escherichia coli K1, a pathogenic bacterium that causes neonatal meningitis, invades the endothelium of the blood-brain barrier, but the entry route remains unclear. Here, we demonstrate that the bacteria trigger an actin-mediated uptake route, stimulating fluid phase uptake, membrane ruffling and macropinocytosis. The route of uptake requires intact lipid rafts as shown by cholesterol depletion. Using a variety of perturbants we demonstrate that small Rho GTPases and their downstream effectors have a significant effect on bacterial invasion. Furthermore, clathrin-mediated endocytosis appears to play an indirect role in E. coli K1 uptake. The data suggest that the bacteria effect a complex interplay between the Rho GTPases to increase their chances of uptake by macropinocytosis into human brain microvascular endothelial cells. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The PPE2 protein of Mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production

PubMed Central

Bhat, Khalid Hussain; Srivastava, Shruti; Kotturu, Sandeep Kumar; Ghosh, Sudip; Mukhopadhyay, Sangita

2017-01-01

Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is one of the most successful pathogens of humans. It has evolved several adaptive skills and evasion mechanisms to hijack the immunologically educated host to suit its intracellular lifestyle. Here, we show that one of the unique PPE family member proteins of M. tuberculosis, PPE2, can limit nitric oxide (NO) production by inhibiting inos gene transcription. PPE2 protein has a leucine zipper DNA-binding motif and a functional nuclear localization signal. PPE2 was translocated into the macrophage nucleus via the classical importin α/β pathway where it interacted with a GATA-binding site overlapping with the TATA box of inos promoter and inhibited NO production. PPE2 prolonged intracellular survival of a surrogate bacterium M. smegmatis in vitro as well as in vivo. This information are likely to improve our knowledge of host-pathogen interactions during M. tuberculosis infection which is crucial for designing effective anti-TB therapeutics. PMID:28071726

A Chemical-Genomic Screen of Neglected Antibiotics Reveals Illicit Transport of Kasugamycin and Blasticidin S

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

Shiver, Anthony L.; Osadnik, Hendrik; Kritikos, George

Fighting antibiotic resistance requires a deeper understanding of the genetic factors that determine the antibiotic susceptibility of bacteria. Here we describe a chemical-genomic screen in Escherichia coli K-12 that was designed to discover new aspects of antibiotic resistance by focusing on a set of 26 antibiotics and other stresses with poorly characterized mode-of-action and determinants of resistance. We show that the screen identifies new resistance determinants for these antibiotics including a common signature from two antimicrobials, kasugamycin and blasticidin S, used to treat crop diseases like rice blast and fire blight. Following this signature, we further investigated the mechanistic basismore » for susceptibility to kasugamycin and blasticidin S in E. coli using both genetic and biochemical approaches. We provide evidence that these compounds hijack an overlapping set of peptide ABC-importers to enter the bacterial cell. As a result, the loss of uptake may be an underappreciated mechanism for the development of kasugamycin resistance in bacterial plant pathogens.« less

Canonical and Non-Canonical Autophagy in HIV-1 Replication Cycle

PubMed Central

Leymarie, Olivier; Lepont, Leslie; Berlioz-Torrent, Clarisse

2017-01-01

Autophagy is a lysosomal-dependent degradative process essential for maintaining cellular homeostasis, and is a key player in innate and adaptive immune responses to intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). In HIV-1 target cells, autophagy mechanisms can (i) selectively direct viral proteins and viruses for degradation; (ii) participate in the processing and presentation of viral-derived antigens through major histocompatibility complexes; and (iii) contribute to interferon production in response to HIV-1 infection. As a consequence, HIV-1 has evolved different strategies to finely regulate the autophagy pathway to favor its replication and dissemination. HIV-1 notably encodes accessory genes encoding Tat, Nef and Vpu proteins, which are able to perturb and hijack canonical and non-canonical autophagy mechanisms. This review outlines the current knowledge on the complex interplay between autophagy and HIV-1 replication cycle, providing an overview of the autophagy-mediated molecular processes deployed both by infected cells to combat the virus and by HIV-1 to evade antiviral response. PMID:28946621

Immunomodulatory effects of exosomes produced by virus-infected cells.

PubMed

Petrik, Juraj

2016-08-01

Viruses have developed a spectrum of ways to modify cellular pathways to hijack the cell machinery for the synthesis of their nucleic acid and proteins. Similarly, they use intracellular vesicular mechanisms of trafficking for their assembly and eventual release, with a number of viruses acquiring their envelope from internal or plasma cell membranes. There is an increasing number of reports on viral exploitation of cell secretome pathways to avoid recognition and stimulation of the immune response. Extracellular vesicles (EV) containing viral particles have been shown to shield viruses after exiting the host cell, in some cases challenging the boundaries between viral groups traditionally characterised as enveloped and non-enveloped. Apart from viral particles, EV can spread the virus also carrying viral genome and can modify the target cells through their cargo of virus-coded miRNAs and proteins as well as selectively packaged cellular mRNAs, miRNAs, proteins and lipids, differing in composition and quantities from the cell of origin. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Wholly Rickettsia! Reconstructed Metabolic Profile of the Quintessential Bacterial Parasite of Eukaryotic Cells.

PubMed

Driscoll, Timothy P; Verhoeve, Victoria I; Guillotte, Mark L; Lehman, Stephanie S; Rennoll, Sherri A; Beier-Sexton, Magda; Rahman, M Sayeedur; Azad, Abdu F; Gillespie, Joseph J

2017-09-26

Reductive genome evolution has purged many metabolic pathways from obligate intracellular Rickettsia ( Alphaproteobacteria ; Rickettsiaceae ). While some aspects of host-dependent rickettsial metabolism have been characterized, the array of host-acquired metabolites and their cognate transporters remains unknown. This dearth of information has thwarted efforts to obtain an axenic Rickettsia culture, a major impediment to conventional genetic approaches. Using phylogenomics and computational pathway analysis, we reconstructed the Rickettsia metabolic and transport network, identifying 51 host-acquired metabolites (only 21 previously characterized) needed to compensate for degraded biosynthesis pathways. In the absence of glycolysis and the pentose phosphate pathway, cell envelope glycoconjugates are synthesized from three imported host sugars, with a range of additional host-acquired metabolites fueling the tricarboxylic acid cycle. Fatty acid and glycerophospholipid pathways also initiate from host precursors, and import of both isoprenes and terpenoids is required for the synthesis of ubiquinone and the lipid carrier of lipid I and O-antigen. Unlike metabolite-provisioning bacterial symbionts of arthropods, rickettsiae cannot synthesize B vitamins or most other cofactors, accentuating their parasitic nature. Six biosynthesis pathways contain holes (missing enzymes); similar patterns in taxonomically diverse bacteria suggest alternative enzymes that await discovery. A paucity of characterized and predicted transporters emphasizes the knowledge gap concerning how rickettsiae import host metabolites, some of which are large and not known to be transported by bacteria. Collectively, our reconstructed metabolic network offers clues to how rickettsiae hijack host metabolic pathways. This blueprint for growth determinants is an important step toward the design of axenic media to rescue rickettsiae from the eukaryotic cell. IMPORTANCE A hallmark of obligate intracellular bacteria is the tradeoff of metabolic genes for the ability to acquire host metabolites. For species of Rickettsia , arthropod-borne parasites with the potential to cause serious human disease, the range of pilfered host metabolites is unknown. This information is critical for dissociating rickettsiae from eukaryotic cells to facilitate rickettsial genetic manipulation. In this study, we reconstructed the Rickettsia metabolic network and identified 51 host metabolites required to compensate patchwork Rickettsia biosynthesis pathways. Remarkably, some metabolites are not known to be transported by any bacteria, and overall, few cognate transporters were identified. Several pathways contain missing enzymes, yet similar pathways in unrelated bacteria indicate convergence and possible novel enzymes awaiting characterization. Our work illuminates the parasitic nature by which rickettsiae hijack host metabolism to counterbalance numerous disintegrated biosynthesis pathways that have arisen through evolution within the eukaryotic cell. This metabolic blueprint reveals what a Rickettsia axenic medium might entail. Copyright © 2017 Driscoll et al.

AMP-activated Protein Kinase As a Target For Pathogens: Friends Or Foes?

PubMed

Moreira, Diana; Silvestre, Ricardo; Cordeiro-da-Silva, Anabela; Estaquier, Jérôme; Foretz, Marc; Viollet, Benoit

2016-01-01

Intracellular pathogens are known to manipulate host cell regulatory pathways to establish an optimal environment for their growth and survival. Pathogens employ active mechanisms to hijack host cell metabolism and acquire existing nutrient and energy store. The role of the cellular energy sensor AMP-activated protein kinase (AMPK) in the regulation of cellular energy homeostasis is well documented. Here, we highlight recent advances showing the importance of AMPK signaling in pathogen-host interactions. Pathogens interact with AMPK by a variety of mechanisms aimed at reprogramming host cell metabolism to their own benefit. Stimulation of AMPK activity provides an efficient process to rapidly adapt pathogen metabolism to the major nutritional changes often encountered during the different phases of infection. However, inhibition of AMPK is also used by pathogens to manipulate innate host response, indicating that AMPK appears relevant to restriction of pathogen infection. We also document the effects of pharmacological AMPK modulators on pathogen proliferation and survival. This review illustrates intricate pathogen-AMPK interactions that may be exploited to the development of novel anti-pathogen therapies.

The Cancer Cell Map Initiative: Defining the Hallmark Networks of Cancer

PubMed Central

Krogan, Nevan J.; Lippman, Scott; Agard, David A.; Ashworth, Alan; Ideker, Trey

2017-01-01

Progress in DNA sequencing has revealed the startling complexity of cancer genomes, which typically carry thousands of somatic mutations. However, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathogenesis and response to therapy. Although tumors of similar types and clinical outcomes can have patterns of mutations that are strikingly different, it is becoming apparent that these mutations recurrently hijack the same hallmark molecular pathways and networks. For this reason, it is likely that successful interpretation of cancer genomes will require comprehensive knowledge of the molecular networks under selective pressure in oncogenesis. Here we announce the creation of a new effort, called The Cancer Cell Map Initiative (CCMI), aimed at systematically detailing these complex interactions among cancer genes and how they differ between diseased and healthy states. We discuss recent progress that enables creation of these Cancer Cell Maps across a range of tumor types and how they can be used to target networks disrupted in individual patients, significantly accelerating the development of precision medicine. PMID:26000852

The cancer cell map initiative: defining the hallmark networks of cancer.

PubMed

Krogan, Nevan J; Lippman, Scott; Agard, David A; Ashworth, Alan; Ideker, Trey

2015-05-21

Progress in DNA sequencing has revealed the startling complexity of cancer genomes, which typically carry thousands of somatic mutations. However, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathogenesis and response to therapy. Although tumors of similar types and clinical outcomes can have patterns of mutations that are strikingly different, it is becoming apparent that these mutations recurrently hijack the same hallmark molecular pathways and networks. For this reason, it is likely that successful interpretation of cancer genomes will require comprehensive knowledge of the molecular networks under selective pressure in oncogenesis. Here we announce the creation of a new effort, The Cancer Cell Map Initiative (CCMI), aimed at systematically detailing these complex interactions among cancer genes and how they differ between diseased and healthy states. We discuss recent progress that enables creation of these cancer cell maps across a range of tumor types and how they can be used to target networks disrupted in individual patients, significantly accelerating the development of precision medicine. Copyright © 2015 Elsevier Inc. All rights reserved.

Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin.

PubMed

Nikitas, Georgios; Deschamps, Chantal; Disson, Olivier; Niault, Théodora; Cossart, Pascale; Lecuit, Marc

2011-10-24

Listeria monocytogenes (Lm) is a foodborne pathogen that crosses the intestinal barrier upon interaction between its surface protein InlA and its species-specific host receptor E-cadherin (Ecad). Ecad, the key constituent of adherens junctions, is typically situated below tight junctions and therefore considered inaccessible from the intestinal lumen. In this study, we investigated how Lm specifically targets its receptor on intestinal villi and crosses the intestinal epithelium to disseminate systemically. We demonstrate that Ecad is luminally accessible around mucus-expelling goblet cells (GCs), around extruding enterocytes at the tip and lateral sides of villi, and in villus epithelial folds. We show that upon preferential adherence to accessible Ecad on GCs, Lm is internalized, rapidly transcytosed across the intestinal epithelium, and released in the lamina propria by exocytosis from where it disseminates systemically. Together, these results show that Lm exploits intrinsic tissue heterogeneity to access its receptor and reveal transcytosis as a novel and unanticipated pathway that is hijacked by Lm to breach the intestinal epithelium and cause systemic infection.

Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin

PubMed Central

Nikitas, Georgios; Deschamps, Chantal; Disson, Olivier; Niault, Théodora; Cossart, Pascale

2011-01-01

Listeria monocytogenes (Lm) is a foodborne pathogen that crosses the intestinal barrier upon interaction between its surface protein InlA and its species-specific host receptor E-cadherin (Ecad). Ecad, the key constituent of adherens junctions, is typically situated below tight junctions and therefore considered inaccessible from the intestinal lumen. In this study, we investigated how Lm specifically targets its receptor on intestinal villi and crosses the intestinal epithelium to disseminate systemically. We demonstrate that Ecad is luminally accessible around mucus-expelling goblet cells (GCs), around extruding enterocytes at the tip and lateral sides of villi, and in villus epithelial folds. We show that upon preferential adherence to accessible Ecad on GCs, Lm is internalized, rapidly transcytosed across the intestinal epithelium, and released in the lamina propria by exocytosis from where it disseminates systemically. Together, these results show that Lm exploits intrinsic tissue heterogeneity to access its receptor and reveal transcytosis as a novel and unanticipated pathway that is hijacked by Lm to breach the intestinal epithelium and cause systemic infection. PMID:21967767

Targeting eukaryotic Rab proteins: a smart strategy for chlamydial survival and replication.

PubMed

Damiani, María Teresa; Gambarte Tudela, Julián; Capmany, Anahí

2014-09-01

Chlamydia, an obligate intracellular bacterium which passes its entire lifecycle within a membrane-bound vacuole called the inclusion, has evolved a variety of unique strategies to establish an advantageous intracellular niche for survival. This review highlights the mechanisms by which Chlamydia subverts vesicular transport in host cells, particularly by hijacking the master controllers of eukaryotic trafficking, the Rab proteins. A subset of Rabs and Rab interacting proteins that control the recycling pathway or the biosynthetic route are selectively recruited to the chlamydial inclusion membrane. By interfering with Rab-controlled transport steps, this intracellular pathogen not only prevents its own degradation in the phagocytic pathway, but also creates a favourable intracellular environment for growth and replication. Chlamydia, a highly adapted and successful intracellular pathogen, has several redundant strategies to re-direct vesicles emerging from biosynthetic compartments that carry host molecules essential for bacterial development. Although current knowledge is limited, the latest findings have shed light on the role of Rab proteins in the course of chlamydial infections and could open novel opportunities for anti-chlamydial therapy. © 2014 John Wiley & Sons Ltd.

Mad dogs, vampires, and zombie ants: a multidisciplinary approach to teaching neuroscience, behavior, and microbiology.

PubMed

Esteban, David J; Holloway, Kevin S

2015-01-01

Viruses, parasites, and some bacteria use host organisms to complete their lifecycle. These infectious agents are able to hijack host processes to replicate and transmit to the next host. While we tend to think of infections as just making us sick, they are also capable of changing host behavior. In fact, many infectious agents are able to mediate host behavior in ways that can enhance transmission of the disease. In this course we explore the process of host behavior mediation by infectious agents, combining aspects of multiple fields including neurobiology, animal behavior, infectious disease microbiology, and epidemiology. The goals for this course are: 1) To explore the neurological and behavioral effects of infectious organisms on their hosts, in particular pathogen mediation of host behavior to the benefit of the pathogen, 2) to introduce students to primary literature in a multidisciplinary field, and 3) when applicable, to address cultural/historical/mythological perspectives that might alter societal norms and pressures and influence the impact of the biological processes of behavior modification by infections.

Dynamic sample size detection in learning command line sequence for continuous authentication.

PubMed

Traore, Issa; Woungang, Isaac; Nakkabi, Youssef; Obaidat, Mohammad S; Ahmed, Ahmed Awad E; Khalilian, Bijan

2012-10-01

Continuous authentication (CA) consists of authenticating the user repetitively throughout a session with the goal of detecting and protecting against session hijacking attacks. While the accuracy of the detector is central to the success of CA, the detection delay or length of an individual authentication period is important as well since it is a measure of the window of vulnerability of the system. However, high accuracy and small detection delay are conflicting requirements that need to be balanced for optimum detection. In this paper, we propose the use of sequential sampling technique to achieve optimum detection by trading off adequately between detection delay and accuracy in the CA process. We illustrate our approach through CA based on user command line sequence and naïve Bayes classification scheme. Experimental evaluation using the Greenberg data set yields encouraging results consisting of a false acceptance rate (FAR) of 11.78% and a false rejection rate (FRR) of 1.33%, with an average command sequence length (i.e., detection delay) of 37 commands. When using the Schonlau (SEA) data set, we obtain FAR = 4.28% and FRR = 12%.

Analysis of Ebola Virus Entry Into Macrophages.

PubMed

Dahlmann, Franziska; Biedenkopf, Nadine; Babler, Anne; Jahnen-Dechent, Willi; Karsten, Christina B; Gnirß, Kerstin; Schneider, Heike; Wrensch, Florian; O'Callaghan, Christopher A; Bertram, Stephanie; Herrler, Georg; Becker, Stephan; Pöhlmann, Stefan; Hofmann-Winkler, Heike

2015-10-01

Ebolaviruses constitute a public health threat, particularly in Central and Western Africa. Host cell factors required for spread of ebolaviruses may serve as targets for antiviral intervention. Lectins, TAM receptor tyrosine kinases (Tyro3, Axl, Mer), T cell immunoglobulin and mucin domain (TIM) proteins, integrins, and Niemann-Pick C1 (NPC1) have been reported to promote entry of ebolaviruses into certain cellular systems. However, the factors used by ebolaviruses to invade macrophages, major viral targets, are poorly defined. Here, we show that mannose-specific lectins, TIM-1 and Axl augment entry into certain cell lines but do not contribute to Ebola virus (EBOV)-glycoprotein (GP)-driven transduction of macrophages. In contrast, expression of Mer, integrin αV, and NPC1 was required for efficient GP-mediated transduction and EBOV infection of macrophages. These results define cellular factors hijacked by EBOV for entry into macrophages and, considering that Mer and integrin αV promote phagocytosis of apoptotic cells, support the concept that EBOV relies on apoptotic mimicry to invade target cells. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Molecular mechanism for the subversion of the retromer coat by the Legionella effector RidL

PubMed Central

Romano-Moreno, Miguel; Rojas, Adriana L.; Williamson, Chad D.; Lucas, María; Isupov, Michail N.; Bonifacino, Juan S.; Machner, Matthias P.; Hierro, Aitor

2017-01-01

Microbial pathogens employ sophisticated virulence strategies to cause infections in humans. The intracellular pathogen Legionella pneumophila encodes RidL to hijack the host scaffold protein VPS29, a component of retromer and retriever complexes critical for endosomal cargo recycling. Here, we determined the crystal structure of L. pneumophila RidL in complex with the human VPS29–VPS35 retromer subcomplex. A hairpin loop protruding from RidL inserts into a conserved pocket on VPS29 that is also used by cellular ligands, such as Tre-2/Bub2/Cdc16 domain family member 5 (TBC1D5) and VPS9-ankyrin repeat protein for VPS29 binding. Consistent with the idea of molecular mimicry in protein interactions, RidL outcompeted TBC1D5 for binding to VPS29. Furthermore, the interaction of RidL with retromer did not interfere with retromer dimerization but was essential for association of RidL with retromer-coated vacuolar and tubular endosomes. Our work thus provides structural and mechanistic evidence into how RidL is targeted to endosomal membranes. PMID:29229824

Dendritic transport of tick-borne flavivirus RNA by neuronal granules affects development of neurological disease.

PubMed

Hirano, Minato; Muto, Memi; Sakai, Mizuki; Kondo, Hirofumi; Kobayashi, Shintaro; Kariwa, Hiroaki; Yoshii, Kentaro

2017-09-12

Neurological diseases caused by encephalitic flaviviruses are severe and associated with high levels of mortality. However, little is known about the detailed mechanisms of viral replication and pathogenicity in the brain. Previously, we reported that the genomic RNA of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus , is transported and replicated in the dendrites of neurons. In the present study, we analyzed the transport mechanism of the viral genome to dendrites. We identified specific sequences of the 5' untranslated region of TBEV genomic RNA that act as a cis -acting element for RNA transport. Mutated TBEV with impaired RNA transport in dendrites caused a reduction in neurological symptoms in infected mice. We show that neuronal granules, which regulate the transport and local translation of dendritic mRNAs, are involved in TBEV genomic RNA transport. TBEV genomic RNA bound an RNA-binding protein of neuronal granules and disturbed the transport of dendritic mRNAs. These results demonstrated a neuropathogenic virus hijacking the neuronal granule system for the transport of viral genomic RNA in dendrites, resulting in severe neurological disease.

AMP-activated protein kinase as a target for pathogens: friends or foes?

PubMed Central

Moreira, Diana; Silvestre, Ricardo; Cordeiro-Da-Silva, Anabela; Estaquier, Jérôme; Foretz, Marc; Viollet, Benoit

2016-01-01

Intracellular pathogens are known to manipulate host cell regulatory pathways to establish an optimal environment for their growth and survival. Pathogens employ active mechanisms to hijack host cell metabolism and acquire existing nutrient and energy store. The role of the cellular energy sensor AMP-activated protein kinase (AMPK) in the regulation of cellular energy homeostasis is well documented. Here, we highlight recent advances showing the importance of AMPK signaling in pathogen-host interactions. Pathogens interact with AMPK by a variety of mechanisms aimed at reprogramming host cell metabolism to their own benefit. Stimulation of AMPK activity provides an efficient process to rapidly adapt pathogen metabolism to the major nutritional changes often encountered during the different phases of infection. However, inhibition of AMPK is also used by pathogens to manipulate innate host response, indicating that AMPK appears relevant to restriction of pathogen infection. We also document the effects of pharmacological AMPK modulators on pathogen proliferation and survival. This review illustrates intricate pathogen-AMPK interactions that maybe exploited to the development of novel anti-pathogen therapies. PMID:25882224

Mad Dogs, Vampires, and Zombie Ants: A Multidisciplinary Approach to Teaching Neuroscience, Behavior, and Microbiology

PubMed Central

Esteban, David J.; Holloway, Kevin S.

2015-01-01

Viruses, parasites, and some bacteria use host organisms to complete their lifecycle. These infectious agents are able to hijack host processes to replicate and transmit to the next host. While we tend to think of infections as just making us sick, they are also capable of changing host behavior. In fact, many infectious agents are able to mediate host behavior in ways that can enhance transmission of the disease. In this course we explore the process of host behavior mediation by infectious agents, combining aspects of multiple fields including neurobiology, animal behavior, infectious disease microbiology, and epidemiology. The goals for this course are: 1) To explore the neurological and behavioral effects of infectious organisms on their hosts, in particular pathogen mediation of host behavior to the benefit of the pathogen, 2) to introduce students to primary literature in a multidisciplinary field, and 3) when applicable, to address cultural/historical/mythological perspectives that might alter societal norms and pressures and influence the impact of the biological processes of behavior modification by infections. PMID:25838806

Insights on how the Mycobacterium tuberculosis heme uptake pathway can be used as a drug target

PubMed Central

Owens, Cedric P; Chim, Nicholas; Goulding, Celia W

2013-01-01

Mycobacterium tuberculosis (Mtb) acquires non-heme iron through salicylate-derived siderophores termed mycobactins whereas heme iron is obtained through a cascade of heme uptake proteins. Three proteins are proposed to mediate Mtb heme iron uptake, a secreted heme transporter (Rv0203), and MmpL3 and MmpL11, which are potential transmembrane heme transfer proteins. Furthermore, MhuD, a cytoplasmic heme-degrading enzyme, has been identified. Rv0203, MmpL3 and MmpL11 are mycobacteria-specific proteins, making them excellent drug targets. Importantly, MmpL3, a necessary protein, has also been implicated in trehalose monomycolate export. Recent drug-discovery efforts revealed that MmpL3 is the target of several compounds with antimycobacterial activity. Inhibition of the Mtb heme uptake pathway has yet to be explored. We propose that inhibitor design could focus on heme analogs, with the goal of blocking specific steps of this pathway. In addition, heme uptake could be hijacked as a method of importing drugs into the mycobacterial cytosol. PMID:23919550

RNA viruses can hijack vertebrate microRNAs to suppress innate immunity

NASA Astrophysics Data System (ADS)

Trobaugh, Derek W.; Gardner, Christina L.; Sun, Chengqun; Haddow, Andrew D.; Wang, Eryu; Chapnik, Elik; Mildner, Alexander; Weaver, Scott C.; Ryman, Kate D.; Klimstra, William B.

2014-02-01

Currently, there is little evidence for a notable role of the vertebrate microRNA (miRNA) system in the pathogenesis of RNA viruses. This is primarily attributed to the ease with which these viruses mutate to disrupt recognition and growth suppression by host miRNAs. Here we report that the haematopoietic-cell-specific miRNA miR-142-3p potently restricts the replication of the mosquito-borne North American eastern equine encephalitis virus in myeloid-lineage cells by binding to sites in the 3' non-translated region of its RNA genome. However, by limiting myeloid cell tropism and consequent innate immunity induction, this restriction directly promotes neurologic disease manifestations characteristic of eastern equine encephalitis virus infection in humans. Furthermore, the region containing the miR-142-3p binding sites is essential for efficient virus infection of mosquito vectors. We propose that RNA viruses can adapt to use antiviral properties of vertebrate miRNAs to limit replication in particular cell types and that this restriction can lead to exacerbation of disease severity.

Mechanisms for Cell-to-Cell Transmission of HIV-1

PubMed Central

Bracq, Lucie; Xie, Maorong; Benichou, Serge; Bouchet, Jérôme

2018-01-01

While HIV-1 infection of target cells with cell-free viral particles has been largely documented, intercellular transmission through direct cell-to-cell contact may be a predominant mode of propagation in host. To spread, HIV-1 infects cells of the immune system and takes advantage of their specific particularities and functions. Subversion of intercellular communication allows to improve HIV-1 replication through a multiplicity of intercellular structures and membrane protrusions, like tunneling nanotubes, filopodia, or lamellipodia-like structures involved in the formation of the virological synapse. Other features of immune cells, like the immunological synapse or the phagocytosis of infected cells are hijacked by HIV-1 and used as gateways to infect target cells. Finally, HIV-1 reuses its fusogenic capacity to provoke fusion between infected donor cells and target cells, and to form infected syncytia with high capacity of viral production and improved capacities of motility or survival. All these modes of cell-to-cell transfer are now considered as viral mechanisms to escape immune system and antiretroviral therapies, and could be involved in the establishment of persistent virus reservoirs in different host tissues. PMID:29515578

Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism.

PubMed

Schuijers, Jurian; Manteiga, John Colonnese; Weintraub, Abraham Selby; Day, Daniel Sindt; Zamudio, Alicia Viridiana; Hnisz, Denes; Lee, Tong Ihn; Young, Richard Allen

2018-04-10

Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Targeting Virus-host Interactions of HIV Replication.

PubMed

Weydert, Caroline; De Rijck, Jan; Christ, Frauke; Debyser, Zeger

2016-01-01

Cellular proteins that are hijacked by HIV in order to complete its replication cycle, form attractive new targets for antiretroviral therapy. In particular, the protein-protein interactions between these cellular proteins (cofactors) and viral proteins are of great interest to develop new therapies. Research efforts have led to the validation of different cofactors and some successes in therapeutic applications. Maraviroc, the first cofactor inhibitor approved for human medicinal use, provided a proof of concept. Furthermore, compounds developed as Integrase-LEDGF/p75 interaction inhibitors (LEDGINs) have advanced to early clinical trials. Other compounds targeting cofactors and cofactor-viral protein interactions are currently under development. Likewise, interactions between cellular restriction factors and their counteracting HIV protein might serve as interesting targets in order to impair HIV replication. In this respect, compounds targeting the Vif-APOBEC3G interaction have been described. In this review, we focus on compounds targeting the Integrase- LEDGF/p75 interaction, the Tat-P-TEFb interaction and the Vif-APOBEC3G interaction. Additionally we give an overview of currently discovered compounds presumably targeting cellular cofactor-HIV protein interactions.

Addiction and the brain-disease fallacy.

PubMed

Satel, Sally; Lilienfeld, Scott O

2013-01-01

From Brainwashed: The Seductive Appeal of Mindless Neuroscience by Sally Satel and Scott Lilienfeld, copyright © 2013. Reprinted by permission of Basic Books, a member of The Perseus Books Group. The notion that addiction is a "brain disease" has become widespread and rarely challenged. The brain-disease model implies erroneously that the brain is necessarily the most important and useful level of analysis for understanding and treating addiction. This paper will explain the limits of over-medicalizing - while acknowledging a legitimate place for medication in the therapeutic repertoire - and why a broader perspective on the problems of the addicted person is essential to understanding addiction and to providing optimal care. In short, the brain-disease model obscures the dimension of choice in addiction, the capacity to respond to incentives, and also the essential fact people use drugs for reasons (as consistent with a self-medication hypothesis). The latter becomes obvious when patients become abstinent yet still struggle to assume rewarding lives in the realm of work and relationships. Thankfully, addicts can choose to recover and are not helpless victims of their own "hijacked brains."

Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research.

PubMed

Simmons, Graham; Zmora, Pawel; Gierer, Stefanie; Heurich, Adeline; Pöhlmann, Stefan

2013-12-01

The severe acute respiratory syndrome (SARS) pandemic revealed that zoonotic transmission of animal coronaviruses (CoV) to humans poses a significant threat to public health and warrants surveillance and the development of countermeasures. The activity of host cell proteases, which cleave and activate the SARS-CoV spike (S) protein, is essential for viral infectivity and constitutes a target for intervention. However, the identities of the proteases involved have been unclear. Pioneer studies identified cathepsins and type II transmembrane serine proteases as cellular activators of SARS-CoV and demonstrated that several emerging viruses might exploit these enzymes to promote their spread. Here, we will review the proteolytic systems hijacked by SARS-CoV for S protein activation, we will discuss their contribution to viral spread in the host and we will outline antiviral strategies targeting these enzymes. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10years of research on highly pathogenic human coronaviruses.'' Copyright © 2013 Elsevier B.V. All rights reserved.

Brucella TIR-like protein TcpB/Btp1 specifically targets the host adaptor protein MAL/TIRAP to promote infection.

PubMed

Li, Wenna; Ke, Yuehua; Wang, Yufei; Yang, Mingjuan; Gao, Junguang; Zhan, Shaoxia; Xinying, Du; Huang, Liuyu; Li, Wenfeng; Chen, Zeliang; Li, Juan

2016-08-26

Brucella spp. are known to avoid host immune recognition and weaken the immune response to infection. Brucella like accomplish this by employing two clever strategies, called the stealth strategy and hijacking strategy. The TIR domain-containing protein (TcpB/Btp1) of Brucella melitensis is thought to be involved in inhibiting host NF-κB activation by binding to adaptors downstream of Toll-like receptors. However, of the five TIR domain-containing adaptors conserved in mammals, whether MyD88 or MAL, even other three adaptors, are specifically targeted by TcpB has not been identified. Here, we confirmed the effect of TcpB on B.melitensis virulence in mice and found that TcpB selectively targets MAL. By using siRNA against MAL, we found that TcpB from B.melitensis is involved in intracellular survival and that MAL affects intracellular replication of B.melitensis. Our results confirm that TcpB specifically targets MAL/TIRAP to disrupt downstream signaling pathways and promote intra-host survival of Brucella spp. Copyright © 2016 Elsevier Inc. All rights reserved.

Human sexual conflict from molecules to culture.

PubMed

Gorelik, Gregory; Shackelford, Todd K

2011-12-15

Coevolutionary arms races between males and females have equipped both sexes with mutually manipulative and defensive adaptations. These adaptations function to benefit individual reproductive interests at the cost of the reproductive interests of opposite-sex mates, and arise from evolutionary dynamics such as parental investment (unequal reproductive costs between the sexes) and sexual selection (unequal access to opposite-sex mates). Individuals use these adaptations to hijack others' reproductive systems, psychological states, and behaviors--essentially using other individuals as extended phenotypes of themselves. Such extended phenotypic manipulation of sexual rivals and opposite-sex mates is enacted by humans with the aid of hormones, pheromones, neurotransmitters, emotions, language, mind-altering substances, social institutions, technologies, and ideologies. Furthermore, sexual conflict may be experienced at an individual level when maternal genes and paternal genes are in conflict within an organism. Sexual conflict may be physically and emotionally destructive, but may also be exciting and constructive for relationships. By extending the biological concept of sexual conflict into social and cultural domains, scholars may successfully bridge many of the interdisciplinary gaps that separate the sciences from the humanities.

The neurobiology of the emotional adolescent: From the inside out

PubMed Central

Guyer, Amanda E.; Silk, Jennifer S.; Nelson, Eric E.

2016-01-01

Adolescents are commonly portrayed as highly emotional, with their behaviors often hijacked by their emotions. Research on the neural substrates of adolescent affective behavior is beginning to paint a more nuanced picture of how neurodevelopmental changes in brain function influence affective behavior, and how these influences are modulated by external factors in the environment. Recent neurodevelopmental models suggest that the brain is designed to promote emotion regulation, learning, and affiliation across development, and that affective behavior reciprocally interacts with age-specific social demands and different social contexts. In this review, we discuss current findings on neurobiological mechanisms of adolescents’ affective behavior and highlight individual differences in and social-contextual influences on adolescents’ emotionality. Neurobiological mechanisms of affective processes related to anxiety and depression are also discussed as examples. As the field progresses, it will be critical to test new hypotheses generated from the foundational empirical and conceptual work and to focus on identifying more precisely how and when neural networks change in ways that promote or thwart adaptive affective behavior during adolescence. PMID:27506384

Complement factor H in host defense and immune evasion.

PubMed

Parente, Raffaella; Clark, Simon J; Inforzato, Antonio; Day, Anthony J

2017-05-01

Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.

Automatic detection and measurement of viral replication compartments by ellipse adjustment

PubMed Central

Garcés, Yasel; Guerrero, Adán; Hidalgo, Paloma; López, Raul Eduardo; Wood, Christopher D.; Gonzalez, Ramón A.; Rendón-Mancha, Juan Manuel

2016-01-01

Viruses employ a variety of strategies to hijack cellular activities through the orchestrated recruitment of macromolecules to specific virus-induced cellular micro-environments. Adenoviruses (Ad) and other DNA viruses induce extensive reorganization of the cell nucleus and formation of nuclear Replication Compartments (RCs), where the viral genome is replicated and expressed. In this work an automatic algorithm designed for detection and segmentation of RCs using ellipses is presented. Unlike algorithms available in the literature, this approach is deterministic, automatic, and can adjust multiple RCs using ellipses. The proposed algorithm is non iterative, computationally efficient and is invariant to affine transformations. The method was validated over both synthetic images and more than 400 real images of Ad-infected cells at various timepoints of the viral replication cycle obtaining relevant information about the biogenesis of adenoviral RCs. As proof of concept the algorithm was then used to quantitatively compare RCs in cells infected with the adenovirus wild type or an adenovirus mutant that is null for expression of a viral protein that is known to affect activities associated with RCs that result in deficient viral progeny production. PMID:27819325

Hepatitis C Virus Infection Activates a Novel Innate Pathway Involving IKKα in Lipogenesis and Viral Assembly

PubMed Central

Li, Qisheng; Pène, Véronique; Krishnamurthy, Siddharth; Cha, Helen; Liang, T. Jake

2013-01-01

Hepatitis C virus interacts extensively with host factors not only to establish productive infection but also to trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IKKα is a critical host factor for HCV. Here we describe a novel NF-κB-independent and kinase-mediated nuclear function of IKKα in HCV assembly. HCV infection, through its 3’-untranslated region, interacts with DDX3X to activate IKKα, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving SREBPs. This novel innate pathway induces lipogenic genes and enhances core-associated lipid droplet formation to facilitate viral assembly. Chemical inhibitors of IKKα suppress HCV infection and IKKα-induced lipogenesis, offering a proof-of-concept approach for novel HCV therapeutic development. Our results show that HCV commands a novel mechanism to its advantage by exploiting intrinsic innate response and hijacking lipid metabolism, which likely contributes to a high chronicity rate and the pathological hallmark of steatosis in HCV infection. PMID:23708292

HTLV-1 Tax activates HIV-1 transcription in latency models.

PubMed

Geddes, Victor Emmanuel Viana; José, Diego Pandeló; Leal, Fabio E; Nixon, Douglas F; Tanuri, Amilcar; Aguiar, Renato Santana

2017-04-01

HIV-1 latency is a major obstacle to HIV-1 eradication. Coinfection with HTLV-1 has been associated with faster progression to AIDS. HTLV-1 encodes the transactivator Tax which can activate both HTLV-1 and HIV-1 transcription. Here, we demonstrate that Tax activates HIV transcription in latent CD4 + T cells. Tax promotes the activation of P-TEFb, releasing CDK9 and Cyclin T1 from inactive forms, promoting transcription elongation and reactivation of latent HIV-1. Tax mutants lacking interaction with the HIV-1-LTR promoter were not able to activate P-TEFb, with no subsequent activation of latent HIV. In HIV-infected primary resting CD4 + T cells, Tax-1 reactivated HIV-1 transcription up to five fold, confirming these findings in an ex vivo latency model. Finally, our results confirms that HTLV-1/Tax hijacks cellular partners, promoting HIV-1 transcription, and this interaction should be further investigated in HIV-1 latency studies in patients with HIV/HTLV-1 co-infection. Copyright © 2017 Elsevier Inc. All rights reserved.

Addiction and the Brain-Disease Fallacy

PubMed Central

Satel, Sally; Lilienfeld, Scott O.

2014-01-01

From Brainwashed: The Seductive Appeal of Mindless Neuroscience by Sally Satel and Scott Lilienfeld, copyright © 2013. Reprinted by permission of Basic Books, a member of The Perseus Books Group. The notion that addiction is a “brain disease” has become widespread and rarely challenged. The brain-disease model implies erroneously that the brain is necessarily the most important and useful level of analysis for understanding and treating addiction. This paper will explain the limits of over-medicalizing – while acknowledging a legitimate place for medication in the therapeutic repertoire – and why a broader perspective on the problems of the addicted person is essential to understanding addiction and to providing optimal care. In short, the brain-disease model obscures the dimension of choice in addiction, the capacity to respond to incentives, and also the essential fact people use drugs for reasons (as consistent with a self-medication hypothesis). The latter becomes obvious when patients become abstinent yet still struggle to assume rewarding lives in the realm of work and relationships. Thankfully, addicts can choose to recover and are not helpless victims of their own “hijacked brains.” PMID:24624096

Invasive Aspergillus terreus morphological transitions and immunoadaptations mediating antifungal resistance.

PubMed

Bengyella, Louis; Yekwa, Elsie Laban; Subhani, Muhammad Nasir; Tambo, Ernest; Nawaz, Kiran; Hetsa, Bakoena Ashton; Iftikhar, Sehrish; Waikhom, Sayanika Devi; Roy, Pranab

2017-01-01

Aspergillus terreus Thom is a pathogen of public health and agricultural importance for its seamless abilities to expand its ecological niche. The aim of this study was holistically to investigate A. terreus morphological and immunoadaptations and their implication in antifungal resistance and proliferation during infection. In-depth unstructured mining of relevant peer-reviewed literature was performed for A. terreus morphological, immune, resistance, and genetic diversity based on the sequenced calmodulin-like gene. Accessory conidia and phialidic conidia produced by A. terreus confer discrete anti-fungal resistance that ensures survivability during therapies. Interestingly, by producing unique metabolites such as Asp-melanin and terretonin, A. terreus is capable of hijacking macrophages and scavenging iron, respectively. As such, A. terreus has established a rare mechanism to mitigate phagocytosis and swing the interaction dynamics in favor of its proliferation and survival in hosts. It is further unraveled that besides A. terreus genetic diversity, morphological, biochemical, and immunologic adaptations associated with conidia germination and discharge of chemical signals during infection enable masking of the host defense as an integral part of its strategy to survive and rapidly colonize hosts.

Stress-mediated translational control in cancer cells.

PubMed

Leprivier, Gabriel; Rotblat, Barak; Khan, Debjit; Jan, Eric; Sorensen, Poul H

2015-07-01

Tumor cells are continually subjected to diverse stress conditions of the tumor microenvironment, including hypoxia, nutrient deprivation, and oxidative or genotoxic stress. Tumor cells must evolve adaptive mechanisms to survive these conditions to ultimately drive tumor progression. Tight control of mRNA translation is critical for this response and the adaptation of tumor cells to such stress forms. This proceeds though a translational reprogramming process which restrains overall translation activity to preserve energy and nutrients, but which also stimulates the selective synthesis of major stress adaptor proteins. Here we present the different regulatory signaling pathways which coordinate mRNA translation in the response to different stress forms, including those regulating eIF2α, mTORC1 and eEF2K, and we explain how tumor cells hijack these pathways for survival under stress. Finally, mechanisms for selective mRNA translation under stress, including the utilization of upstream open reading frames (uORFs) and internal ribosome entry sites (IRESes) are discussed in the context of cell stress. This article is part of a Special Issue entitled: Translation and Cancer. Copyright © 2014 Elsevier B.V. All rights reserved.

Automatic detection and measurement of viral replication compartments by ellipse adjustment

NASA Astrophysics Data System (ADS)

Garcés, Yasel; Guerrero, Adán; Hidalgo, Paloma; López, Raul Eduardo; Wood, Christopher D.; Gonzalez, Ramón A.; Rendón-Mancha, Juan Manuel

2016-11-01

Viruses employ a variety of strategies to hijack cellular activities through the orchestrated recruitment of macromolecules to specific virus-induced cellular micro-environments. Adenoviruses (Ad) and other DNA viruses induce extensive reorganization of the cell nucleus and formation of nuclear Replication Compartments (RCs), where the viral genome is replicated and expressed. In this work an automatic algorithm designed for detection and segmentation of RCs using ellipses is presented. Unlike algorithms available in the literature, this approach is deterministic, automatic, and can adjust multiple RCs using ellipses. The proposed algorithm is non iterative, computationally efficient and is invariant to affine transformations. The method was validated over both synthetic images and more than 400 real images of Ad-infected cells at various timepoints of the viral replication cycle obtaining relevant information about the biogenesis of adenoviral RCs. As proof of concept the algorithm was then used to quantitatively compare RCs in cells infected with the adenovirus wild type or an adenovirus mutant that is null for expression of a viral protein that is known to affect activities associated with RCs that result in deficient viral progeny production.

[Personal genomics: are we debating the right Issues?].

PubMed

Vayena, E; Mauch, F

2012-07-25

The debate about personal genomics and their role in personalized medicine has been, to some extent, hijacked by the controversy about commercially available genomic tests sold directly to consumers. The clinical validity and utility of such tests are currently limited and most medical associations recommend that consumers refrain from testing. Conversely, DTC genomics proponents and particularly the DTC industry argue that there is personal utility in acquiring genomic information. While it is necessary to debate risks and benefits of DTC genomics, we should not lose sight of the increasingly important role that genomics will play in medical practice and public health. Therefore, and in anticipation of this shift we also need to focus on important implications from the use of genomics information such as genetic discrimination, privacy protection and equitable access to health care. Undoubtedly, personal genomics will challenge our social norms maybe more than our medicine. Sticking to the polarization of «to have or not to have DTC genomics» risks to takes us away from the critical issues we need to be debating.

Transition metals at the host–pathogen interface: How Neisseria exploit human metalloproteins for acquiring iron and zinc

PubMed Central

Neumann, Wilma; Hadley, Rose C.; Nolan, Elizabeth M.

2017-01-01

Transition metals are essential nutrients for all organisms and important players in the host-microbe interaction. During bacterial infection, a tug-of-war between the host and microbe for nutrient metals occurs: the host innate immune system responds to the pathogen by reducing metal availability and the pathogen tries to outmaneuver this response. The outcome of this competition, which involves metal-sequestering host-defense proteins and microbial metal acquisition machinery, is an important variable for whether infection occurs. One strategy bacterial pathogens employ to overcome metal restriction involves hijacking abundant host metalloproteins. The obligate human pathogens Neisseria spp. express TonB-dependent transport systems that capture human metalloproteins, extract the bound metal ions, and deliver these nutrients into the bacterial cell. This Essay highlights structural and mechanistic investigations that provide insights into how Neisseria acquire iron from the Fe(III)-transport protein transferrin, the Fe(III)-chelating host-defense protein lactoferrin, and the oxygen-transport protein hemoglobin, and obtain zinc from the metal-sequestering antimicrobial protein calprotectin. PMID:28487398

HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type I receptor

NASA Astrophysics Data System (ADS)

Sakata, Kotaro; Hara, Mitsuko; Terada, Takaho; Watanabe, Noriyuki; Takaya, Daisuke; Yaguchi, So-Ichi; Matsumoto, Takehisa; Matsuura, Tomokazu; Shirouzu, Mikako; Yokoyama, Shigeyuki; Yamaguchi, Tokio; Miyazawa, Keiji; Aizaki, Hideki; Suzuki, Tetsuro; Wakita, Takaji; Imoto, Masaya; Kojima, Soichi

2013-11-01

Viruses sometimes mimic host proteins and hijack the host cell machinery. Hepatitis C virus (HCV) causes liver fibrosis, a process largely mediated by the overexpression of transforming growth factor (TGF)-β and collagen, although the precise underlying mechanism is unknown. Here, we report that HCV non-structural protein 3 (NS3) protease affects the antigenicity and bioactivity of TGF-β2 in (CAGA)9-Luc CCL64 cells and in human hepatic cell lines via binding to TGF-β type I receptor (TβRI). Tumor necrosis factor (TNF)-α facilitates this mechanism by increasing the colocalization of TβRI with NS3 protease on the surface of HCV-infected cells. An anti-NS3 antibody against computationally predicted binding sites for TβRI blocked the TGF-β mimetic activities of NS3 in vitro and attenuated liver fibrosis in HCV-infected chimeric mice. These data suggest that HCV NS3 protease mimics TGF-β2 and functions, at least in part, via directly binding to and activating TβRI, thereby enhancing liver fibrosis.

Cell Wall Remodeling by a Synthetic Analog Reveals Metabolic Adaptation in Vancomycin Resistant Enterococci.

PubMed

Pidgeon, Sean E; Pires, Marcos M

2017-07-21

Drug-resistant bacterial infections threaten to overburden our healthcare system and disrupt modern medicine. A large class of potent antibiotics, including vancomycin, operate by interfering with bacterial cell wall biosynthesis. Vancomycin-resistant enterococci (VRE) evade the blockage of cell wall biosynthesis by altering cell wall precursors, rendering them drug insensitive. Herein, we reveal the phenotypic plasticity and cell wall remodeling of VRE in response to vancomycin in live bacterial cells via a metabolic probe. A synthetic cell wall analog was designed and constructed to monitor cell wall structural alterations. Our results demonstrate that the biosynthetic pathway for vancomycin-resistant precursors can be hijacked by synthetic analogs to track the kinetics of phenotype induction. In addition, we leveraged this probe to interrogate the response of VRE cells to vancomycin analogs and a series of cell wall-targeted antibiotics. Finally, we describe a proof-of-principle strategy to visually inspect drug resistance induction. Based on our findings, we anticipate that our metabolic probe will play an important role in further elucidating the interplay among the enzymes involved in the VRE biosynthetic rewiring.

Ribosome hijacking: a role for small protein B during trans-translation

PubMed Central

Nonin-Lecomte, Sylvie; Germain-Amiot, Noella; Gillet, Reynald; Hallier, Marc; Ponchon, Luc; Dardel, Frédéric; Felden, Brice

2009-01-01

Tight recognition of codon–anticodon pairings by the ribosome ensures the accuracy and fidelity of protein synthesis. In eubacteria, translational surveillance and ribosome rescue are performed by the ‘tmRNA–SmpB' system (transfer messenger RNA–small protein B). Remarkably, entry and accommodation of aminoacylated-tmRNA into stalled ribosomes occur without a codon–anticodon interaction but in the presence of SmpB. Here, we show that within a stalled ribosome, SmpB interacts with the three universally conserved bases G530, A1492 and A1493 that form the 30S subunit decoding centre, in which canonical codon–anticodon pairing occurs. The footprints at positions A1492 and A1493 of a small decoding centre, as well as on a set of conserved SmpB amino acids, were identified by nuclear magnetic resonance. Mutants at these residues display the same growth defects as for ΔsmpB strains. The SmpB protein has functional and structural similarities with initiation factor 1, and is proposed to be a functional mimic of the pairing between a codon and an anticodon. PMID:19132006

Ribosome hijacking: a role for small protein B during trans-translation.

PubMed

Nonin-Lecomte, Sylvie; Germain-Amiot, Noella; Gillet, Reynald; Hallier, Marc; Ponchon, Luc; Dardel, Frédéric; Felden, Brice

2009-02-01

Tight recognition of codon-anticodon pairings by the ribosome ensures the accuracy and fidelity of protein synthesis. In eubacteria, translational surveillance and ribosome rescue are performed by the 'tmRNA-SmpB' system (transfer messenger RNA-small protein B). Remarkably, entry and accommodation of aminoacylated-tmRNA into stalled ribosomes occur without a codon-anticodon interaction but in the presence of SmpB. Here, we show that within a stalled ribosome, SmpB interacts with the three universally conserved bases G530, A1492 and A1493 that form the 30S subunit decoding centre, in which canonical codon-anticodon pairing occurs. The footprints at positions A1492 and A1493 of a small decoding centre, as well as on a set of conserved SmpB amino acids, were identified by nuclear magnetic resonance. Mutants at these residues display the same growth defects as for DeltasmpB strains. The SmpB protein has functional and structural similarities with initiation factor 1, and is proposed to be a functional mimic of the pairing between a codon and an anticodon.

Plasma membrane signaling in HIV-1 infection.

PubMed

Abbas, Wasim; Herbein, Georges

2014-04-01

Plasma membrane is a multifunctional structure that acts as the initial barrier against infection by intracellular pathogens. The productive HIV-1 infection depends upon the initial interaction of virus and host plasma membrane. Immune cells such as CD4+ T cells and macrophages contain essential cell surface receptors and molecules such as CD4, CXCR4, CCR5 and lipid raft components that facilitate HIV-1 entry. From plasma membrane HIV-1 activates signaling pathways that prepare the grounds for viral replication. Through viral proteins HIV-1 hijacks host plasma membrane receptors such as Fas, TNFRs and DR4/DR5, which results in immune evasion and apoptosis both in infected and uninfected bystander cells. These events are hallmark in HIV-1 pathogenesis that leads towards AIDS. The interplay between HIV-1 and plasma membrane signaling has much to offer in terms of viral fitness and pathogenicity, and a better understanding of this interplay may lead to development of new therapeutic approaches. This article is part of a Special Issue entitled: Viral Membrane Proteins - Channels for Cellular Networking. Copyright © 2013 Elsevier B.V. All rights reserved.

Explaining Human Recreational Use of ‘pesticides’: The Neurotoxin Regulation Model of Substance Use vs. the Hijack Model and Implications for Age and Sex Differences in Drug Consumption

PubMed Central

Hagen, Edward H.; Roulette, Casey J.; Sullivan, Roger J.

2013-01-01

Most globally popular drugs are plant neurotoxins or their close chemical analogs. These compounds evolved to deter, not reward or reinforce, consumption. Moreover, they reliably activate virtually all toxin defense mechanisms, and are thus correctly identified by human neurophysiology as toxins. Acute drug toxicity must therefore play a more central role in drug use theory. We accordingly challenge the popular idea that the rewarding and reinforcing properties of drugs “hijack” the brain, and propose instead that the brain evolved to carefully regulate neurotoxin consumption to minimize fitness costs and maximize fitness benefits. This perspective provides a compelling explanation for the dramatic changes in substance use that occur during the transition from childhood to adulthood, and for pervasive sex differences in substance use: because nicotine and many other plant neurotoxins are teratogenic, children, and to a lesser extent women of childbearing age, evolved to avoid ingesting them. However, during the course of human evolution many adolescents and adults reaped net benefits from regulated intake of plant neurotoxins. PMID:24204348

Rewiring Host Lipid Metabolism by Large Viruses Determines the Fate of Emiliania huxleyi, a Bloom-Forming Alga in the Ocean[C][W][OPEN

PubMed Central

Rosenwasser, Shilo; Mausz, Michaela A.; Schatz, Daniella; Sheyn, Uri; Malitsky, Sergey; Aharoni, Asaph; Weinstock, Eyal; Tzfadia, Oren; Ben-Dor, Shifra; Feldmesser, Ester; Pohnert, Georg; Vardi, Assaf

2014-01-01

Marine viruses are major ecological and evolutionary drivers of microbial food webs regulating the fate of carbon in the ocean. We combined transcriptomic and metabolomic analyses to explore the cellular pathways mediating the interaction between the bloom-forming coccolithophore Emiliania huxleyi and its specific coccolithoviruses (E. huxleyi virus [EhV]). We show that EhV induces profound transcriptome remodeling targeted toward fatty acid synthesis to support viral assembly. A metabolic shift toward production of viral-derived sphingolipids was detected during infection and coincided with downregulation of host de novo sphingolipid genes and induction of the viral-encoded homologous pathway. The depletion of host-specific sterols during lytic infection and their detection in purified virions revealed their novel role in viral life cycle. We identify an essential function of the mevalonate-isoprenoid branch of sterol biosynthesis during infection and propose its downregulation as an antiviral mechanism. We demonstrate how viral replication depends on the hijacking of host lipid metabolism during the chemical “arms race” in the ocean. PMID:24920329

Pathological gambling and the loss of willpower: a neurocognitive perspective.

PubMed

Brevers, Damien; Noël, Xavier

2013-01-01

The purpose of this review is to gain more insight on the neurocognitive processes involved in the maintenance of pathological gambling. Firstly, we describe structural factors of gambling games that could promote the repetition of gambling experiences to such an extent that some individuals may become unable to control their gambling habits. Secondly, we review findings of neurocognitive studies on pathological gambling. As a whole, poor ability to resist gambling is a product of an imbalance between any one or a combination of three key neural systems: (1) an hyperactive 'impulsive' system, which is fast, automatic, and unconscious and promotes automatic and habitual actions; (2) a hypoactive 'reflective' system, which is slow and deliberative, forecasting the future consequences of a behavior, inhibitory control, and self-awareness; and (3) the interoceptive system, translating bottom-up somatic signals into a subjective state of craving, which in turn potentiates the activity of the impulsive system, and/or weakens or hijacks the goal-driven cognitive resources needed for the normal operation of the reflective system. Based on this theoretical background, we focus on certain clinical interventions that could reduce the risks of both gambling addiction and relapse.

The late endocytic Rab39a GTPase regulates the interaction between multivesicular bodies and chlamydial inclusions.

PubMed

Gambarte Tudela, Julian; Capmany, Anahi; Romao, Maryse; Quintero, Cristian; Miserey-Lenkei, Stephanie; Raposo, Graca; Goud, Bruno; Damiani, Maria Teresa

2015-08-15

Given their obligate intracellular lifestyle, Chlamydia trachomatis ensure that they have access to multiple host sources of essential lipids by interfering with vesicular transport. These bacteria hijack Rab6-, Rab11- and Rab14-controlled trafficking pathways to acquire sphingomyelin from the Golgi complex. Another important source of sphingolipids, phospholipids and cholesterol are multivesicular bodies (MVBs). Despite their participation in chlamydial inclusion development and bacterial replication, the molecular mechanisms mediating the interaction between MVBs and chlamydial inclusions remain unknown. In the present study, we demonstrate that Rab39a labels a subset of late endocytic vesicles - mainly MVBs - that move along microtubules. Moreover, Rab39a is actively recruited to chlamydial inclusions throughout the pathogen life cycle by a bacterial-driven process that depends on the Rab39a GTP- or GDP-binding state. Interestingly, Rab39a participates in the delivery of MVBs and host sphingolipids to maturing chlamydial inclusions, thereby promoting inclusion growth and bacterial development. Taken together, our findings indicate that Rab39a favours chlamydial replication and infectivity. This is the first report showing that a late endocytic Rab GTPase is involved in chlamydial infection development. © 2015. Published by The Company of Biologists Ltd.

Hacking and securing the AR.Drone 2.0 quadcopter: investigations for improving the security of a toy

NASA Astrophysics Data System (ADS)

Pleban, Johann-Sebastian; Band, Ricardo; Creutzburg, Reiner

2014-02-01

In this article we describe the security problems of the Parrot AR.Drone 2.0 quadcopter. Due to the fact that it is promoted as a toy with low acquisition costs, it may end up being used by many individuals which makes it a target for harmful attacks. In addition, the videostream of the drone could be of interest for a potential attacker due to its ability of revealing confidential information. Therefore, we will perform a security threat analysis on this particular drone. We will set the focus mainly on obvious security vulnerabilities like the unencrypted Wi-Fi connection or the user management of the GNU/Linux operating system which runs on the drone. We will show how the drone can be hacked in order to hijack the AR.Drone 2.0. Our aim is to sensitize the end-user of AR.Drones by describing the security vulnerabilities and to show how the AR.Drone 2.0 could be secured from unauthorized access. We will provide instructions to secure the drones Wi-Fi connection and its operation with the official Smartphone App and third party PC software.

The first 24 hours of the World Trade Center attacks of 2001--the Centers for Disease Control and Prevention emergency phase response.

PubMed

Cruz, Miguel A; Burger, Ronald; Keim, Mark

2007-01-01

On 11 September 2001, terrorists hijacked two passenger planes and crashed them into the two towers of the World Trade Center (WTC) in New York City. These synchronized attacks were the largest act of terrorism ever committed on US soil. The impacts, fires, and subsequent collapse of the towers killed and injured thousands of people. Within minutes after the first plane crashed into the WTC, the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, initiated one of the largest public health responses in its history. Staff of the CDC provided technical assistance on several key public health issues. During the acute phase of the event, CDC personnel assisted with: (1) assessing hospital capacity; (2) establishing injury and disease surveillance activities; (3) deploying emergency coordinators/liaisons to facilitate inter-agency coordination with the affected jurisdictions; and (4) arranging rapid delivery of emergency medical supplies, therapeutics, and personal protective equipment. This incident highlighted the need for adequate planning for all potential hazards and the importance of interagency and interdepartmental coordination in preparing for and responding to public health emergencies.

Pathological gambling and the loss of willpower: a neurocognitive perspective

PubMed Central

Brevers, Damien; Noël, Xavier

2013-01-01

The purpose of this review is to gain more insight on the neurocognitive processes involved in the maintenance of pathological gambling. Firstly, we describe structural factors of gambling games that could promote the repetition of gambling experiences to such an extent that some individuals may become unable to control their gambling habits. Secondly, we review findings of neurocognitive studies on pathological gambling. As a whole, poor ability to resist gambling is a product of an imbalance between any one or a combination of three key neural systems: (1) an hyperactive ‘impulsive’ system, which is fast, automatic, and unconscious and promotes automatic and habitual actions; (2) a hypoactive ‘reflective’ system, which is slow and deliberative, forecasting the future consequences of a behavior, inhibitory control, and self-awareness; and (3) the interoceptive system, translating bottom-up somatic signals into a subjective state of craving, which in turn potentiates the activity of the impulsive system, and/or weakens or hijacks the goal-driven cognitive resources needed for the normal operation of the reflective system. Based on this theoretical background, we focus on certain clinical interventions that could reduce the risks of both gambling addiction and relapse. PMID:24693357

Preparation of BFV Gag antiserum and preliminary study on cellular distribution of BFV.

PubMed

Wang, Jian; Guo, Hong-yan; Jia, Rui; Xu, Xuan; Tan, Juan; Geng, Yun-qi; Qiao, Wen-tao

2010-04-01

Viruses (e.g. Human immunodeficiency virus, Human simplex virus and Prototype foamy virus) are obligate intracellular parasites and therefore depend on the cellular machinery for cellular trafficking. Bovine foamy virus (BFV) is a member of the Spumaretrovirinae subfamily of Retroviruses, however, details of its cellular trafficking remain unknown. In this study, we cloned the BFV gag gene into prokaryotic expression vector pET28a and purified the denaturalized Gag protein. The protein was used to immunize BALB/c mouse to produce antiserum, which could specifically recognize the BFV Gag protein in BFV-infected cells through western blot assay. Additionally, these results demonstrated that both the optimal and suboptimal cleavage of Gag protein occur in BFV-infected cells. Subsequently, the Gag antiserum was used to investigate subcellular localization of BFV. In immunofluorescence microscopy assays, colocalization microtubules (MTs) and assembling viral particles were clearly observed, which implied that BFV may transport along cellular MTs in host cells. Furthermore, MTs-depolymerizing assay indicated MTs were required for the efficient replication of BFV. In conclusion, our study suggests that BFV has evolved the mechanism to hijack the cellular cytoskeleton for its replication.

HMGB1 Protein Binds to Influenza Virus Nucleoprotein and Promotes Viral Replication

PubMed Central

Moisy, Dorothée; Avilov, Sergiy V.; Jacob, Yves; Laoide, Brid M.; Ge, Xingyi; Baudin, Florence; Jestin, Jean-Luc

2012-01-01

Influenza virus has evolved replication strategies that hijack host cell pathways. To uncover interactions between viral macromolecules and host proteins, we applied a phage display strategy. A library of human cDNA expression products displayed on filamentous phages was submitted to affinity selection for influenza viral ribonucleoproteins (vRNPs). High-mobility-group box (HMGB) proteins were found to bind to the nucleoprotein (NP) component of vRNPs. HMGB1 and HMGB2 bind directly to the purified NP in the absence of viral RNA, and the HMG box A domain is sufficient to bind the NP. We show that HMGB1 associates with the viral NP in the nuclei of infected cells, promotes viral growth, and enhances the activity of the viral polymerase. The presence of a functional HMGB1 DNA-binding site is required to enhance influenza virus replication. Glycyrrhizin, which reduces HMGB1 binding to DNA, inhibits influenza virus polymerase activity. Our data show that the HMGB1 protein can play a significant role in intranuclear replication of influenza viruses, thus extending previous findings on the bornavirus and on a number of DNA viruses. PMID:22696656

The 2017 Academic College of Emergency Experts and Academy of Family Physicians of India position statement on preventing violence against health-care workers and vandalization of health-care facilities in India.

PubMed

Chauhan, Vivek; Galwankar, Sagar; Kumar, Raman; Raina, Sunil Kumar; Aggarwal, Praveen; Agrawal, Naman; Krishnan, S Vimal; Bhoi, Sanjeev; Kalra, O P; Soans, Santosh T; Aggarwal, Vandana; Kubendra, Mohan; Bijayraj, R; Datta, Sumana; Srivastava, R P

2017-01-01

There have been multiple incidents where doctors have been assaulted by patient relatives and hospital facilities have been vandalized. This has led to mass agitations by Physicians across India. Violence and vandalism against health-care workers (HCWs) is one of the biggest public health and patient care challenge in India. The sheer intensity of emotional hijack and the stress levels in both practicing HCWs and patient relative's needs immediate and detail attention. The suffering of HCWs who are hurt, the damage to hospital facilities and the reactionary agitation which affects patients who need care are all together doing everything to damage the delivery of health care and relationship between a doctor and a patient. This is detrimental to India where illnesses and Injuries continue to be the biggest challenge to its growth curve. The expert group set by The Academic College of Emergency Experts and The Academy of Family Physicians of India makes an effort to study this Public Health and Patient Care Challenge and provide recommendations to solve it.

Media coverage of controlled substance diversion through theft or loss.

PubMed

Brushwood, David B; Kimberlin, Carole A

2004-01-01

To determine the frequency of media reports of controlled substance diversion. Quantitative search of news articles from LexisNexis Academic, using search strings related to four different types of controlled substance diversion. Not applicable. Not applicable. Number of media reports about diversion of controlled substances at the prescriber or dispenser levels, through pharmacy robberies or thefts, and through hijackings or robberies of shipments. Media reports of controlled substance diversion indicate that theft and loss are important problems and that inappropriate prescribing and dispensing are substantial problems as well. Leaks of controlled substances from the closed system of distribution seem to be increasing as rapidly through theft and loss as through inappropriate prescribing and dispensing. During the five biennia between 1993 and 2002, these percentage increases in media reports were observed for the different types of diversion: 200% for prescribers; 350% for dispensers; 133% for pharmacy robberies and thefts; and 1,800% for thefts from shipping channels. A balanced approach to the prevention of controlled substance diversion, aimed at reducing illicit acquisition of drugs from theft and loss as well as from prescribing and dispensing, may produce the greatest success without adversely affecting the quality of patient care.

Ty3 Retrotransposon Hijacks Mating Yeast RNA Processing Bodies to Infect New Genomes

PubMed Central

Kaake, Robyn; Dawson, Anthony R.; Matheos, Dina; Nagashima, Kunio; Sitlani, Parth; Patterson, Kurt; Chang, Ivan; Huang, Lan; Sandmeyer, Suzanne

2015-01-01

Retrotransposition of the budding yeast long terminal repeat retrotransposon Ty3 is activated during mating. In this study, proteins that associate with Ty3 Gag3 capsid protein during virus-like particle (VLP) assembly were identified by mass spectrometry and screened for roles in mating-stimulated retrotransposition. Components of RNA processing bodies including DEAD box helicases Dhh1/DDX6 and Ded1/DDX3, Sm-like protein Lsm1, decapping protein Dcp2, and 5’ to 3’ exonuclease Xrn1 were among the proteins identified. These proteins associated with Ty3 proteins and RNA, and were required for formation of Ty3 VLP retrosome assembly factories and for retrotransposition. Specifically, Dhh1/DDX6 was required for normal levels of Ty3 genomic RNA, and Lsm1 and Xrn1 were required for association of Ty3 protein and RNA into retrosomes. This role for components of RNA processing bodies in promoting VLP assembly and retrotransposition during mating in a yeast that lacks RNA interference, contrasts with roles proposed for orthologous components in animal germ cell ribonucleoprotein granules in turnover and epigenetic suppression of retrotransposon RNAs. PMID:26421679

Parasitic nematodes modulate PIN-mediated auxin transport to facilitate infection.

PubMed

Grunewald, Wim; Cannoot, Bernard; Friml, Jirí; Gheysen, Godelieve

2009-01-01

Plant-parasitic nematodes are destructive plant pathogens that cause significant yield losses. They induce highly specialized feeding sites (NFS) in infected plant roots from which they withdraw nutrients. In order to establish these NFS, it is thought that the nematodes manipulate the molecular and physiological pathways of their hosts. Evidence is accumulating that the plant signalling molecule auxin is involved in the initiation and development of the feeding sites of sedentary plant-parasitic nematodes. Intercellular transport of auxin is essential for various aspects of plant growth and development. Here, we analysed the spatial and temporal expression of PIN auxin transporters during the early events of NFS establishment using promoter-GUS/GFP fusion lines. Additionally, single and double pin mutants were used in infection studies to analyse the role of the different PIN proteins during cyst nematode infection. Based on our results, we postulate a model in which PIN1-mediated auxin transport is needed to deliver auxin to the initial syncytial cell, whereas PIN3 and PIN4 distribute the accumulated auxin laterally and are involved in the radial expansion of the NFS. Our data demonstrate that cyst nematodes are able to hijack the auxin distribution network in order to facilitate the infection process.

Class I ADP-Ribosylation Factors Are Involved in Enterovirus 71 Replication

PubMed Central

Wang, Jianmin; Du, Jiang; Jin, Qi

2014-01-01

Enterovirus 71 is one of the major causative agents of hand, foot, and mouth disease in infants and children. Replication of enterovirus 71 depends on host cellular factors. The viral replication complex is formed in novel, cytoplasmic, vesicular compartments. It has not been elucidated which cellular pathways are hijacked by the virus to create these vesicles. Here, we investigated whether proteins associated with the cellular secretory pathway were involved in enterovirus 71 replication. We used a loss-of-function assay, based on small interfering RNA. We showed that enterovirus 71 RNA replication was dependent on the activity of Class I ADP-ribosylation factors. Simultaneous depletion of ADP-ribosylation factors 1 and 3, but not three others, inhibited viral replication in cells. We also demonstrated with various techniques that the brefeldin-A-sensitive guanidine nucleotide exchange factor, GBF1, was critically important for enterovirus 71 replication. Our results suggested that enterovirus 71 replication depended on GBF1-mediated activation of Class I ADP-ribosylation factors. These results revealed a connection between enterovirus 71 replication and the cellular secretory pathway; this pathway may represent a novel target for antiviral therapies. PMID:24911624

Immune Ecosystem of Virus-Infected Host Tissues.

PubMed

Maarouf, Mohamed; Rai, Kul Raj; Goraya, Mohsan Ullah; Chen, Ji-Long

2018-05-06

Virus infected host cells serve as a central immune ecological niche during viral infection and replication and stimulate the host immune response via molecular signaling. The viral infection and multiplication process involves complex intracellular molecular interactions between viral components and the host factors. Various types of host cells are also involved to modulate immune factors in delicate and dynamic equilibrium to maintain a balanced immune ecosystem in an infected host tissue. Antiviral host arsenals are equipped to combat or eliminate viral invasion. However, viruses have evolved with strategies to counter against antiviral immunity or hijack cellular machinery to survive inside host tissue for their multiplication. However, host immune systems have also evolved to neutralize the infection; which, in turn, either clears the virus from the infected host or causes immune-mediated host tissue injury. A complex relationship between viral pathogenesis and host antiviral defense could define the immune ecosystem of virus-infected host tissues. Understanding of the molecular mechanism underlying this ecosystem would uncover strategies to modulate host immune function for antiviral therapeutics. This review presents past and present updates of immune-ecological components of virus infected host tissue and explains how viruses subvert the host immune surveillances.

Type IV secretion system of Brucella spp. and its effectors

PubMed Central

Ke, Yuehua; Wang, Yufei; Li, Wengfeng; Chen, Zeliang

2015-01-01

Brucella spp. are intracellular bacterial pathogens that cause infection in domestic and wild animals. They are often used as model organisms to study intracellular bacterial infections. Brucella VirB T4SS is a key virulence factor that plays important roles in mediating intracellular survival and manipulating host immune response to infection. In this review, we discuss the roles of Brucella VirB T4SS and 15 effectors that are proposed to be crucial for Brucella pathogenesis. VirB T4SS regulates the inflammation response and manipulates vesicle trafficking inside host cells. VirB T4SS also plays crucial roles in the inhibition of the host immune response and intracellular survival during infection. Here, we list the key molecular events in the intracellular life cycle of Brucella that are potentially targeted by the VirB T4SS effectors. Elucidating the functions of these effectors will help clarify the molecular role of T4SS during infection. Furthermore, studying the effectors secreted by Brucella spp. might provide insights into the mechanisms used by the bacteria to hijack the host signaling pathways and aid in the development of better vaccines and therapies against brucellosis. PMID:26528442

Type IV secretion system of Brucella spp. and its effectors.

PubMed

Ke, Yuehua; Wang, Yufei; Li, Wengfeng; Chen, Zeliang

2015-01-01

Brucella spp. are intracellular bacterial pathogens that cause infection in domestic and wild animals. They are often used as model organisms to study intracellular bacterial infections. Brucella VirB T4SS is a key virulence factor that plays important roles in mediating intracellular survival and manipulating host immune response to infection. In this review, we discuss the roles of Brucella VirB T4SS and 15 effectors that are proposed to be crucial for Brucella pathogenesis. VirB T4SS regulates the inflammation response and manipulates vesicle trafficking inside host cells. VirB T4SS also plays crucial roles in the inhibition of the host immune response and intracellular survival during infection. Here, we list the key molecular events in the intracellular life cycle of Brucella that are potentially targeted by the VirB T4SS effectors. Elucidating the functions of these effectors will help clarify the molecular role of T4SS during infection. Furthermore, studying the effectors secreted by Brucella spp. might provide insights into the mechanisms used by the bacteria to hijack the host signaling pathways and aid in the development of better vaccines and therapies against brucellosis.

Y-box-binding protein 1 interacts with hepatitis C virus NS3/4A and influences the equilibrium between viral RNA replication and infectious particle production.

PubMed

Chatel-Chaix, Laurent; Melançon, Pierre; Racine, Marie-Ève; Baril, Martin; Lamarre, Daniel

2011-11-01

The hepatitis C virus (HCV) NS3/4A protein has several essential roles in the virus life cycle, most probably through dynamic interactions with host factors. To discover cellular cofactors that are co-opted by HCV for its replication, we elucidated the NS3/4A interactome using mass spectrometry and identified Y-box-binding protein 1 (YB-1) as an interacting partner of NS3/4A protein and HCV genomic RNA. Importantly, silencing YB-1 expression decreased viral RNA replication and severely impaired the propagation of the infectious HCV molecular clone JFH-1. Immunofluorescence studies further revealed a drastic HCV-dependent redistribution of YB-1 to the surface of the lipid droplets, an important organelle for HCV assembly. Core and NS3 protein-dependent polyprotein maturation were shown to be required for YB-1 relocalization. Unexpectedly, YB-1 knockdown cells showed the increased production of viral infectious particles while HCV RNA replication was impaired. Our data support that HCV hijacks YB-1-containing ribonucleoparticles and that YB-1-NS3/4A-HCV RNA complexes regulate the equilibrium between HCV RNA replication and viral particle production.

GIS plays key role in NYC Rescue and Relief Operation

NASA Astrophysics Data System (ADS)

Showstack, Randy

New York City, Sept. 17—The posters of missing loved ones are pasted onto New York City walls and street signs six days after 2 hijacked commercial airlines destroyed the World Trade Center in lower Manhattan on September 11. Several miles uptown from “ground zero,” heightened security hovers around the city's Office of Emergency Management rescue and relief command center, an around-the-clock operation. Police, firefighters, military, officials with the Federal Emergency Management Agency, communications technicians, and a beehive of others work in controlled chaos in this cavernous, convention center-sized hall, lined with computers and adorned with several American flags.After the original command center at 7 World Trade Center collapsed to rubble as an after-effect of the plane strikes, city officials scrambled to recreate it. Alan Leidner, director of New York's citywide geographic information systems (GIS), and who is with the Department of Information Technology and Telecommunications, knew that maps would be an integral component of the rescue and relief efforts. Maps provide emergency workers and others with accurate and detailed scientific data in the form of visual aids upon which they can make informed decisions.

The HIV glycan shield as a target for broadly neutralizing antibodies.

PubMed

Doores, Katie J

2015-12-01

The HIV envelope glycoprotein (Env) is the sole target for HIV broadly neutralizing antibodies (bnAbs). HIV Env is one of the most heavily glycosylated proteins known, with approximately half of its mass consisting of host-derived N-linked glycans. The high density of glycans creates a shield that impedes antibody recognition but, critically, some of the most potent and broadly active bnAbs have evolved to recognize epitopes formed by these glycans. Although the virus hijacks the host protein synthesis and glycosylation machinery to generate glycosylated HIV Env, studies have shown that HIV Env glycosylation diverges from that typically observed on host-derived glycoproteins. In particular, the high density of glycans leads to a nonself motif of underprocessed oligomannose-type glycans that forms the target of some of the most broad and potent HIV bnAbs. This review discusses the changing perception of the HIV glycan shield, and summarizes the protein-directed and cell-directed factors controlling HIV Env glycosylation that impact on HIV bnAb recognition and HIV vaccine design strategies. © The Author. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Human T Cell Leukemia Virus Type 1 Tax Inhibits Innate Antiviral Signaling via NF-κB-Dependent Induction of SOCS1▿

PubMed Central

Charoenthongtrakul, Soratree; Zhou, Qinjie; Shembade, Noula; Harhaj, Nicole S.; Harhaj, Edward W.

2011-01-01

Human T cell leukemia virus type 1 (HTLV-1) inhibits host antiviral signaling pathways although the underlying mechanisms are unclear. Here we found that the HTLV-1 Tax oncoprotein induced the expression of SOCS1, an inhibitor of interferon signaling. Tax required NF-κB, but not CREB, to induce the expression of SOCS1 in T cells. Furthermore, Tax interacted with SOCS1 in both transfected cells and in HTLV-1-transformed cell lines. Although SOCS1 is normally a short-lived protein, in the presence of Tax, the stability of SOCS1 was greatly increased. Accordingly, Tax enhanced the replication of a heterologous virus, vesicular stomatitis virus (VSV), in a SOCS1-dependent manner. Surprisingly, Tax required SOCS1 to inhibit RIG-I-dependent antiviral signaling, but not the interferon-induced JAK/STAT pathway. Inhibition of SOCS1 by RNA-mediated interference in the HTLV-1-transformed cell line MT-2 resulted in increased IFN-β expression accompanied by reduced HTLV-1 replication and p19Gag levels. Taken together, our results reveal that Tax inhibits antiviral signaling, in part, by hijacking an interferon regulatory protein. PMID:21593151

Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis

PubMed Central

Nichols, Daniel Brian; De Martini, William; Cottrell, Jessica

2017-01-01

Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: Orthopoxvirus, Molluscipoxvirus, and Leporipoxvirus. All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence. PMID:28786952

The Mediator Complex Subunit PFT1 Is a Key Regulator of Jasmonate-Dependent Defense in Arabidopsis[C][W

PubMed Central

Kidd, Brendan N.; Edgar, Cameron I.; Kumar, Krish K.; Aitken, Elizabeth A.; Schenk, Peer M.; Manners, John M.; Kazan, Kemal

2009-01-01

Jasmonate signaling plays an important role in both plant defense and development. Here, we have identified a subunit of the Mediator complex as a regulator of the jasmonate signaling pathway in Arabidopsis thaliana. The Mediator complex is a conserved multiprotein complex that acts as a universal adaptor between transcription factors and the RNA polymerase II transcriptional machinery. We report that the PHYTOCHROME AND FLOWERING TIME1 (PFT1) gene, which encodes the MEDIATOR25 subunit of Mediator, is required for jasmonate-dependent defense gene expression and resistance to leaf-infecting necrotrophic fungal pathogens. Conversely, PFT1 appears to confer susceptibility to Fusarium oxysporum, a root-infecting hemibiotrophic fungal pathogen known to hijack jasmonate responses for disease development. Consistent with this, jasmonate gene expression was suppressed in the pft1 mutant during infection with F. oxysporum. In addition, a wheat (Triticum aestivum) homolog of PFT1 complemented the defense and the developmental phenotypes of the pft1 mutant, suggesting that the jasmonate signaling functions of PFT1 may be conserved in higher plants. Overall, our results identify an important control point in the regulation of the jasmonate signaling pathway within the transcriptional machinery. PMID:19671879

Rift Valley fever virus NSs protein functions and the similarity to other bunyavirus NSs proteins.

PubMed

Ly, Hoai J; Ikegami, Tetsuro

2016-07-02

Rift Valley fever is a mosquito-borne zoonotic disease that affects both ruminants and humans. The nonstructural (NS) protein, which is a major virulence factor for Rift Valley fever virus (RVFV), is encoded on the S-segment. Through the cullin 1-Skp1-Fbox E3 ligase complex, the NSs protein promotes the degradation of at least two host proteins, the TFIIH p62 and the PKR proteins. NSs protein bridges the Fbox protein with subsequent substrates, and facilitates the transfer of ubiquitin. The SAP30-YY1 complex also bridges the NSs protein with chromatin DNA, affecting cohesion and segregation of chromatin DNA as well as the activation of interferon-β promoter. The presence of NSs filaments in the nucleus induces DNA damage responses and causes cell-cycle arrest, p53 activation, and apoptosis. Despite the fact that NSs proteins have poor amino acid similarity among bunyaviruses, the strategy utilized to hijack host cells are similar. This review will provide and summarize an update of recent findings pertaining to the biological functions of the NSs protein of RVFV as well as the differences from those of other bunyaviruses.

Ultrastructure of the replication sites of positive-strand RNA viruses

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

Harak, Christian; Lohmann, Volker, E-mail: volker_lohmann@med.uni-heidelberg.de

2015-05-15

Positive strand RNA viruses replicate in the cytoplasm of infected cells and induce intracellular membranous compartments harboring the sites of viral RNA synthesis. These replication factories are supposed to concentrate the components of the replicase and to shield replication intermediates from the host cell innate immune defense. Virus induced membrane alterations are often generated in coordination with host factors and can be grouped into different morphotypes. Recent advances in conventional and electron microscopy have contributed greatly to our understanding of their biogenesis, but still many questions remain how viral proteins capture membranes and subvert host factors for their need. Inmore » this review, we will discuss different representatives of positive strand RNA viruses and their ways of hijacking cellular membranes to establish replication complexes. We will further focus on host cell factors that are critically involved in formation of these membranes and how they contribute to viral replication. - Highlights: • Positive strand RNA viruses induce massive membrane alterations. • Despite the great diversity, replication complexes share many similarities. • Host factors play a pivotal role in replication complex biogenesis. • Use of the same host factors by several viruses hints to similar functions.« less

An atlas of the human kinome reveals the mutational landscape underlying dysregulated phosphorylation cascades in cancer

PubMed Central

Olow, Aleksandra; Chen, Zhongzhong; Niedner, R. Hannes; Wolf, Denise M.; Yau, Christina; Pankov, Aleksandr; Lee, Evelyn Pei Rong; Brown-Swigart, Lamorna; van’t Veer, Laura J.; Coppé, Jean-Philippe

2016-01-01

Kinase inhibitors are used widely to treat various cancers, but adaptive reprogramming of kinase cascades and activation of feedback loop mechanisms often contribute to therapeutic resistance. Determining comprehensive, accurate maps of kinase circuits may therefore help elucidate mechanisms of response and resistance to kinase inhibitor therapies. In this study, we identified and validated phosphorylatable target sites across human cell and tissue types to generate PhosphoAtlas, a map of 1,733 functionally interconnected proteins comprising the human phospho-reactome. A systematic curation approach was used to distill protein phosphorylation data cross-referenced from 38 public resources. We demonstrated how a catalog of 2,617 stringently verified heptameric peptide regions at the catalytic interface of kinases and substrates could expose mutations that recurrently perturb specific phospho-hubs. In silico mapping of 2,896 nonsynonymous tumor variants identified from thousands of tumor tissues, also revealed that normal and aberrant catalytic interactions co-occur frequently, showing how tumors systematically hijack, as well as spare, particular sub-networks. Overall, our work provides an important new resource for interrogating the human tumor kinome to strategically identify therapeutically actionable kinase networks which drive tumorigenesis. PMID:26921330

A Xanthomonas oryzae pv. oryzae effector, XopR, associates with receptor-like cytoplasmic kinases and suppresses PAMP-triggered stomatal closure.

PubMed

Wang, Shuangfeng; Sun, Jianhang; Fan, Fenggui; Tan, Zhaoyun; Zou, Yanmin; Lu, Dongping

2016-09-01

Receptor-like kinases (RLKs) play important roles in plant immunity signaling; thus, many are hijacked by pathogen effectors to promote successful pathogenesis. Xanthomonas oryzae pv. oryzae (Xoo) is the causal agent of rice leaf blight disease. The strain PXO99A has 18 non-TAL (transcription activation-like) effectors; however, their mechanisms of action and host target proteins remain largely unknown. Although the effector XopR from the Xoo strain MAFF311018 was shown to suppress PAMP-triggered immune responses in Arabidopsis, its target has not yet been identified. Here, we show that PXO99A XopR interacts with BIK1 at the plasma membrane. BIK1 is a receptor-like cytoplasmic kinase (RLCK) belonging to the RLK family of proteins and mediates PAMP-triggered stomatal immunity. In turn, BIK1 phosphorylates XopR. Furthermore, XopR suppresses PAMP-triggered stomatal closure in transgenic Arabidopsis expressing XopR. In addition, XopR is able to associate with RLCKs other than BIK1. These results suggest that XopR likely suppresses plant immunity by targeting BIK1 and other RLCKs.

The targeting of plant cellular systems by injected type III effector proteins.

PubMed

Lewis, Jennifer D; Guttman, David S; Desveaux, Darrell

2009-12-01

The battle between phytopathogenic bacteria and their plant hosts has revealed a diverse suite of strategies and mechanisms employed by the pathogen or the host to gain the higher ground. Pathogens continually evolve tactics to acquire host resources and dampen host defences. Hosts must evolve surveillance and defence systems that are sensitive enough to rapidly respond to a diverse range of pathogens, while reducing costly and damaging inappropriate misexpression. The primary virulence mechanism employed by many bacteria is the type III secretion system, which secretes and translocates effector proteins directly into the cells of their plant hosts. Effectors have diverse enzymatic functions and can target specific components of plant systems. While these effectors should favour bacterial fitness, the host may be able to thwart infection by recognizing the activity or presence of these foreign molecules and initiating retaliatory immune measures. We review the diverse host cellular systems exploited by bacterial effectors, with particular focus on plant proteins directly targeted by effectors. Effector-host interactions reveal different stages of the battle between pathogen and host, as well as the diverse molecular strategies employed by bacterial pathogens to hijack eukaryotic cellular systems.

Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila.

PubMed

Lamiable, Olivier; Kellenberger, Christine; Kemp, Cordula; Troxler, Laurent; Pelte, Nadège; Boutros, Michael; Marques, Joao Trindade; Daeffler, Laurent; Hoffmann, Jules A; Roussel, Alain; Imler, Jean-Luc

2016-01-19

Viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. Rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. For example, many vertebrate DNA viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. Insect viruses express suppressors of RNA interference or apoptosis, highlighting the importance of these cell intrinsic antiviral mechanisms in invertebrates. Here, we report the identification and characterization of a family of proteins encoded by insect DNA viruses that are homologous to a 12-kDa circulating protein encoded by the virus-induced Drosophila gene diedel (die). We show that die mutant flies have shortened lifespan and succumb more rapidly than controls when infected with Sindbis virus. This reduced viability is associated with deregulated activation of the immune deficiency (IMD) pathway of host defense and can be rescued by mutations in the genes encoding the homolog of IKKγ or IMD itself. Our results reveal an endogenous pathway that is exploited by insect viruses to modulate NF-κB signaling and promote fly survival during the antiviral response.

Site management of health issues in the 2001 World Trade Center disaster.

PubMed

Bradt, David A

2003-06-01

The terrorist destruction of the World Trade Center led to the greatest loss of life from a criminal incident in the history of the United States. There were 2,801 persons killed or missing at the disaster site, including 147 dead on two hijacked aircraft. Hundreds of buildings sustained direct damage or contamination. Forty different agencies responded with command and control exercised by an incident command system as well as an emergency operations center. Dozens of hazards complicated relief and recovery efforts. Five victims were rescued from the rubble. Up to 1,000 personnel worked daily at the World Trade Center disaster site. These workers collectively made an average of 270 daily presentations to health care providers in the first month post-disaster. Of presentations for clinical symptoms, leading clinical diagnoses were ocular injuries, headaches, and lung injuries. Mechanical injury accounted for 39% of clinical presentations and appeared preventable by personal protective equipment. Limitations emerged in the site application of emergency triage and clinical care. Notable assets in the site management of health issues include action plans from the incident command system, geographic information system products, wireless application technology, technical consensus among health and safety authorities, and workers' respite care.

A Molecular Sensor To Characterize Arenavirus Envelope Glycoprotein Cleavage by Subtilisin Kexin Isozyme 1/Site 1 Protease.

PubMed

Oppliger, Joel; da Palma, Joel Ramos; Burri, Dominique J; Bergeron, Eric; Khatib, Abdel-Majid; Spiropoulou, Christina F; Pasquato, Antonella; Kunz, Stefan

2016-01-15

Arenaviruses are emerging viruses including several causative agents of severe hemorrhagic fevers in humans. The advent of next-generation sequencing technology has greatly accelerated the discovery of novel arenavirus species. However, for many of these viruses, only genetic information is available, and their zoonotic disease potential remains unknown. During the arenavirus life cycle, processing of the viral envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P) is crucial for productive infection. The ability of newly emerging arenaviruses to hijack human SKI-1/S1P appears, therefore, to be a requirement for efficient zoonotic transmission and human disease potential. Here we implement a newly developed cell-based molecular sensor for SKI-1/S1P to characterize the processing of arenavirus GPC-derived target sequences by human SKI-1/S1P in a quantitative manner. We show that only nine amino acids flanking the putative cleavage site are necessary and sufficient to accurately recapitulate the efficiency and subcellular location of arenavirus GPC processing. In a proof of concept, our sensor correctly predicts efficient processing of the GPC of the newly emergent pathogenic Lujo virus by human SKI-1/S1P and defines the exact cleavage site. Lastly, we employed our sensor to show efficient GPC processing of a panel of pathogenic and nonpathogenic New World arenaviruses, suggesting that GPC cleavage represents no barrier for zoonotic transmission of these pathogens. Our SKI-1/S1P sensor thus represents a rapid and robust test system for assessment of the processing of putative cleavage sites derived from the GPCs of newly discovered arenavirus by the SKI-1/S1P of humans or any other species, based solely on sequence information. Arenaviruses are important emerging human pathogens that can cause severe hemorrhagic fevers with high mortality in humans. A crucial step in productive arenavirus infection of human cells is the processing of the viral envelope glycoprotein by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). In order to break the species barrier during zoonotic transmission and cause severe disease in humans, newly emerging arenaviruses must be able to hijack human SKI-1/S1P efficiently. Here we implement a newly developed cell-based molecular sensor for human SKI-1/S1P to characterize the processing of arenavirus glycoproteins in a quantitative manner. We further use our sensor to correctly predict efficient processing of the glycoprotein of the newly emergent pathogenic Lujo virus by human SKI-1/S1P. Our sensor thus represents a rapid and robust test system with which to assess whether the glycoprotein of any newly emerging arenavirus can be efficiently processed by human SKI-1/S1P, based solely on sequence information. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes.

PubMed

Ronca, Roberto; Van Ginderachter, Jo A; Turtoi, Andrei

2018-01-01

Tumor stroma is composed of many cellular subtypes, of which the most abundant are fibroblasts, macrophages and endothelial cells. During the process of tissue injury, these three cellular subtypes must coordinate their activity to efficiently contribute to tissue regeneration. In tumor, this mechanism is hijacked by cancer cells, which rewire the interaction of stromal cells to benefit tumor development. The present review aims at summarizing most relevant information concerning both pro-tumorigenic and anti-tumorigenic actions implicating the three stromal cell subtypes as well as their mutual interactions. Although stromal cells are generally regarded as tumor-supportive and at will manipulated by cancer cells, several novel studies point at many defaults in cancer cell-mediated stromal reprograming. Indeed, parts of initial tissue-protective and homeostatic functions of the stromal cells remain in place even after tumor development. Both tumor-supportive and tumor-suppressive functions have been well described for macrophages, whereas similar results are emerging for fibroblasts and endothelial cells. Recent success of immunotherapies have finally brought the long awaited proof that stroma is key for efficient tumor targeting. However, a better understanding of paracrine stromal interactions is needed in order to encourage drug development not only aiming at disruption of tumor-supportive communication but also re-enforcing, existing, tumor-suppressive mechanisms.

NMR Structure of the Myristylated Feline Immunodeficiency Virus Matrix Protein

PubMed Central

Brown, Lola A.; Cox, Cassiah; Baptiste, Janae; Summers, Holly; Button, Ryan; Bahlow, Kennedy; Spurrier, Vaughn; Kyser, Jenna; Luttge, Benjamin G.; Kuo, Lillian; Freed, Eric O.; Summers, Michael F.

2015-01-01

Membrane targeting by the Gag proteins of the human immunodeficiency viruses (HIV types-1 and -2) is mediated by Gag’s N-terminally myristylated matrix (MA) domain and is dependent on cellular phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. To determine if other lentiviruses employ a similar membrane targeting mechanism, we initiated studies of the feline immunodeficiency virus (FIV), a widespread feline pathogen with potential utility for development of human therapeutics. Bacterial co-translational myristylation was facilitated by mutation of two amino acids near the amino-terminus of the protein (Q5A/G6S; myrMAQ5A/G6S). These substitutions did not affect virus assembly or release from transfected cells. NMR studies revealed that the myristyl group is buried within a hydrophobic pocket in a manner that is structurally similar to that observed for the myristylated HIV-1 protein. Comparisons with a recent crystal structure of the unmyristylated FIV protein [myr(-)MA] indicate that only small changes in helix orientation are required to accommodate the sequestered myr group. Depletion of PI(4,5)P2 from the plasma membrane of FIV-infected CRFK cells inhibited production of FIV particles, indicating that, like HIV, FIV hijacks the PI(4,5)P2 cellular signaling system to direct intracellular Gag trafficking during virus assembly. PMID:25941825

Purinergic Signaling in Neuron-Astrocyte Interactions, Circadian Rhythms, and Alcohol Use Disorder

PubMed Central

Lindberg, Daniel; Andres-Beck, Lindsey; Jia, Yun-Fang; Kang, Seungwoo; Choi, Doo-Sup

2018-01-01

Alcohol use disorder (AUD) is a debilitating condition marked by cyclic patterns of craving, use, and withdrawal. These pathological behaviors are mediated by multiple neurotransmitter systems utilizing glutamate, GABA, dopamine, ATP, and adenosine. In particular, purines such as ATP and adenosine have been demonstrated to alter the phase and function of the circadian clock and are reciprocally regulated by the clock itself. Importantly, chronic ethanol intake has been demonstrated to disrupt the molecular circadian clock and is associated with altered circadian patterns of activity and sleep. Moreover, ethanol has been demonstrated to disrupt purinergic signaling, while dysfunction of the purinergic system has been implicated in conditions of drug abuse such as AUD. In this review, we summarize our current knowledge regarding circadian disruption by ethanol, focusing on the reciprocal relationship that exists between oscillatory neurotransmission and the molecular circadian clock. In particular, we offer detailed explanations and hypotheses regarding the concerted regulation of purinergic signaling and circadian oscillations by neurons and astrocytes, and review the diverse mechanisms by which purinergic dysfuction may contribute to circadian disruption or alcohol abuse. Finally, we describe the mechanisms by which ethanol may disrupt or hijack endogenous circadian rhythms to induce the maladaptive behavioral patterns associated with AUD. PMID:29467662

Chronic cocaine disrupts mesocortical learning mechanisms

PubMed Central

Buchta, William C.; Riegel, Arthur C.

2016-01-01

The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extra-synaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts. PMID:25704202

Translational control by eIF2α phosphorylation regulates vulnerability to the synaptic and behavioral effects of cocaine

PubMed Central

Huang, Wei; Placzek, Andon N; Viana Di Prisco, Gonzalo; Khatiwada, Sanjeev; Sidrauski, Carmela; Krnjević, Krešimir; Walter, Peter; Dani, John A; Costa-Mattioli, Mauro

2016-01-01

Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)—whose disruption is postulated to increase vulnerability to drug addiction—was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction. DOI: http://dx.doi.org/10.7554/eLife.12052.001 PMID:26928234

Local and systemic tumor immune dynamics

NASA Astrophysics Data System (ADS)

Enderling, Heiko

Tumor-associated antigens, stress proteins, and danger-associated molecular patterns are endogenous immune adjuvants that can both initiate and continually stimulate an immune response against a tumor. In retaliation, tumors can hijack intrinsic immune regulatory programs that are intended to prevent autoimmune disease, thereby facilitating continued growth despite the activated antitumor immune response. In metastatic disease, this ongoing tumor-immune battle occurs at each site. Adding an additional layer of complexity, T cells activated at one tumor site can cycle through the blood circulation system and extravasate in a different anatomic location to surveil a distant metastasis. We propose a mathematical modeling framework that incorporates the trafficking of activated T cells between metastatic sites. We extend an ordinary differential equation model of tumor-immune system interactions to multiple metastatic sites. Immune cells are activated in response to tumor burden and tumor cell death, and are recruited from tumor sites elsewhere in the body. A model of T cell trafficking throughout the circulatory system can inform the tumor-immune interaction model about the systemic distribution and arrival of T cells at specific tumor sites. Model simulations suggest that metastases not only contribute to immune surveillance, but also that this contribution varies between metastatic sites. Such information may ultimately help harness the synergy of focal therapy with the immune system to control metastatic disease.

Attenuated CagA oncoprotein in Helicobacter pylori from Amerindians in Peruvian Amazon.

PubMed

Suzuki, Masato; Kiga, Kotaro; Kersulyte, Dangeruta; Cok, Jaime; Hooper, Catherine C; Mimuro, Hitomi; Sanada, Takahito; Suzuki, Shiho; Oyama, Masaaki; Kozuka-Hata, Hiroko; Kamiya, Shigeru; Zou, Quan-Ming; Gilman, Robert H; Berg, Douglas E; Sasakawa, Chihiro

2011-08-26

Population genetic analyses of bacterial genes whose products interact with host tissues can give new understanding of infection and disease processes. Here we show that strains of the genetically diverse gastric pathogen Helicobacter pylori from Amerindians from the remote Peruvian Amazon contain novel alleles of cagA, a major virulence gene, and reveal distinctive properties of their encoded CagA proteins. CagA is injected into the gastric epithelium where it hijacks pleiotropic signaling pathways, helps Hp exploit its special gastric mucosal niche, and affects the risk that infection will result in overt gastroduodenal diseases including gastric cancer. The Amerindian CagA proteins contain unusual but functional tyrosine phosphorylation motifs and attenuated CRPIA motifs, which affect gastric epithelial proliferation, inflammation, and bacterial pathogenesis. Amerindian CagA proteins induced less production of IL-8 and cancer-associated Mucin 2 than did those of prototype Western or East Asian strains and behaved as dominant negative inhibitors of action of prototype CagA during mixed infection of Mongolian gerbils. We suggest that Amerindian cagA is of relatively low virulence, that this may have been selected in ancestral strains during infection of the people who migrated from Asia into the Americas many thousands of years ago, and that such attenuated CagA proteins could be useful therapeutically.

Amoeba host-Legionella synchronization of amino acid auxotrophy and its role in bacterial adaptation and pathogenic evolution

PubMed Central

Price, Christopher T. D.; Richards, Ashley M.; Von Dwingelo, Juanita E.; Samara, Hala A.; Kwaik, Yousef Abu

2013-01-01

Summary Legionella pneumophila, the causative agent of Legionnaires’ disease, invades and proliferates within a diverse range of free-living amoeba in the environment but upon transmission to humans the bacteria hijack alveolar macrophages. Intracellular proliferation of L. pneumophila in two evolutionarily distant hosts is facilitated by bacterial exploitation of conserved host processes that are targeted by bacterial protein effectors injected into the host cell. A key aspect of microbe-host interaction is microbial extraction of nutrients from the host but understanding of this is still limited. AnkB functions as a nutritional virulence factor and promotes host proteasomal degradation of polyubiquitinated proteins generating gratuitous levels of limiting host cellular amino acids. L. pneumophila is auxotrophic for several amino acids including cysteine, which is a metabolically preferred source of carbon and energy during intracellular proliferation, but is limiting in both amoebae and humans. We propose that synchronization of bacterial amino acids auxotrophy with the host is a driving force in pathogenic evolution and nutritional adaptation of L. pneumophila and other intracellular bacteria to life within the host cell. Understanding microbial strategies of nutrient generation and acquisition in the host will provide novel antimicrobial strategies to disrupt pathogen access to essential sources of carbon and energy. PMID:24112119

Development of a stress response therapy targeting aggressive prostate cancer.

PubMed

Nguyen, Hao G; Conn, Crystal S; Kye, Yae; Xue, Lingru; Forester, Craig M; Cowan, Janet E; Hsieh, Andrew C; Cunningham, John T; Truillet, Charles; Tameire, Feven; Evans, Michael J; Evans, Christopher P; Yang, Joy C; Hann, Byron; Koumenis, Constantinos; Walter, Peter; Carroll, Peter R; Ruggero, Davide

2018-05-02

Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2-α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain

PubMed Central

Courret, Nathalie; Darche, Sylvie; Sonigo, Pierre; Milon, Geneviève; Buzoni-Gâtel, Dominique; Tardieux, Isabelle

2006-01-01

The protozoan parasite Toxoplasma gondii enters hosts through the intestinal mucosa and colonizes distant tissues such as the brain, where its progeny persists for a lifetime. We investigated the role of CD11c- and CD11b-expressing leukocytes in T gondii transport during the early step of parasitism from the mouse small intestine and during subsequent parasite localization in the brain. Following intragastric inoculation of cyst-containing parasites in mice, CD11c+ dendritic cells from the intestinal lamina propria, the Peyer patches, and the mesenteric lymph nodes were parasitized while in the blood, parasites were associated with the CD11c- CD11b+ monocytes. Using adoptive transfer experiments, we demonstrated that these parasitized cells triggered a parasitic process in the brain of naive recipient mice. Ex vivo analysis of parasitized leukocytes showed that single tachyzoites remained at the cell periphery, often surrounded by the host cell plasma membrane, but did not divide. Using either a dye that labels circulating leukocytes or an antibody known to prevent CD11b+ circulating leukocytes from leaving the microvascular bed lumen, and chimeric mice in which the hematopoietic cells expressed the green fluorescent protein, we established that T gondii zoites hijacked CD11b+ leukocytes to reach the brain extravascular space. PMID:16051744

Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis

PubMed Central

Moore, Jason T; Chen, Jingqiu; Han, Bo; Meng, Qing Cheng; Veasey, Sigrid C; Beck, Sheryl G; Kelz, Max B

2013-01-01

Summary Background Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep. Results Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, while neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized, but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance. Conclusions Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties. PMID:23103189

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

PubMed Central

Sheng, Xinlei; Song, Bokai; Cristea, Ileana M.

2016-01-01

In mammalian cells, early defenses against infection by pathogens are mounted through a complex network of signaling pathways shepherded by immune-modulatory pattern-recognition receptors. As obligate parasites, the survival of viruses is dependent upon the evolutionary acquisition of mechanisms that tactfully dismantle and subvert the cellular intrinsic and innate immune responses. Here, we review the diverse mechanisms by which viruses that accommodate DNA genomes are able to circumvent activation of cellular immunity. We start by discussing viral manipulation of host defense protein levels by either transcriptional regulation or protein degradation. We next review viral strategies used to repurpose or inhibit these cellular immune factors by molecular hijacking or by regulating their post-translational modification status. Additionally, we explore the infection-induced temporal modulation of apoptosis to facilitate viral replication and spread. Lastly, the co-evolution of viruses with their hosts is highlighted by the acquisition of elegant mechanisms for suppressing host defenses via viral mimicry of host factors. In closing, we present a perspective on how characterizing these viral evasion tactics both broadens the understanding of virus-host interactions and reveals essential functions of the immune system at the molecular level. This knowledge is critical in understanding the sources of viral pathogenesis, as well as for the design of antiviral therapeutics and autoimmunity treatments. PMID:27650455

Insights into the nuclear export of murine leukemia virus intron-containing RNA.

PubMed

Pessel-Vivares, Lucie; Houzet, Laurent; Lainé, Sébastien; Mougel, Marylène

2015-01-01

The retroviral genome consists of an intron-containing transcript that has essential cytoplasmic functions in the infected cell. This viral transcript can escape splicing, circumvent the nuclear checkpoint mechanisms and be transported to the cytoplasm by hijacking the host machinery. Once in the cytoplasm, viral unspliced RNA acts as mRNA to be translated and as genomic RNA to be packaged into nascent viruses. The murine leukemia virus (MLV) is among the first retroviruses discovered and is classified as simple Retroviridae due to its minimal encoding capacity. The oncogenic and transduction abilities of MLV are extensively studied, whereas surprisingly the crucial step of its nuclear export has remained unsolved until 2014. Recent work has revealed the recruitment by MLV of the cellular NXF1/Tap-dependent pathway for export. Unconventionally, MLV uses of Tap to export both spliced and unspliced viral RNAs. Unlike other retroviruses, MLV does not harbor a unique RNA signal for export. Indeed, multiple sequences throughout the MLV genome appear to promote export of the unspliced MLV RNA. We review here the current understanding of the export mechanism and highlight the determinants that influence MLV export. As the molecular mechanism of MLV export is elucidated, we will gain insight into the contribution of the export pathway to the cytoplasmic fate of the viral RNA.

Tail proteins of phage T5: investigation of the effect of the His6-tag position, from expression to crystallisation.

PubMed

Noirclerc-Savoye, Marjolaine; Flayhan, Ali; Pereira, Cindy; Gallet, Benoit; Gans, Pierre; Ebel, Christine; Breyton, Cécile

2015-05-01

Upon binding to its bacterial host receptor, the tail tip of phage T5 perforates, by an unknown mechanism, the heavily armoured cell wall of the host. This allows the injection of phage DNA into the cytoplasm to hijack the cell machinery and enable the production of new virions. In the perspective of a structural study of the phage tail, we have systematically overproduced eight of the eleven T5 tail proteins, with or without a N- or a C-terminal His6-tag. The widely used Hi6-tag is very convenient to purify recombinant proteins using immobilised-metal affinity chromatography. The presence of a tag however is not always innocuous. We combined automated gene cloning and expression tests to rapidly identify the most promising constructs for proteins of phage T5 tail, and performed biochemical and biophysical characterisation and crystallisation screening on available proteins. Automated small-scale purification was adapted for two highly expressed proteins. We obtained structural information for three of the proteins. We showed that the presence of a His6-tag can have drastic effect on protein expression, solubility, oligomerisation propensity and crystal quality. Copyright © 2015 Elsevier Inc. All rights reserved.

Recent Progress in Understanding Coxsackievirus Replication, Dissemination, and Pathogenesis

PubMed Central

Sin, Jon; Mangale, Vrushali; Thienphrapa, Wdee; Gottlieb, Roberta A.; Feuer, Ralph

2015-01-01

Coxsackieviruses (CVs) are relatively common viruses associated with a number of serious human diseases, including myocarditis and meningo-encephalitis. These viruses are considered cytolytic yet can persist for extended periods of time within certain host tissues requiring evasion from the host immune response and a greatly reduced rate of replication. A member of Picornaviridae family, CVs have been historically considered non-enveloped viruses – although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection and the establishment of chronic disease in adults. CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis. PMID:26142496

Genome Wide Identification and Expression Profiling of SWEET Genes Family Reveals Its Role During Plasmodiophora brassicae-Induced Formation of Clubroot in Brassica rapa.

PubMed

Li, Hong; Li, Xiaonan; Xuan, Yuanhu; Jiang, Jing; Wei, Yangdou; Piao, Zhongyun

2018-01-01

Plasmodiophora brassicae is a soil borne pathogen and the causal agent of clubroot, a devastating disease of Brassica crops. The pathogen lives inside roots, and hijacks nutrients from the host plants. It is suggested that clubroot galls created an additional nutrient sink in infected roots. However, the molecular mechanism underlying P. brassicae infection and sugar transport is unclear. Here, we analyzed sugar contents in leaves and roots before and after P. brassicae infection using a pair of Chinese cabbage near-isogenic lines (NILs), carrying either a clubroot resistant (CR) or susceptible (CS) allele at the CRb locus. P. brassicae infection caused significant increase of glucose and fructose contents in the root of CS-NIL compared to CR-NIL, suggesting that sugar translocation and P. brassicae growth are closely related. Among 32 B. rapa SWEET homologs, several BrSWEETs belonging to Clade I and III were significantly up-regulated, especially in CS-NIL upon P. brassicae infection. Moreover, Arabidopsis sweet11 mutant exhibited slower gall formation compared to the wild-type plants. Our studies suggest that P. brassicae infection probably triggers active sugar translocation between the sugar producing tissues and the clubbed tissues, and the SWEET family genes are involved in this process.

SWEET sugar transporters for phloem transport and pathogen nutrition.

PubMed

Chen, Li-Qing

2014-03-01

Many intercellular solute transport processes require an apoplasmic step, that is, efflux from one cell and subsequent uptake by an adjacent cell. Cellular uptake transporters have been identified for many solutes, including sucrose; however, efflux transporters have remained elusive for a long time. Cellular efflux of sugars plays essential roles in many processes, such as sugar efflux as the first step in phloem loading, sugar efflux for nectar secretion, and sugar efflux for supplying symbionts such as mycorrhiza, and maternal efflux for filial tissue development. Furthermore, sugar efflux systems can be hijacked by pathogens for access to nutrition from hosts. Mutations that block recruitment of the efflux mechanism by the pathogen thus cause pathogen resistance. Until recently, little was known regarding the underlying mechanism of sugar efflux. The identification of sugar efflux carriers, SWEETs (Sugars Will Eventually be Exported Transporters), has shed light on cellular sugar efflux. SWEETs appear to function as uniporters, facilitating diffusion of sugars across cell membranes. Indeed, SWEETs probably mediate sucrose efflux from putative phloem parenchyma into the phloem apoplasm, a key step proceeding phloem loading. Engineering of SWEET mutants using transcriptional activator-like effector nuclease (TALEN)-based genomic editing allowed the engineering of pathogen resistance. The widespread expression of the SWEET family promises to provide insights into many other cellular efflux mechanisms.

Transcriptional Elongation Control of Hepatitis B Virus Covalently Closed Circular DNA Transcription by Super Elongation Complex and BRD4.

PubMed

Francisco, Joel Celio; Dai, Qian; Luo, Zhuojuan; Wang, Yan; Chong, Roxanne Hui-Heng; Tan, Yee Joo; Xie, Wei; Lee, Guan-Huei; Lin, Chengqi

2017-10-01

Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. HBV reactivation during or after chemotherapy is a potentially fatal complication for cancer patients with chronic HBV infection. Transcription of HBV is a critical intermediate step of the HBV life cycle. However, factors controlling HBV transcription remain largely unknown. Here, we found that different P-TEFb complexes are involved in the transcription of the HBV viral genome. Both BRD4 and the super elongation complex (SEC) bind to the HBV genome. The treatment of bromodomain inhibitor JQ1 stimulates HBV transcription and increases the occupancy of BRD4 on the HBV genome, suggesting the bromodomain-independent recruitment of BRD4 to the HBV genome. JQ1 also leads to the increased binding of SEC to the HBV genome, and SEC is required for JQ1-induced HBV transcription. These findings reveal a novel mechanism by which the HBV genome hijacks the host P-TEFb-containing complexes to promote its own transcription. Our findings also point out an important clinical implication, that is, the potential risk of HBV reactivation during therapy with a BRD4 inhibitor, such as JQ1 or its analogues, which are a potential treatment for acute myeloid leukemia. Copyright © 2017 American Society for Microbiology.

Quorum-quenching limits quorum-sensing exploitation by signal-negative invaders

NASA Astrophysics Data System (ADS)

Tannières, Mélanie; Lang, Julien; Barnier, Claudie; Shykoff, Jacqui A.; Faure, Denis

2017-01-01

Some bacteria produce and perceive quorum-sensing (QS) signals that coordinate several behaviours, including the costly processes that are exoenzyme production and plasmid transfer. In the case of plasmid transfer, the emergence of QS signal-altered invaders and their policing are poorly documented. In Agrobacterium tumefaciens, the virulence Ti-plasmid encodes both synthesis and sensing of QS-signals, which promote its transfer from a donor to a recipient cell. Here, we reported that QS-altered A. tumefaciens mutants arose during experimental evolution. All showed improved growth compared to their ancestor. Genome sequencing revealed that, though some had lost the Ti-plasmid, most were defective for QS-signal synthesis and Ti-plasmid conjugation (traR mutations) and one exhibited a QS-signal exploitation behaviour, using signal produced by other cells to enhance its own Ti-plasmid transfer. We explored mechanisms that can limit this QS-hijacking. We showed that the A. tumefaciens capacity to inactivate QS-signals by expressing QS-degrading enzyme could attenuate dissemination of the QS signal-negative Ti-plasmids. This work shows that enzymatic QS-disruption whether encoded by the QS-producing Ti-plasmid itself, by a companion plasmid in the same donor cells, or by one in the recipient cells, in all cases can serve as a mechanism for controlling QS exploitation by QS signal-negative mutants.

VirHostNet 2.0: surfing on the web of virus/host molecular interactions data.

PubMed

Guirimand, Thibaut; Delmotte, Stéphane; Navratil, Vincent

2015-01-01

VirHostNet release 2.0 (http://virhostnet.prabi.fr) is a knowledgebase dedicated to the network-based exploration of virus-host protein-protein interactions. Since the previous VirhostNet release (2009), a second run of manual curation was performed to annotate the new torrent of high-throughput protein-protein interactions data from the literature. This resource is shared publicly, in PSI-MI TAB 2.5 format, using a PSICQUIC web service. The new interface of VirHostNet 2.0 is based on Cytoscape web library and provides a user-friendly access to the most complete and accurate resource of virus-virus and virus-host protein-protein interactions as well as their projection onto their corresponding host cell protein interaction networks. We hope that the VirHostNet 2.0 system will facilitate systems biology and gene-centered analysis of infectious diseases and will help to identify new molecular targets for antiviral drugs design. This resource will also continue to help worldwide scientists to improve our knowledge on molecular mechanisms involved in the antiviral response mediated by the cell and in the viral strategies selected by viruses to hijack the host immune system. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Viral degradasome hijacks mitochondria to suppress innate immunity

PubMed Central

Goswami, Ramansu; Majumdar, Tanmay; Dhar, Jayeeta; Chattopadhyay, Saurabh; Bandyopadhyay, Sudip K; Verbovetskaya, Valentina; Sen, Ganes C; Barik, Sailen

2013-01-01

The balance between the innate immunity of the host and the ability of a pathogen to evade it strongly influences pathogenesis and virulence. The two nonstructural (NS) proteins, NS1 and NS2, of respiratory syncytial virus (RSV) are critically required for RSV virulence. Together, they strongly suppress the type I interferon (IFN)-mediated innate immunity of the host cells by degrading or inhibiting multiple cellular factors required for either IFN induction or response pathways, including RIG-I, IRF3, IRF7, TBK1 and STAT2. Here, we provide evidence for the existence of a large and heterogeneous degradative complex assembled by the NS proteins, which we named “NS-degradasome” (NSD). The NSD is roughly ∼300-750 kD in size, and its degradative activity was enhanced by the addition of purified mitochondria in vitro. Inside the cell, the majority of the NS proteins and the substrates of the NSD translocated to the mitochondria upon RSV infection. Genetic and pharmacological evidence shows that optimal suppression of innate immunity requires mitochondrial MAVS and mitochondrial motility. Together, we propose a novel paradigm in which the mitochondria, known to be important for the innate immune activation of the host, are also important for viral suppression of the innate immunity. PMID:23877405

More than just immune evasion: Hijacking complement by Plasmodium falciparum.

PubMed

Schmidt, Christoph Q; Kennedy, Alexander T; Tham, Wai-Hong

2015-09-01

Malaria remains one of the world's deadliest diseases. Plasmodium falciparum is responsible for the most severe and lethal form of human malaria. P. falciparum's life cycle involves two obligate hosts: human and mosquito. From initial entry into these hosts, malaria parasites face the onslaught of the first line of host defence, the complement system. In this review, we discuss the complex interaction between complement and malaria infection in terms of hosts immune responses, parasite survival and pathogenesis of severe forms of malaria. We will focus on the role of complement receptor 1 and its associated polymorphisms in malaria immune complex clearance, as a mediator of parasite rosetting and as an entry receptor for P. falciparum invasion. Complement evasion strategies of P. falciparum parasites will also be highlighted. The sexual forms of the malaria parasites recruit the soluble human complement regulator Factor H to evade complement-mediated killing within the mosquito host. A novel evasion strategy is the deployment of parasite organelles to divert complement attack from infective blood stage parasites. Finally we outline the future challenge to understand the implications of these exploitation mechanisms in the interplay between successful infection of the host and pathogenesis observed in severe malaria. Copyright © 2015 Elsevier Ltd. All rights reserved.

CRM1 Inhibitors for Antiviral Therapy

PubMed Central

Mathew, Cynthia; Ghildyal, Reena

2017-01-01

Infectious diseases are a major global concern and despite major advancements in medical research, still cause significant morbidity and mortality. Progress in antiviral therapy is particularly hindered by appearance of mutants capable of overcoming the effects of drugs targeting viral components. Alternatively, development of drugs targeting host proteins essential for completion of viral lifecycle holds potential as a viable strategy for antiviral therapy. Nucleocytoplasmic trafficking pathways in particular are involved in several pathological conditions including cancer and viral infections, where hijacking or alteration of function of key transporter proteins, such as Chromosome Region Maintenance1 (CRM1) is observed. Overexpression of CRM1-mediated nuclear export is evident in several solid and hematological malignancies. Interestingly, CRM1-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly. This review summarizes the role of CRM1 in cancer and selected viruses. Leptomycin B (LMB) is the prototypical inhibitor of CRM1 potent against various cancer cell lines overexpressing CRM1 and in limiting viral infections at nanomolar concentrations in vitro. However, the irreversible shutdown of nuclear export results in high cytotoxicity and limited efficacy in vivo. This has prompted search for synthetic and natural CRM1 inhibitors that can potentially be developed as broadly active antivirals, some of which are summarized in this review. PMID:28702009

In vitro evolution of high-titer, virus-like vesicles containing a single structural protein

PubMed Central

Rose, Nina F.; Buonocore, Linda; Schell, John B.; Chattopadhyay, Anasuya; Bahl, Kapil; Liu, Xinran; Rose, John K.

2014-01-01

Self-propagating, infectious, virus-like vesicles (VLVs) are generated when an alphavirus RNA replicon expresses the vesicular stomatitis virus glycoprotein (VSV G) as the only structural protein. The mechanism that generates these VLVs lacking a capsid protein has remained a mystery for over 20 years. We present evidence that VLVs arise from membrane-enveloped RNA replication factories (spherules) containing VSV G protein that are largely trapped on the cell surface. After extensive passaging, VLVs evolve to grow to high titers through acquisition of multiple point mutations in their nonstructural replicase proteins. We reconstituted these mutations into a plasmid-based system from which high-titer VLVs can be recovered. One of these mutations generates a late domain motif (PTAP) that is critical for high-titer VLV production. We propose a model in which the VLVs have evolved in vitro to exploit a cellular budding pathway that is hijacked by many enveloped viruses, allowing them to bud efficiently from the cell surface. Our results suggest a basic mechanism of propagation that may have been used by primitive RNA viruses lacking capsid proteins. Capsids may have evolved later to allow more efficient packaging of RNA, greater virus stability, and evasion of innate immunity. PMID:25385608

Neutrophil-Mediated Delivery of Therapeutic Nanoparticles across Blood Vessel Barrier for Treatment of Inflammation and Infection.

PubMed

Chu, Dafeng; Gao, Jin; Wang, Zhenjia

2015-12-22

Endothelial cells form a monolayer in lumen of blood vessels presenting a great barrier for delivery of therapeutic nanoparticles (NPs) into extravascular tissues where most diseases occur, such as inflammation disorders and infection. Here, we report a strategy for delivering therapeutic NPs across this blood vessel barrier by nanoparticle in situ hitchhiking activated neutrophils. Using intravital microscopy of TNF-α-induced inflammation of mouse cremaster venules and a mouse model of acute lung inflammation, we demonstrated that intravenously (iv) infused NPs made from denatured bovine serum albumin (BSA) were specifically internalized by activated neutrophils, and subsequently, the neutrophils containing NPs migrated across blood vessels into inflammatory tissues. When neutrophils were depleted using anti-Gr-1 in a mouse, the transport of albumin NPs across blood vessel walls was robustly abolished. Furthermore, it was found that albumin nanoparticle internalization did not affect neutrophil mobility and functions. Administration of drug-loaded albumin NPs markedly mitigated the lung inflammation induced by LPS (lipopolysaccharide) or infection by Pseudomonas aeruginosa. These results demonstrate the use of an albumin nanoparticle platform for in situ targeting of activated neutrophils for delivery of therapeutics across the blood vessel barriers into diseased sites. This study demonstrates our ability to hijack neutrophils to deliver nanoparticles to targeted diseased sites.

Nitazoxanide stimulates autophagy and inhibits mTORC1 signaling and intracellular proliferation of Mycobacterium tuberculosis.

PubMed

Lam, Karen K Y; Zheng, Xingji; Forestieri, Roberto; Balgi, Aruna D; Nodwell, Matt; Vollett, Sarah; Anderson, Hilary J; Andersen, Raymond J; Av-Gay, Yossef; Roberge, Michel

2012-01-01

Tuberculosis, caused by Mycobacterium tuberculosis infection, is a major cause of morbidity and mortality in the world today. M. tuberculosis hijacks the phagosome-lysosome trafficking pathway to escape clearance from infected macrophages. There is increasing evidence that manipulation of autophagy, a regulated catabolic trafficking pathway, can enhance killing of M. tuberculosis. Therefore, pharmacological agents that induce autophagy could be important in combating tuberculosis. We report that the antiprotozoal drug nitazoxanide and its active metabolite tizoxanide strongly stimulate autophagy and inhibit signaling by mTORC1, a major negative regulator of autophagy. Analysis of 16 nitazoxanide analogues reveals similar strict structural requirements for activity in autophagosome induction, EGFP-LC3 processing and mTORC1 inhibition. Nitazoxanide can inhibit M. tuberculosis proliferation in vitro. Here we show that it inhibits M. tuberculosis proliferation more potently in infected human THP-1 cells and peripheral monocytes. We identify the human quinone oxidoreductase NQO1 as a nitazoxanide target and propose, based on experiments with cells expressing NQO1 or not, that NQO1 inhibition is partly responsible for mTORC1 inhibition and enhanced autophagy. The dual action of nitazoxanide on both the bacterium and the host cell response to infection may lead to improved tuberculosis treatment.

Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation.

PubMed

Marsolier, J; Perichon, M; DeBarry, J D; Villoutreix, B O; Chluba, J; Lopez, T; Garrido, C; Zhou, X Z; Lu, K P; Fritsch, L; Ait-Si-Ali, S; Mhadhbi, M; Medjkane, S; Weitzman, J B

2015-04-16

Infectious agents develop intricate mechanisms to interact with host cell pathways and hijack their genetic and epigenetic machinery to change host cell phenotypic states. Among the Apicomplexa phylum of obligate intracellular parasites, which cause veterinary and human diseases, Theileria is the only genus that transforms its mammalian host cells. Theileria infection of bovine leukocytes induces proliferative and invasive phenotypes associated with activated signalling pathways, notably JNK and AP-1 (ref. 2). The transformed phenotypes are reversed by treatment with the theilericidal drug buparvaquone. We used comparative genomics to identify a homologue of the peptidyl-prolyl isomerase PIN1 in T. annulata (TaPIN1) that is secreted into the host cell and modulates oncogenic signalling pathways. Here we show that TaPIN1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation. We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain. Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.

Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation

PubMed Central

Marsolier, J.; Perichon, M.; DeBarry, JD.; Villoutreix, BO.; Chluba, J.; Lopez, T.; Garrido, C.; Zhou, XZ.; Lu, KP.; Fritsch, L.; Ait-Si-Ali, S.; Mhadhbi, M; Medjkane, S.; Weitzman, JB.

2014-01-01

Infectious agents develop intricate mechanisms to interact with host cell pathways and hijack the genetic and epigenetic machinery to change phenotypic states. Amongst the Apicomplexa phylum of obligate intracellular parasites which cause veterinary and human diseases, Theileria is the only genus which transforms its mammalian host cells1. Theileria infection of bovine leukocytes induces proliferative and invasive phenotypes associated with activated signalling pathways, notably JNK and AP-12. The transformed phenotypes are reversed by treatment with the theilericidal drug Buparvaquone3. We used comparative genomics to identify a homologue of the Peptidyl Prolyl Isomerase Pin1 (designated TaPin1) in T. annulata which is secreted into the host cell and modulates oncogenic signalling pathways. Here we show that TaPin1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7 leading to its degradation and subsequent stabilization of c-Jun which promotes transformation. We performed in vitro analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPin1 is directly inhibited by the anti-parasite drug Buparvaquone (and other known Pin1 inhibitors) and is mutated in a drug-resistant strain. Prolyl isomerisation is thus a conserved mechanism which is important in cancer and is used by Theileria parasites to manipulate host oncogenic signaling. PMID:25624101

Androgenesis: where males hijack eggs to clone themselves

PubMed Central

2016-01-01

Androgenesis is a form of quasi-sexual reproduction in which a male is the sole source of the nuclear genetic material in the embryo. Two types of androgenesis occur in nature. Under the first type, females produce eggs without a nucleus and the embryo develops from the male gamete following fertilization. Evolution of this type of androgenesis is poorly understood as the parent responsible for androgenesis (the mother) gains no benefit from it. Ultimate factors driving the evolution of the second type of androgenesis are better understood. In this case, a zygote is formed between a male and a female gamete, but the female genome is eliminated. When rare, androgenesis with genome elimination is favoured because an androgenesis-determining allele has twice the reproductive success of an allele that determines sexual reproduction. Paradoxically, except in hermaphrodites, a successful androgenetic strain can drive such a male-biased sex ratio that the population goes extinct. This likely explains why androgenesis with genome elimination appears to be rarer than androgenesis via non-nucleate eggs, although both forms are either very rare or remain largely undetected in nature. Nonetheless, some highly invasive species including ants and freshwater clams are androgenetic, for reasons that are largely unexplained. This article is part of the themed issue ‘Weird sex: the underappreciated diversity of sexual reproduction’. PMID:27619698

Beyond the feminisation of poverty: gender-aware poverty reduction.

PubMed

Lockwood, M; Baden, S

1995-09-01

There must be an awareness of gender issues in poverty reduction programs. For example, program efforts that direct aid to the promotion of labor intensive employment options disregard women's already overburdened work regime. Public expenditures to benefit the poor, such as primary education or reformed agricultural extension, may be based on the assumption that men and women will benefit equally, yet there is often gender bias in the delivery of services. One recommendation is to target female headed households in budget-constrained anti-poverty programs. One of the few examples of such programs provides urban female household heads in Chile with employment training, housing, health care, child care, and legal aid services. Causes of female headship vary, and a simple correlation with poverty is not always the case. Well-intentioned women-in-development credit programs in Ghana and Bangladesh have been "hijacked" by men. Programs to address gender discrimination only among the poor may overlook other oppressed women. In India gender discrimination is often greatest among women in wealthy households. Programs must offer more than economic resources, they must help women stretch traditional gender boundaries and obtain skills such as literacy or financial management. They must help women organize collectively to protest injustices and achieve institutional reforms.

The Mutable Nature of Risk and Acceptability: A Hybrid Risk Governance Framework.

PubMed

Wong, Catherine Mei Ling

2015-11-01

This article focuses on the fluid nature of risk problems and the challenges it presents to establishing acceptability in risk governance. It introduces an actor-network theory (ANT) perspective as a way to deal with the mutable nature of risk controversies and the configuration of stakeholders. To translate this into a practicable framework, the article proposes a hybrid risk governance framework that combines ANT with integrative risk governance, deliberative democracy, and responsive regulation. This addresses a number of the limitations in existing risk governance models, including: (1) the lack of more substantive public participation throughout the lifecycle of a project; (2) hijacking of deliberative forums by particular groups; and (3) the treatment of risk problems and their associated stakeholders as immutable entities. The framework constitutes a five-stage process of co-selection, co-design, co-planning, and co-regulation to facilitate the co-production of collective interests and knowledge, build capacities, and strengthen accountability in the process. The aims of this article are twofold: conceptually, it introduces a framework of risk governance that accounts for the mutable nature of risk problems and configuration of stakeholders. In practice, this article offers risk managers and practitioners of risk governance a set of procedures with which to operationalize this conceptual approach to risk and stakeholder engagement. © 2015 Society for Risk Analysis.

NMR structure of the myristylated feline immunodeficiency virus matrix protein.

PubMed

Brown, Lola A; Cox, Cassiah; Baptiste, Janae; Summers, Holly; Button, Ryan; Bahlow, Kennedy; Spurrier, Vaughn; Kyser, Jenna; Luttge, Benjamin G; Kuo, Lillian; Freed, Eric O; Summers, Michael F

2015-04-30

Membrane targeting by the Gag proteins of the human immunodeficiency viruses (HIV types-1 and -2) is mediated by Gag's N-terminally myristylated matrix (MA) domain and is dependent on cellular phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. To determine if other lentiviruses employ a similar membrane targeting mechanism, we initiated studies of the feline immunodeficiency virus (FIV), a widespread feline pathogen with potential utility for development of human therapeutics. Bacterial co-translational myristylation was facilitated by mutation of two amino acids near the amino-terminus of the protein (Q5A/G6S; myrMAQ5A/G6S). These substitutions did not affect virus assembly or release from transfected cells. NMR studies revealed that the myristyl group is buried within a hydrophobic pocket in a manner that is structurally similar to that observed for the myristylated HIV-1 protein. Comparisons with a recent crystal structure of the unmyristylated FIV protein [myr(-)MA] indicate that only small changes in helix orientation are required to accommodate the sequestered myr group. Depletion of PI(4,5)P2 from the plasma membrane of FIV-infected CRFK cells inhibited production of FIV particles, indicating that, like HIV, FIV hijacks the PI(4,5)P2 cellular signaling system to direct intracellular Gag trafficking during virus assembly.

Saturated mutagenesis of ketoisovalerate decarboxylase V461 enabled specific synthesis of 1-pentanol via the ketoacid elongation cycle.

PubMed

Chen, Grey S; Siao, Siang Wun; Shen, Claire R

2017-09-12

Iterative ketoacid elongation has been an essential tool in engineering artificial metabolism, in particular the synthetic alcohols. However, precise control of product specificity is still greatly challenged by the substrate promiscuity of the ketoacid decarboxylase, which unselectively hijacks ketoacid intermediates from the elongation cycle along with the target ketoacid. In this work, preferential tuning of the Lactococcus lactis ketoisovalerate decarboxylase (Kivd) specificity toward 1-pentanol synthesis was achieved via saturated mutagenesis of the key residue V461 followed by screening of the resulting alcohol spectrum. Substitution of V461 with the small and polar amino acid glycine or serine significantly improved the Kivd selectivity toward the 1-pentanol precursor 2-ketocaproate by lowering its catalytic efficiency for the upstream ketoacid 2-ketobutyrate and 2-ketovalerate. Conversely, replacing V461 with bulky or charged side chains displayed severely adverse effect. Increasing supply of the iterative addition unit acetyl-CoA by acetate feeding further drove 2-ketoacid flux into the elongation cycle and enhanced 1-pentanol productivity. The Kivd V461G variant enabled a 1-pentanol production specificity around 90% of the total alcohol content with or without oleyl alcohol extraction. This work adds insight to the selectivity of Kivd active site.

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Upregulation of antioxidant genes correlates with regression of melanoma malignancy and with malignant progression when downregulated.

PubMed

Bracalente, Candelaria; Ibañez, Irene L; Berenstein, Ariel; Notcovich, Cintia; Cerda, María B; Klamt, Fabio; Chernomoretz, Ariel; Durán, Hebe

2016-07-05

Reactive oxygen species (ROS) are implicated in tumor transformation. The antioxidant system (AOS) protects cells from ROS damage. However, it is also hijacked by cancers cells to proliferate within the tumor. Thus, identifying proteins altered by redox imbalance in cancer cells is an attractive prognostic and therapeutic tool. Gene expression microarrays in A375 melanoma cells with different ROS levels after overexpressing catalase were performed. Dissimilar phenotypes by differential compensation to hydrogen peroxide scavenging were generated. The melanotic A375-A7 (A7) upregulated TYRP1, CNTN1 and UCHL1 promoting melanogenesis. The metastatic A375-G10 (G10) downregulated MTSS1 and TIAM1, proteins absent in metastasis. Moreover, differential coexpression of AOS genes (EPHX2, GSTM3, MGST1, MSRA, TXNRD3, MGST3 and GSR) was found in A7 and G10. Their increase in A7 improved its AOS ability and therefore, oxidative stress response, resembling less aggressive tumor cells. Meanwhile, their decrease in G10 revealed a disruption in the AOS and therefore, enhanced its metastatic capacity.These gene signatures, not only bring new insights into the physiopathology of melanoma, but also could be relevant in clinical prognostic to classify between non aggressive and metastatic melanomas.

The interaction between HIV-1 Nef and adaptor protein-2 reduces Nef-mediated CD4+ T cell apoptosis.

PubMed

Jacob, Rajesh Abraham; Johnson, Aaron L; Pawlak, Emily N; Dirk, Brennan S; Van Nynatten, Logan R; Haeryfar, S M Mansour; Dikeakos, Jimmy D

2017-09-01

Acquired Immune Deficiency Syndrome is characterized by a decline in CD4 + T cells. Here, we elucidated the mechanism underlying apoptosis in Human Immunodeficiency Virus-1 (HIV-1) infection by examining host apoptotic pathways hijacked by the HIV-1 Nef protein in the CD4 + T-cell line Sup-T1. Using a panel of Nef mutants unable to bind specific host proteins we uncovered that Nef generates pro- and anti-apoptotic signals. Apoptosis increased upon mutating the motifs involved in the interaction of Nef:AP-1 (Nef M20A or Nef EEEE62-65AAAA ) or Nef:AP-2 (Nef LL164/165AA ), implying these interactions limit Nef-mediated apoptosis. In contrast, disrupting the Nef:PAK2 interaction motifs (Nef H89A or Nef F191A ) reduced apoptosis. To validate further, apoptosis was measured after short-hairpin RNA knock-down of AP-1, AP-2 and PAK2. AP-2α depletion enhanced apoptosis, demonstrating that disrupting the Nef:AP-2α interaction limits Nef-mediated apoptosis. Collectively, we describe a mechanism by which HIV-1 regulates cell survival and demonstrate the consequence of interfering with Nef:host protein interactions. Copyright © 2017 Elsevier Inc. All rights reserved.

Evolutionary Relationships among Actinophages and a Putative Adaptation for Growth in Streptomyces spp.

PubMed Central

Hendrix, Roger W.; Dedrick, Rebekah; Mitchell, Kaitlin; Ko, Ching-Chung; Russell, Daniel; Bell, Emma; Gregory, Matthew; Bibb, Maureen J.; Pethick, Florence; Jacobs-Sera, Deborah; Herron, Paul; Buttner, Mark J.; Hatfull, Graham F.

2013-01-01

The genome sequences of eight Streptomyces phages are presented, four of which were isolated for this study. Phages R4, TG1, ϕHau3, and SV1 were isolated previously and have been exploited as tools for understanding and genetically manipulating Streptomyces spp. We also extracted five apparently intact prophages from recent Streptomyces spp. genome projects and, together with six phage genomes in the database, we analyzed all 19 Streptomyces phage genomes with a view to understanding their relationships to each other and to other actinophages, particularly the mycobacteriophages. Fifteen of the Streptomyces phages group into four clusters of related genomes. Although the R4-like phages do not share nucleotide sequence similarity with other phages, they clearly have common ancestry with cluster A mycobacteriophages, sharing many protein homologues, common gene syntenies, and similar repressor-stoperator regulatory systems. The R4-like phage ϕHau3 and the prophage StrepC.1 (from Streptomyces sp. strain C) appear to have hijacked a unique adaptation of the streptomycetes, i.e., use of the rare UUA codon, to control translation of the essential phage protein, the terminase. The Streptomyces venezuelae generalized transducing phage SV1 was used to predict the presence of other generalized transducing phages for different Streptomyces species. PMID:23995638

Actin Cytoskeleton Manipulation by Effector Proteins Secreted by Diarrheagenic Escherichia coli Pathotypes

PubMed Central

Navarro-Garcia, Fernando; Serapio-Palacios, Antonio; Ugalde-Silva, Paul; Tapia-Pastrana, Gabriela; Chavez-Dueñas, Lucia

2013-01-01

The actin cytoskeleton is a dynamic structure necessary for cell and tissue organization, including the maintenance of epithelial barriers. Disruption of the epithelial barrier coincides with alterations of the actin cytoskeleton in several disease states. These disruptions primarily affect the paracellular space, which is normally regulated by tight junctions. Thereby, the actin cytoskeleton is a common and recurring target of bacterial virulence factors. In order to manipulate the actin cytoskeleton, bacteria secrete and inject toxins and effectors to hijack the host cell machinery, which interferes with host-cell pathways and with a number of actin binding proteins. An interesting model to study actin manipulation by bacterial effectors is Escherichia coli since due to its genome plasticity it has acquired diverse genetic mobile elements, which allow having different E. coli varieties in one bacterial species. These E. coli pathotypes, including intracellular and extracellular bacteria, interact with epithelial cells, and their interactions depend on a specific combination of virulence factors. In this paper we focus on E. coli effectors that mimic host cell proteins to manipulate the actin cytoskeleton. The study of bacterial effector-cytoskeleton interaction will contribute not only to the comprehension of the molecular causes of infectious diseases but also to increase our knowledge of cell biology. PMID:23509714

Model of OSBP-Mediated Cholesterol Supply to Aichi Virus RNA Replication Sites Involving Protein-Protein Interactions among Viral Proteins, ACBD3, OSBP, VAP-A/B, and SAC1.

PubMed

Ishikawa-Sasaki, Kumiko; Nagashima, Shigeo; Taniguchi, Koki; Sasaki, Jun

2018-04-15

Positive-strand RNA viruses, including picornaviruses, utilize cellular machinery for genome replication. Previously, we reported that each of the 2B, 2BC, 2C, 3A, and 3AB proteins of Aichi virus (AiV), a picornavirus, forms a complex with the Golgi apparatus protein ACBD3 and phosphatidylinositol 4-kinase IIIβ (PI4KB) at viral RNA replication sites (replication organelles [ROs]), enhancing PI4KB-dependent phosphatidylinositol 4-phosphate (PI4P) production. Here, we demonstrate AiV hijacking of the cellular cholesterol transport system involving oxysterol-binding protein (OSBP), a PI4P-binding cholesterol transfer protein. AiV RNA replication was inhibited by silencing cellular proteins known to be components of this pathway, OSBP, the ER membrane proteins VAPA and VAPB (VAP-A/B), the PI4P-phosphatase SAC1, and PI-transfer protein β. OSBP, VAP-A/B, and SAC1 were present at RNA replication sites. We also found various previously unknown interactions among the AiV proteins (2B, 2BC, 2C, 3A, and 3AB), ACBD3, OSBP, VAP-A/B, and SAC1, and the interactions were suggested to be involved in recruiting the component proteins to AiV ROs. Importantly, the OSBP-2B interaction enabled PI4P-independent recruitment of OSBP to AiV ROs, indicating preferential recruitment of OSBP among PI4P-binding proteins. Protein-protein interaction-based OSBP recruitment has not been reported for other picornaviruses. Cholesterol was accumulated at AiV ROs, and inhibition of OSBP-mediated cholesterol transfer impaired cholesterol accumulation and AiV RNA replication. Electron microscopy showed that AiV-induced vesicle-like structures were close to ER membranes. Altogether, we conclude that AiV directly recruits the cholesterol transport machinery through protein-protein interactions, resulting in formation of membrane contact sites between the ER and AiV ROs and cholesterol supply to the ROs. IMPORTANCE Positive-strand RNA viruses utilize host pathways to modulate the lipid composition of viral RNA replication sites for replication. Previously, we demonstrated that Aichi virus (AiV), a picornavirus, forms a complex comprising certain proteins of AiV, the Golgi apparatus protein ACBD3, and the lipid kinase PI4KB to synthesize PI4P lipid at the sites for AiV RNA replication. Here, we confirmed cholesterol accumulation at the AiV RNA replication sites, which are established by hijacking the host cholesterol transfer machinery mediated by a PI4P-binding cholesterol transfer protein, OSBP. We showed that the component proteins of the machinery, OSBP, VAP, SAC1, and PITPNB, are all essential host factors for AiV replication. Importantly, the machinery is directly recruited to the RNA replication sites through previously unknown interactions of VAP/OSBP/SAC1 with the AiV proteins and with ACBD3. Consequently, we propose a specific strategy employed by AiV to efficiently accumulate cholesterol at the RNA replication sites via protein-protein interactions. Copyright © 2018 American Society for Microbiology.

Non-nutritive sweeteners are not super-normal stimuli

PubMed Central

Antenucci, Rachel G.; Hayes, John E.

2014-01-01

Background It is often claimed that non-nutritive sweeteners (NNS) are ‘sweeter than sugar’, with the implicit implication high potency sweeteners are super-normal stimuli that encourage exaggerated responses. This study aimed to investigate the perceived sweetness intensity of a variety of nutritive (Sucrose, Maple Syrup, and Agave Nectar) and NNS (Acesulfame-K (AceK), Rebaudioside A (RebA), Aspartame, and Sucralose) in a large cohort of untrained participants using contemporary psychophysical methods. Methods Participants (n=401 total) rated the intensity of sweet, bitter, and metallic sensations for nutritive and NNS in water using the general labeled magnitude scale (gLMS). Results Sigmoidal Dose-Response functions were observed for all stimuli except AceK. That is, sucrose follows a sigmoidal function if the data are not artifactually linearized via prior training. More critically, there is no evidence that NNS have a maximal sweetness (intensity) greater than sucrose; indeed, the maximal sweetness for AceK, RebA and Sucralose were significantly lower than for concentrated sucrose. For these sweeteners, mixture suppression due to endogenous dose-dependent bitter or metallic sensations appears to limit maximal perceived sweetness. Conclusions In terms of perceived sweetness, non-nutritive sweeteners cannot be considered super-normal stimuli. These data do not support the view that non-nutritive sweeteners hijack or over-stimulate sweet receptors to product elevated sweet sensations. PMID:24942868

Post-translational modifications are key players of the Legionella pneumophila infection strategy

PubMed Central

Michard, Céline; Doublet, Patricia

2015-01-01

Post-translational modifications (PTMs) are widely used by eukaryotes to control the enzymatic activity, localization or stability of their proteins. Traditionally, it was believed that the broad biochemical diversity of the PTMs is restricted to eukaryotic cells, which exploit it in extensive networks to fine-tune various and complex cellular functions. During the last decade, the advanced detection methods of PTMs and functional studies of the host–pathogen relationships highlight that bacteria have also developed a large arsenal of PTMs, particularly to subvert host cell pathways to their benefit. Legionella pneumophila, the etiological agent of the severe pneumonia legionellosis, is the paradigm of highly adapted intravacuolar pathogens that have set up sophisticated biochemical strategies. Among them, L. pneumophila has evolved eukaryotic-like and rare/novel PTMs to hijack host cell processes. Here, we review recent progress about the diversity of PTMs catalyzed by Legionella: ubiquitination, prenylation, phosphorylation, glycosylation, methylation, AMPylation, and de-AMPylation, phosphocholination, and de-phosphocholination. We focus on the host cell pathways targeted by the bacteria catalyzed PTMs and we stress the importance of the PTMs in the Legionella infection strategy. Finally, we highlight that the discovery of these PTMs undoubtedly made significant breakthroughs on the molecular basis of Legionella pathogenesis but also lead the way in improving our knowledge of the eukaryotic PTMs and complex cellular processes that are associated to. PMID:25713573

A conserved RNA structural element within the hepatitis B virus post-transcriptional regulatory element enhance nuclear export of intronless transcripts and repress the splicing mechanism.

PubMed

Visootsat, Akasit; Payungporn, Sunchai; T-Thienprasert, Nattanan P

2015-12-01

Hepatitis B virus (HBV) infection is a primary cause of hepatocellular carcinoma and liver cirrhosis worldwide. To develop novel antiviral drugs, a better understanding of HBV gene expression regulation is vital. One important aspect is to understand how HBV hijacks the cellular machinery to export unspliced RNA from the nucleus. The HBV post-transcriptional regulatory element (HBV PRE) has been proposed to be the HBV RNA nuclear export element. However, the function remains controversial, and the core element is unclear. This study, therefore, aimed to identify functional regulatory elements within the HBV PRE and investigate their functions. Using bioinformatics programs based on sequence conservation and conserved RNA secondary structures, three regulatory elements were predicted, namely PRE 1151-1410, PRE 1520-1620 and PRE 1650-1684. PRE 1151-1410 significantly increased intronless and unspliced luciferase activity in both HepG2 and COS-7 cells. Likewise, PRE 1151-1410 significantly elevated intronless and unspliced HBV surface transcripts in liver cancer cells. Moreover, motif analysis predicted that PRE 1151-1410 contains several regulatory motifs. This study reported the roles of PRE 1151-1410 in intronless transcript nuclear export and the splicing mechanism. Additionally, these results provide knowledge in the field of HBV RNA regulation. Moreover, PRE 1151-1410 may be used to enhance the expression of other mRNAs in intronless reporter plasmids.

A Spontaneous 3D Bone-On-a-Chip for Bone Metastasis Study of Breast Cancer Cells.

PubMed

Hao, Sijie; Ha, Laura; Cheng, Gong; Wan, Yuan; Xia, Yiqiu; Sosnoski, Donna M; Mastro, Andrea M; Zheng, Si-Yang

2018-03-01

Bone metastasis occurs at ≈70% frequency in metastatic breast cancer. The mechanisms used by tumors to hijack the skeleton, promote bone metastases, and confer therapeutic resistance are poorly understood. This has led to the development of various bone models to investigate the interactions between cancer cells and host bone marrow cells and related physiological changes. However, it is challenging to perform bone studies due to the difficulty in periodic sampling. Herein, a bone-on-a-chip (BC) is reported for spontaneous growth of a 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 µm thickness containing heavily mineralized collagen fibers naturally formed in 720 h without the aid of differentiation agents. Moreover, co-culture of metastatic breast cancer cells is examined with osteoblastic tissues. The new bone-on-a-chip design not only increases experimental throughput by miniaturization, but also maximizes the chances of cancer cell interaction with bone matrix of a concentrated surface area and facilitates easy, frequent observation. As a result, unique hallmarks of breast cancer bone colonization, previously confirmed only in vivo, are observed. The spontaneous 3D BC keeps the promise as a physiologically relevant model for the in vitro study of breast cancer bone metastasis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rab11-family of interacting protein 2 associates with chlamydial inclusions through its Rab-binding domain and promotes bacterial multiplication.

PubMed

Leiva, Natalia; Capmany, Anahí; Damiani, María Teresa

2013-01-01

Chlamydia trachomatis, an obligate intracellular pathogen, survives within host cells in a special compartment named 'inclusion' and takes advantage of host vesicular transport pathways for its growth and replication. Rab GTPases are key regulatory proteins of intracellular trafficking. Several Rabs, among them Rab11 and Rab14, are implicated in chlamydial development. FIP2, a member of the Rab11-Family of Interacting Proteins, presents at the C-terminus a Rab-binding domain that interacts with both Rab11 and Rab14. In this study, we determined and characterized the recruitment of endogenous and GFP-tagged FIP2 to the chlamydial inclusions. The recruitment of FIP2 is specific since other members of the Rab11-Family of Interacting Proteins do not associate with the chlamydial inclusions. The Rab-binding domain of FIP2 is essential for its association. Our results indicate that FIP2 binds to Rab11 at the chlamydial inclusion membrane through its Rab-binding domain. The presence of FIP2 at the chlamydial inclusion favours the recruitment of Rab14. Furthermore, our results show that FIP2 promotes inclusion development and bacterial replication. In agreement, the silencing of FIP2 decreases the bacterial progeny. C. trachomatis likely recruits FIP2 to hijack host intracellular trafficking to redirect vesicles full of nutrients towards the inclusion. © 2012 Blackwell Publishing Ltd.

Host target modification as a strategy to counter pathogen hijacking of the jasmonate hormone receptor

DOE PAGES

Zhang, Li; Yao, Jian; Withers, John; ...

2015-11-02

In the past decade, characterization of the host targets of pathogen virulence factors took a center stage in the study of pathogenesis and disease susceptibility in plants and humans. However, the impressive knowledge of host targets has not been broadly exploited to inhibit pathogen infection. In this paper, we show that host target modification could be a promising new approach to “protect” the disease-vulnerable components of plants. In particular, recent studies have identified the plant hormone jasmonate (JA) receptor as one of the common targets of virulence factors from highly evolved biotrophic/hemibiotrophic pathogens. Strains of the bacterial pathogen Pseudomonas syringae,more » for example, produce proteinaceous effectors, as well as a JA-mimicking toxin, coronatine (COR), to activate JA signaling as a mechanism to promote disease susceptibility. Guided by the crystal structure of the JA receptor and evolutionary clues, we succeeded in modifying the JA receptor to allow for sufficient endogenous JA signaling but greatly reduced sensitivity to COR. Transgenic Arabidopsis expressing this modified receptor not only are fertile and maintain a high level of insect defense, but also gain the ability to resist COR-producing pathogens Pseudomonas syringae pv. tomato and P. syringae pv. maculicola. Finally, our results provide a proof-of-concept demonstration that host target modification can be a promising new approach to prevent the virulence action of highly evolved pathogens.« less

Leishmania Hijacks Myeloid Cells for Immune Escape

PubMed Central

Martínez-López, María; Soto, Manuel; Iborra, Salvador; Sancho, David

2018-01-01

Protozoan parasites of the Leishmania genus are the causative agents of leishmaniasis, a group of neglected tropical diseases whose clinical manifestations vary depending on the infectious Leishmania species but also on host factors. Recognition of the parasite by host myeloid immune cells is a key to trigger an effective Leishmania-specific immunity. However, the parasite is able to persist in host myeloid cells by evading, delaying and manipulating host immunity in order to escape host resistance and ensure its transmission. Neutrophils are first in infiltrating infection sites and could act either favoring or protecting against infection, depending on factors such as the genetic background of the host or the parasite species. Macrophages are the main host cells where the parasites grow and divide. However, macrophages are also the main effector population involved in parasite clearance. Parasite elimination by macrophages requires the priming and development of an effector Th1 adaptive immunity driven by specific subtypes of dendritic cells. Herein, we will provide a comprehensive outline of how myeloid cells regulate innate and adaptive immunity against Leishmania, and the mechanisms used by the parasites to promote their evasion and sabotage. Understanding the interactions between Leishmania and the host myeloid cells may lead to the development of new therapeutic approaches and improved vaccination to leishmaniases, an important worldwide health problem in which current therapeutic or preventive approaches are limited. PMID:29867798

Greasy tactics in the plant-pathogen molecular arms race.

PubMed

Boyle, Patrick C; Martin, Gregory B

2015-03-01

The modification of proteins by the attachment of fatty acids is a targeting tactic involved in mechanisms of both plant immunity and bacterial pathogenesis. The plant plasma membrane (PM) is a key battleground in the war against disease-causing microbes. This membrane is armed with an array of sensor proteins that function as a surveillance system to detect invading pathogens. Several of these sensor proteins are directed to the plasma membrane through the covalent addition of fatty acids, a process termed fatty acylation. Phytopathogens secrete effector proteins into the plant cell to subvert these surveillance mechanisms, rendering the host susceptible to infection. The targeting of effectors to specific locales within plant cells, particularly the internal face of the host PM, is critical for their virulence function. Several bacterial effectors hijack the host fatty acylation machinery to be modified and directed to this contested locale. To find and fight these fatty acylated effectors the plant leverages lipid-modified intracellular sensors. This review provides examples featuring how fatty acylation is a battle tactic used by both combatants in the molecular arms race between plants and pathogens. Also highlighted is the exploitation of a specific form of host-mediated fatty acid modification, which appears to be exclusively employed by phytopathogenic effector proteins. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Evidence-based medicine was bound to fail: a report to Alvan Feinstein.

PubMed

Fava, Giovanni A

2017-04-01

John Ioannidis has provided a lucid account, in the form of a report to David Sackett, of how evidence-based medicine (EBM) was hijacked to serve vested interests: major randomized controlled trials are largely done by and for the benefit of the industry; meta-analyses and guidelines are flooded with conflicts of interest; national and federal research funds are unable to address basic clinical questions. Nonetheless, EBM would remain a worthwhile goal. In this paper, in the form of a report to Alvan Feinstein, it is argued that current developments were largely predictable. EBM certainly gave an important contribution to questioning unsubstantiated therapeutic claims. Time has come, however, to become aware of its considerable limitations, including overall reductionism and insufficient consideration of problems related to financial conflicts of interest. EBM does not represent the scientific approach to medicine: it is only a restrictive interpretation of the scientific approach to clinical practice. EBM drives the prescribing clinician to an overestimated consideration of potential benefits, paying little attention to the likelihood of responsiveness and to potential vulnerabilities in relations to the adverse effects of treatment. It is time to substitute the fashionable popularity of a strategy developed outside of clinical medicine with models and research based on the insights of clinical judgment and patient-doctor interaction, as Feinstein had outlined. Copyright © 2017 Elsevier Inc. All rights reserved.

HIV-1 and hijacking of the host immune system: the current scenario.

PubMed

Imran, Muhammad; Manzoor, Sobia; Saalim, Muhammad; Resham, Saleha; Ashraf, Javed; Javed, Aneela; Waqar, Ahmed Bilal

2016-10-01

Human immunodeficiency virus (HIV) infection is a major health burden across the world which leads to the development of acquired immune deficiency syndrome (AIDS). This review article discusses the prevalence of HIV, its major routes of transmission, natural immunity, and evasion from the host immune system. HIV is mostly prevalent in Sub-Saharan Africa and low income countries. It is mostly transmitted by sharing syringe needles, blood transfusion, and sexual routes. The host immune system is categorized into three main types; the innate, the adaptive, and the intrinsic immune system. Regarding the innate immune system against HIV, the key players are mucosal membrane, dendritic cells (DCs), complement system, interferon, and host Micro RNAs. The major components of the adaptive immune system exploited by HIV are T cells mainly CD4+ T cells and B cells. The intrinsic immune system confronted by HIV involves (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) APOBEC3G, tripartite motif 5-α (TRIM5a), terherin, and (SAM-domain HD-domain containing protein) SAMHD1. HIV-1 efficiently interacts with the host immune system, exploits the host machinery, successfully replicates and transmits from one cell to another. Further research is required to explore evasion strategies of HIV to develop novel therapeutic approaches against HIV. © 2016 APMIS. Published by John Wiley & Sons Ltd.

Theileria induces oxidative stress and HIF1α activation that are essential for host leukocyte transformation.

PubMed

Medjkane, S; Perichon, M; Marsolier, J; Dairou, J; Weitzman, J B

2014-04-03

Complex links between infection and cancer suggest that we still can learn much about tumorigenesis by studying how infectious agents hijack the host cell machinery. We studied the effects of an intracellular parasite called Theileria that infects bovine leukocytes and turns them into invasive cancer-like cells. We investigated the host cells pathways that are deregulated in infected leukocytes and might link infection and lymphoproliferative disease. We show that intracellular Theileria parasites drive a Warburg-like phenotype in infected host leukocytes, characterized by increased expression of metabolic regulators, increased glucose uptake and elevated lactate production, which were lost when the parasite was eliminated. The cohabitation of the parasites within the host cells leads to disruption of the redox balance (as measured by reduced/oxidized glutathione ratio) and elevated ROS (reactive oxygen species) levels, associated with chronic stabilization of the hypoxia-inducible factor 1 alpha (HIF1α). Inhibition of HIF1α (pharmacologically or genetically), or treatment with antioxidants, led to a marked reduction in expression of aerobic glycolytic genes and inhibited the transformed phenotype. These data show that stabilization of HIF1α, following increased ROS production, modulates host glucose metabolism and is critical for parasite-induced transformation. Our study expands knowledge about the molecular strategy used by the parasite Theileria to induce the transformed phenotypes of infected cells via reprogramming of glucose metabolism and redox signaling.

Hormonally active agents in the environment: a state-of-the-art review.

PubMed

Anwer, Faizan; Chaurasia, Savita; Khan, Abid Ali

2016-12-01

After the Second World War, infatuation with modern products has exponentially widened the spectrum of chemicals used. Some of them are capable of hijacking the endocrine system by blocking or imitating a hormone and are referred to as hormonally active chemicals or endocrine disruptors. These are chemicals that the body was not designed for evolutionarily and they are present in every matrix of the environment. We are living in a chemical world where the exposures are ubiquitous and take place in combinations that can interact with the endocrine system and some other metabolic activities in unexpected ways. The complexity of interaction of these compounds can be understood by the fact that they interfere with gene expression at extremely low levels, consequently harming an individual life form, its offspring or population. As the endocrine system plays a critical role in many biological or physiological functions, by interfering body's endocrine system, endocrine disrupting compounds (EDCs) have various adverse effects on human health, starting from birth defects to developmental disorders, deadly deseases like cancer and even immunological disorders. Most of these compounds have not been tested yet for safety and their effects cannot be assessed by the available techniques. The establishment of proper exposure measurement techniques and integrating correlation is yet to be achieved to completely understand the impacts at various levels of the endocrine axis.

Hijacking membrane transporters for arsenic phytoextraction

PubMed Central

LeBlanc, Melissa S.; McKinney, Elizabeth C.; Meagher, Richard B.; Smith, Aaron P.

2012-01-01

Arsenic is a toxic metalloid and recognized carcinogen. Arsenate and arsenite are the most common arsenic species available for uptake by plants. As an inorganic phosphate (Pi) analog, arsenate is acquired by plant roots through endogenous Pi transport systems. Inside the cell, arsenate is reduced to the thiol-reactive form arsenite. Glutathione (GSH)-conjugates of arsenite may be extruded from the cell or sequestered in vacuoles by members of the ATP-binding cassette (ABC) family of transporters. In the present study we sought to enhance both plant arsenic uptake through Pi transporter overexpression, and plant arsenic tolerance through ABC transporter overexpression. We demonstrate that Arabidopsis thaliana plants overexpressing the high-affinity Pi transporter family members, AtPht1;1 or AtPht1;7, are hypersensitive to arsenate due to increased arsenate uptake. These plants do not exhibit increased sensitivity to arsenite. Co-overexpression of the yeast ABC transporter YCF1 in combination with AtPht1;1 or AtPht1;7 suppresses the arsenate-sensitive phenotype while further enhancing arsenic uptake. Taken together, our results support an arsenic transport mechanism in which arsenate uptake is increased through Pi transporter overexpression, and arsenic tolerance is enhanced through YCF1-mediated vacuolar sequestration. This work substantiates the viability of coupling enhanced uptake and vacuolar sequestration as a means for developing a prototypical engineered arsenic hyperaccumulator. PMID:23108027

The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration

PubMed Central

2013-01-01

Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normal synapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseasesis largely unclear. In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration. PMID:23829673

Synchronization properties of heterogeneous neuronal networks with mixed excitability type

NASA Astrophysics Data System (ADS)

Leone, Michael J.; Schurter, Brandon N.; Letson, Benjamin; Booth, Victoria; Zochowski, Michal; Fink, Christian G.

2015-03-01

We study the synchronization of neuronal networks with dynamical heterogeneity, showing that network structures with the same propensity for synchronization (as quantified by master stability function analysis) may develop dramatically different synchronization properties when heterogeneity is introduced with respect to neuronal excitability type. Specifically, we investigate networks composed of neurons with different types of phase response curves (PRCs), which characterize how oscillating neurons respond to excitatory perturbations. Neurons exhibiting type 1 PRC respond exclusively with phase advances, while neurons exhibiting type 2 PRC respond with either phase delays or phase advances, depending on when the perturbation occurs. We find that Watts-Strogatz small world networks transition to synchronization gradually as the proportion of type 2 neurons increases, whereas scale-free networks may transition gradually or rapidly, depending upon local correlations between node degree and excitability type. Random placement of type 2 neurons results in gradual transition to synchronization, whereas placement of type 2 neurons as hubs leads to a much more rapid transition, showing that type 2 hub cells easily "hijack" neuronal networks to synchronization. These results underscore the fact that the degree of synchronization observed in neuronal networks is determined by a complex interplay between network structure and the dynamical properties of individual neurons, indicating that efforts to recover structural connectivity from dynamical correlations must in general take both factors into account.

Phosphatidic Acid Produced by Phospholipase D Promotes RNA Replication of a Plant RNA Virus

PubMed Central

Hyodo, Kiwamu; Taniguchi, Takako; Manabe, Yuki; Kaido, Masanori; Mise, Kazuyuki; Sugawara, Tatsuya; Taniguchi, Hisaaki; Okuno, Tetsuro

2015-01-01

Eukaryotic positive-strand RNA [(+)RNA] viruses are intracellular obligate parasites replicate using the membrane-bound replicase complexes that contain multiple viral and host components. To replicate, (+)RNA viruses exploit host resources and modify host metabolism and membrane organization. Phospholipase D (PLD) is a phosphatidylcholine- and phosphatidylethanolamine-hydrolyzing enzyme that catalyzes the production of phosphatidic acid (PA), a lipid second messenger that modulates diverse intracellular signaling in various organisms. PA is normally present in small amounts (less than 1% of total phospholipids), but rapidly and transiently accumulates in lipid bilayers in response to different environmental cues such as biotic and abiotic stresses in plants. However, the precise functions of PLD and PA remain unknown. Here, we report the roles of PLD and PA in genomic RNA replication of a plant (+)RNA virus, Red clover necrotic mosaic virus (RCNMV). We found that RCNMV RNA replication complexes formed in Nicotiana benthamiana contained PLDα and PLDβ. Gene-silencing and pharmacological inhibition approaches showed that PLDs and PLDs-derived PA are required for viral RNA replication. Consistent with this, exogenous application of PA enhanced viral RNA replication in plant cells and plant-derived cell-free extracts. We also found that a viral auxiliary replication protein bound to PA in vitro, and that the amount of PA increased in RCNMV-infected plant leaves. Together, our findings suggest that RCNMV hijacks host PA-producing enzymes to replicate. PMID:26020241

The Epstein-Barr virus miR-BHRF1-1 targets RNF4 during productive infection to promote the accumulation of SUMO conjugates and the release of infectious virus.

PubMed

Li, Jinlin; Callegari, Simone; Masucci, Maria G

2017-04-01

Post-translational modification by the Small Ubiquitin-like Modifier (SUMO) regulates a variety of cellular functions, and is hijacked by viruses to remodel the host cell during latent and productive infection. Here we have monitored the activity of the SUMO conjugation machinery in cells productively infected with Epstein-Barr virus (EBV). We found that SUMO2/3 conjugates accumulate during the late phase of the productive virus cycle, and identified several viral proteins as bone fide SUMOylation substrates. Analysis of the mechanism involved in the accumulation of SUMOylated proteins revealed upregulation of several components of the SUMO-conjugation machinery and post-transcriptional downregulation of the SUMO-targeted ubiquitin ligase RNF4. The latter effect was mediated by selective inhibition of RNF4 protein expression by the viral miR-BHRF1-1. Reconstitution of RNF4 in cells expressing an inducible miR-BHRF1-1 sponge or a miR-BHRF1-1 resistant RNF4 was associated with reduced levels of early and late viral proteins and impaired virus release. These findings illustrate a novel strategy for viral interference with the SUMO pathway, and identify the EBV miR-BHRF1-1 and the cellular RNF4 as regulators of the productive virus cycle.

Exploring the Secretomes of Microbes and Microbial Communities Using Filamentous Phage Display

PubMed Central

Gagic, Dragana; Ciric, Milica; Wen, Wesley X.; Ng, Filomena; Rakonjac, Jasna

2016-01-01

Microbial surface and secreted proteins (the secretome) contain a large number of proteins that interact with other microbes, host and/or environment. These proteins are exported by the coordinated activities of the protein secretion machinery present in the cell. A group of bacteriophage, called filamentous phage, have the ability to hijack bacterial protein secretion machinery in order to amplify and assemble via a secretion-like process. This ability has been harnessed in the use of filamentous phage of Escherichia coli in biotechnology applications, including screening large libraries of variants for binding to “bait” of interest, from tissues in vivo to pure proteins or even inorganic substrates. In this review we discuss the roles of secretome proteins in pathogenic and non-pathogenic bacteria and corresponding secretion pathways. We describe the basics of phage display technology and its variants applied to discovery of bacterial proteins that are implicated in colonization of host tissues and pathogenesis, as well as vaccine candidates through filamentous phage display library screening. Secretome selection aided by next-generation sequence analysis was successfully applied for selective display of the secretome at a microbial community scale, the latter revealing the richness of secretome functions of interest and surprising versatility in filamentous phage display of secretome proteins from large number of Gram-negative as well as Gram-positive bacteria and archaea. PMID:27092113

Hemocytes and Plasma of the Eastern Oyster (Crassostrea virginica) Display a Diverse Repertoire of Sulfated and Blood Group A-modified N-Glycans*

PubMed Central

Kurz, Simone; Jin, Chunsheng; Hykollari, Alba; Gregorich, Daniel; Giomarelli, Barbara; Vasta, Gerardo R.; Wilson, Iain B. H.; Paschinger, Katharina

2013-01-01

The eastern oyster (Crassostrea virginica) has become a useful model system for glycan-dependent host-parasite interactions due to the hijacking of the oyster galectin CvGal1 for host entry by the protozoan parasite Perkinsus marinus, the causative agent of Dermo disease. In this study, we examined the N-glycans of both the hemocytes, which via CvGal1 are the target of the parasite, and the plasma of the oyster. In combination with HPLC fractionation, exoglycosidase digestion, and fragmentation of the glycans, mass spectrometry revealed that the major N-glycans of plasma are simple hybrid structures, sometimes methylated and core α1,6-fucosylated, with terminal β1,3-linked galactose; a remarkable high degree of sulfation of such glycans was observed. Hemocytes express a larger range of glycans, including core-difucosylated paucimannosidic forms, whereas bi- and triantennary glycans were found in both sources, including structures carrying sulfated and methylated variants of the histo-blood group A epitope. The primary features of the oyster whole hemocyte N-glycome were also found in dominin, the major plasma glycoprotein, which had also been identified as a CvGal1 glycoprotein ligand associated with hemocytes. The occurrence of terminal blood group moieties on oyster dominin and on hemocyte surfaces can account in part for their affinity for the endogenous CvGal1. PMID:23824194

The good, the (not so) bad and the ugly of immune homeostasis in melanoma.

PubMed

da Gama Duarte, Jessica; Woods, Katherine; Andrews, Miles C; Behren, Andreas

2018-05-01

Within the immune system multiple mechanisms balance the need for efficient pathogen recognition and destruction with the prevention of tissue damage by excessive, inappropriate or even self-targeting (auto)immune reactions. This immune homeostasis is a tightly regulated system which fails during tumor development, often due to the hijacking of its essential self-regulatory mechanisms by cancer cells. It is facilitated not only by tumor intrinsic properties, but also by the microbiome, host genetics and other factors. In certain ways many cancers can therefore be considered a rare failure of immune control rather than an uncommon or rare disease of the tissue of origin, as the acquisition of potentially oncogenic traits through mutation occurs constantly in most tissues during proliferation. Normally, aberrant cells are well-controlled by cell intrinsic (repair or apoptosis) and extrinsic (immune) mechanisms. However, occasionally oncogenic cells survive and escape control. Melanoma is one of the first cancer types where treatments aimed at restoring and enhancing an immune response to regain control over the tumor have been used with various success rates. With the advent of "modern" immunotherapeutics such as anti-CTLA-4 or anti-PD-1 antibodies that both target negative immune-regulatory pathways on immune cells resulting in durable responses in a proportion of patients, the importance of the interplay between the immune system and cancer has been established beyond doubt. © 2017 Australasian Society for Immunology Inc.

Approximate analytical solutions of the pseudospin symmetric Dirac equation for exponential-type potentials

NASA Astrophysics Data System (ADS)

Gately, Iain; Benjamin, Jonathan

2018-04-01

As a discipline that has grown up in the eyes of the camera, maritime and underwater archaeology has struggled historically to distinguish itself from early misrepresentations of it as adventure-seeking, treasure hunting and underwater salvage as popularized in the 1950s and 1960s. Though many professional archaeologists have successfully moved forward from this history through broader theoretical engagement and the development of the discipline within anthropology, public perception of archaeology under water has not advanced in stride. Central to this issue is the portrayal of underwater archaeology within popular culture and the representational structures from the 1950s and 1960s persistently used to introduce the profession to the public, through the consumption of popular books and especially television. This article explores representations of maritime and underwater archaeology to examine how the discipline has been consumed by the public, both methodologically and theoretically, through media. In order to interrogate this, we first examine maritime and underwater archaeology as a combined sub-discipline of archaeology and consider how it has been defined historically and in contemporary professional practice. Finally, we consider how practitioners can take a proactive approach to portray their work and convey archaeological media to the public. In this respect, we aim to advance the theoretical discussion in a way so as to reduce further cases whereby archaeology is accidentally misappropriated or deliberately hijacked.

Structural Basis of the High Affinity Interaction between the Alphavirus Nonstructural Protein-3 (nsP3) and the SH3 Domain of Amphiphysin-2.

PubMed

Tossavainen, Helena; Aitio, Olli; Hellman, Maarit; Saksela, Kalle; Permi, Perttu

2016-07-29

We show that a peptide from Chikungunya virus nsP3 protein spanning residues 1728-1744 binds the amphiphysin-2 (BIN1) Src homology-3 (SH3) domain with an unusually high affinity (Kd 24 nm). Our NMR solution complex structure together with isothermal titration calorimetry data on several related viral and cellular peptide ligands reveal that this exceptional affinity originates from interactions between multiple basic residues in the target peptide and the extensive negatively charged binding surface of amphiphysin-2 SH3. Remarkably, these arginines show no fixed conformation in the complex structure, indicating that a transient or fluctuating polyelectrostatic interaction accounts for this affinity. Thus, via optimization of such dynamic electrostatic forces, viral peptides have evolved a superior binding affinity for amphiphysin-2 SH3 compared with typical cellular ligands, such as dynamin, thereby enabling hijacking of amphiphysin-2 SH3-regulated host cell processes by these viruses. Moreover, our data show that the previously described consensus sequence PXRPXR for amphiphysin SH3 ligands is inaccurate and instead define it as an extended Class II binding motif PXXPXRpXR, where additional positive charges between the two constant arginine residues can give rise to extraordinary high SH3 binding affinity. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

RING-Domain E3 Ligase-Mediated Host–Virus Interactions: Orchestrating Immune Responses by the Host and Antagonizing Immune Defense by Viruses

PubMed Central

Zhang, Yuexiu; Li, Lian-Feng; Munir, Muhammad; Qiu, Hua-Ji

2018-01-01

The RING-domain E3 ligases (RING E3s), a group of E3 ligases containing one or two RING finger domains, are involved in various cellular processes such as cell proliferation, immune regulation, apoptosis, among others. In the host, a substantial number of the RING E3s have been implicated to inhibit viral replication through regulating immune responses, including activation and inhibition of retinoic acid-inducible gene I-like receptors, toll-like receptors, and DNA receptor signaling pathways, modulation of cell-surface expression of major histocompatibility complex, and co-stimulatory molecules. During the course of evolution and adaptation, viruses encode RING E3s to antagonize host immune defense, such as the infected cell protein 0 of herpes simplex virus type 1, the non-structural protein 1 of rotavirus, and the K3 and K5 of Kaposi’s sarcoma-associated herpesvirus. In addition, recent studies suggest that viruses can hijack the host RING E3s to facilitate viral replication. Based on emerging and interesting discoveries, the RING E3s present novel links among the host and viruses. Herein, we focus on the latest research progresses in the RING E3s-mediated host–virus interactions and discuss the outlooks of the RING E3s for future research. PMID:29872431

Terrorism in South Korea.

PubMed

Wang, Soon Joo; Choi, Jin Tae; Arnold, Jeffrey

2003-01-01

South Korea has experienced > 30 suspected terrorism-related events since 1958, including attacks against South Korean citizens in foreign countries. The most common types of terrorism used have included bombings, shootings, hijackings, and kidnappings. Prior to 1990, North Korea was responsible for almost all terrorism-related events inside of South Korea, including multiple assassination attempts on its presidents, regular kidnappings of South Korean fisherman, and several high-profile bombings. Since 1990, most of the terrorist attacks against South Korean citizens have occurred abroad and have been related to the emerging worldwide pattern of terrorism by international terrorist organizations or deranged individuals. The 1988 Seoul Olympic Games provided a major stimulus for South Korea to develop a national emergency response system for terrorism-related events based on the participation of multiple ministries. The 11 September 2001 World Trade Center and Pentagon attacks and the 2001 United States of America (US) anthrax letter attacks prompted South Korea to organize a new national system of emergency response for terrorism-related events. The system is based on five divisions for the response to specific types of terrorist events, involving conventional terrorism, bioterrorism, chemical terrorism, radiological terrorism, and cyber-terrorism. No terrorism-related events occurred during the 2002 World Cup and Asian Games held in South Korea. The emergency management of terrorism-related events in South Korea is adapting to the changing risk of terrorism in the new century.

The Epstein-Barr virus miR-BHRF1-1 targets RNF4 during productive infection to promote the accumulation of SUMO conjugates and the release of infectious virus

PubMed Central

Li, Jinlin; Callegari, Simone

2017-01-01

Post-translational modification by the Small Ubiquitin-like Modifier (SUMO) regulates a variety of cellular functions, and is hijacked by viruses to remodel the host cell during latent and productive infection. Here we have monitored the activity of the SUMO conjugation machinery in cells productively infected with Epstein-Barr virus (EBV). We found that SUMO2/3 conjugates accumulate during the late phase of the productive virus cycle, and identified several viral proteins as bone fide SUMOylation substrates. Analysis of the mechanism involved in the accumulation of SUMOylated proteins revealed upregulation of several components of the SUMO-conjugation machinery and post-transcriptional downregulation of the SUMO-targeted ubiquitin ligase RNF4. The latter effect was mediated by selective inhibition of RNF4 protein expression by the viral miR-BHRF1-1. Reconstitution of RNF4 in cells expressing an inducible miR-BHRF1-1 sponge or a miR-BHRF1-1 resistant RNF4 was associated with reduced levels of early and late viral proteins and impaired virus release. These findings illustrate a novel strategy for viral interference with the SUMO pathway, and identify the EBV miR-BHRF1-1 and the cellular RNF4 as regulators of the productive virus cycle. PMID:28414785

Avian leukosis virus subgroup J induces VEGF expression via NF-κB/PI3K-dependent IL-6 production.

PubMed

Gao, Yanni; Zhang, Yao; Yao, Yongxiu; Guan, Xiaolu; Liu, Yongzhen; Qi, Xiaole; Wang, Yongqiang; Liu, Changjun; Zhang, Yanping; Gao, Honglei; Nair, Venugopal; Wang, Xiaomei; Gao, Yulong

2016-12-06

Avian leukosis virus subgroup J (ALV-J) is an oncogenic virus causing hemangiomas and myeloid tumors in chickens. Interleukin-6 (IL-6) is a multifunctional pro-inflammatory interleukin involved in many types of cancer. We previously demonstrated that IL-6 expression was induced following ALV-J infection in chickens. The aim of this study is to characterize the mechanism by which ALV-J induces IL-6 expression, and the role of IL-6 in tumor development. Our results demonstrate that ALV-J infection increases IL-6 expression in chicken splenocytes, peripheral blood lymphocytes, and vascular endothelial cells. IL-6 production is induced by the ALV-J envelope protein gp85 and capsid protein p27 via PI3K- and NF-κB-mediated signaling. IL-6 in turn induced expression of vascular endothelial growth factor (VEGF)-A and its receptor, VEGFR-2, in vascular endothelial cells and embryonic vascular tissues. Suppression of IL-6 using siRNA inhibited the ALV-J induced VEGF-A and VEGFR-2 expression in vascular endothelial cells, indicating that the ALV-J-induced VEGF-A/VEGFR-2 expression is mediated by IL-6. As VEGF-A and VEGFR-2 are important factors in oncogenesis, our findings suggest that ALV-J hijacks IL-6 to promote tumorigenesis, and indicate that IL-6 could potentially serve as a therapeutic target in ALV-J infections.

HTLV-1 Tax Stabilizes MCL-1 via TRAF6-Dependent K63-Linked Polyubiquitination to Promote Cell Survival and Transformation

PubMed Central

Choi, Young Bong; Harhaj, Edward William

2014-01-01

The human T-cell leukemia virus type 1 (HTLV-1) Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs) and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63)-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation. PMID:25340740

Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion.

PubMed

Hovingh, Elise S; van den Broek, Bryan; Jongerius, Ilse

2016-01-01

The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed.

Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion

PubMed Central

Hovingh, Elise S.; van den Broek, Bryan; Jongerius, Ilse

2016-01-01

The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed. PMID:28066340

Sugar Transporters in Plants: New Insights and Discoveries.

PubMed

Julius, Benjamin T; Leach, Kristen A; Tran, Thu M; Mertz, Rachel A; Braun, David M

2017-09-01

Carbohydrate partitioning is the process of carbon assimilation and distribution from source tissues, such as leaves, to sink tissues, such as stems, roots and seeds. Sucrose, the primary carbohydrate transported long distance in many plant species, is loaded into the phloem and unloaded into distal sink tissues. However, many factors, both genetic and environmental, influence sucrose metabolism and transport. Therefore, understanding the function and regulation of sugar transporters and sucrose metabolic enzymes is key to improving agriculture. In this review, we highlight recent findings that (i) address the path of phloem loading of sucrose in rice and maize leaves; (ii) discuss the phloem unloading pathways in stems and roots and the sugar transporters putatively involved; (iii) describe how heat and drought stress impact carbohydrate partitioning and phloem transport; (iv) shed light on how plant pathogens hijack sugar transporters to obtain carbohydrates for pathogen survival, and how the plant employs sugar transporters to defend against pathogens; and (v) discuss novel roles for sugar transporters in plant biology. These exciting discoveries and insights provide valuable knowledge that will ultimately help mitigate the impending societal challenges due to global climate change and a growing population by improving crop yield and enhancing renewable energy production. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The Polerovirus F box protein P0 targets ARGONAUTE1 to suppress RNA silencing.

PubMed

Bortolamiol, Diane; Pazhouhandeh, Maghsoud; Marrocco, Katia; Genschik, Pascal; Ziegler-Graff, Véronique

2007-09-18

Plants employ post-transcriptional gene silencing (PTGS) as an antiviral defense response. In this mechanism, viral-derived small RNAs are incorporated into the RNA-induced silencing complex (RISC) to guide degradation of the corresponding viral RNAs. ARGONAUTE1 (AGO1) is a key component of RISC: it carries the RNA slicer activity. As a counter-defense, viruses have evolved various proteins that suppress PTGS. Recently, we showed that the Polerovirus P0 protein carries an F box motif required to form an SCF-like complex, which is also essential for P0's silencing suppressor function. Here, we investigate the molecular mechanism by which P0 impairs PTGS. First we show that P0's expression does not affect the biogenesis of primary siRNAs in an inverted repeat-PTGS assay, but it does affect their activity. Moreover, P0's expression in transformed Arabidopsis plants leads to various developmental abnormalities reminiscent of mutants affected in miRNA pathways, which is accompanied by enhanced levels of several miRNA-target transcripts, suggesting that P0 acts at the level of RISC. Interestingly, ectopic expression of P0 triggered AGO1 protein decay in planta. Finally, we provide evidence that P0 physically interacts with AGO1. Based on these results, we propose that P0 hijacks the host SCF machinery to modulate gene silencing by destabilizing AGO1.

Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis.

PubMed

Moore, Jason T; Chen, Jingqiu; Han, Bo; Meng, Qing Cheng; Veasey, Sigrid C; Beck, Sheryl G; Kelz, Max B

2012-11-06

Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep. Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, whereas neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance. Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties. Copyright © 2012 Elsevier Ltd. All rights reserved.

Novel high throughput pooled shRNA screening identifies NQO1 as a potential drug target for host directed therapy for tuberculosis

PubMed Central

Li, Qing; Karim, Ahmad F.; Ding, Xuedong; Das, Biswajit; Dobrowolski, Curtis; Gibson, Richard M.; Quiñones-Mateu, Miguel E.; Karn, Jonathan; Rojas, Roxana E.

2016-01-01

Chemical regulation of macrophage function is one key strategy for developing host-directed adjuvant therapies for tuberculosis (TB). A critical step to develop these therapies is the identification and characterization of specific macrophage molecules and pathways with a high potential to serve as drug targets. Using a barcoded lentivirus-based pooled short-hairpin RNA (shRNA) library combined with next generation sequencing, we identified 205 silenced host genes highly enriched in mycobacteria-resistant macrophages. Twenty-one of these “hits” belonged to the oxidoreductase functional category. NAD(P)H:quinone oxidoreductase 1 (NQO1) was the top oxidoreductase “hit”. NQO1 expression was increased after mycobacterial infection, and NQO1 knockdown increased macrophage differentiation, NF-κB activation, and the secretion of pro-inflammatory cytokines TNF-α and IL-1β in response to infection. This suggests that mycobacteria hijacks NQO1 to down-regulate pro-inflammatory and anti-bacterial functions. The competitive inhibitor of NQO1 dicoumarol synergized with rifampin to promote intracellular killing of mycobacteria. Thus, NQO1 is a new host target in mycobacterial infection that could potentially be exploited to increase antibiotic efficacy in vivo. Our findings also suggest that pooled shRNA libraries could be valuable tools for genome-wide screening in the search for novel druggable host targets for adjunctive TB therapies. PMID:27297123

HIV-1 Nef sequesters MHC-I intracellularly by targeting early stages of endocytosis and recycling

PubMed Central

Dirk, Brennan S.; Pawlak, Emily N.; Johnson, Aaron L.; Van Nynatten, Logan R.; Jacob, Rajesh A.; Heit, Bryan; Dikeakos, Jimmy D.

2016-01-01

A defining characteristic of HIV-1 infection is the ability of the virus to persist within the host. Specifically, MHC-I downregulation by the HIV-1 accessory protein Nef is of critical importance in preventing infected cells from cytotoxic T-cell mediated killing. Nef downregulates MHC-I by modulating the host membrane trafficking machinery, resulting in the endocytosis and eventual sequestration of MHC-I within the cell. In the current report, we utilized the intracellular protein-protein interaction reporter system, bimolecular fluorescence complementation (BiFC), in combination with super-resolution microscopy, to track the Nef/MHC-I interaction and determine its subcellular localization in cells. We demonstrate that this interaction occurs upon Nef binding the MHC-I cytoplasmic tail early during endocytosis in a Rab5-positive endosome. Disruption of early endosome regulation inhibited Nef-dependent MHC-I downregulation, demonstrating that Nef hijacks the early endosome to sequester MHC-I within the cell. Furthermore, super-resolution imaging identified that the Nef:MHC-I BiFC complex transits through both early and late endosomes before ultimately residing at the trans-Golgi network. Together we demonstrate the importance of the early stages of the endocytic network in the removal of MHC-I from the cell surface and its re-localization within the cell, which allows HIV-1 to optimally evade host immune responses. PMID:27841315

Amoeba host-Legionella synchronization of amino acid auxotrophy and its role in bacterial adaptation and pathogenic evolution.

PubMed

Price, Christopher T D; Richards, Ashley M; Von Dwingelo, Juanita E; Samara, Hala A; Abu Kwaik, Yousef

2014-02-01

Legionella pneumophila, the causative agent of Legionnaires' disease, invades and proliferates within a diverse range of free-living amoeba in the environment, but upon transmission to humans, the bacteria hijack alveolar macrophages. Intracellular proliferation of L. pneumophila in two evolutionarily distant hosts is facilitated by bacterial exploitation of conserved host processes that are targeted by bacterial protein effectors injected into the host cell. A key aspect of microbe-host interaction is microbial extraction of nutrients from the host, but understanding of this is still limited. AnkB functions as a nutritional virulence factor and promotes host proteasomal degradation of polyubiquitinated proteins generating gratuitous levels of limiting host cellular amino acids. Legionella pneumophila is auxotrophic for several amino acids including cysteine, which is a metabolically preferred source of carbon and energy during intracellular proliferation, but is limiting in both amoebae and humans. We propose that synchronization of bacterial amino acids auxotrophy with the host is a driving force in pathogenic evolution and nutritional adaptation of L. pneumophila and other intracellular bacteria to life within the host cell. Understanding microbial strategies of nutrient generation and acquisition in the host will provide novel antimicrobial strategies to disrupt pathogen access to essential sources of carbon and energy. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

PubMed Central

2013-01-01

Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease. PMID:23899561

Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Upregulation of antioxidant genes correlates with regression of melanoma malignancy and with malignant progression when downregulated

PubMed Central

Berenstein, Ariel; Notcovich, Cintia; Cerda, María B.; Klamt, Fabio; Chernomoretz, Ariel; Durán, Hebe

2016-01-01

Reactive oxygen species (ROS) are implicated in tumor transformation. The antioxidant system (AOS) protects cells from ROS damage. However, it is also hijacked by cancers cells to proliferate within the tumor. Thus, identifying proteins altered by redox imbalance in cancer cells is an attractive prognostic and therapeutic tool. Gene expression microarrays in A375 melanoma cells with different ROS levels after overexpressing catalase were performed. Dissimilar phenotypes by differential compensation to hydrogen peroxide scavenging were generated. The melanotic A375-A7 (A7) upregulated TYRP1, CNTN1 and UCHL1 promoting melanogenesis. The metastatic A375-G10 (G10) downregulated MTSS1 and TIAM1, proteins absent in metastasis. Moreover, differential coexpression of AOS genes (EPHX2, GSTM3, MGST1, MSRA, TXNRD3, MGST3 and GSR) was found in A7 and G10. Their increase in A7 improved its AOS ability and therefore, oxidative stress response, resembling less aggressive tumor cells. Meanwhile, their decrease in G10 revealed a disruption in the AOS and therefore, enhanced its metastatic capacity. These gene signatures, not only bring new insights into the physiopathology of melanoma, but also could be relevant in clinical prognostic to classify between non aggressive and metastatic melanomas. PMID:27206673

Understanding Substance Use and Addiction Through the Lyrics of Black Sabbath: A Content Analysis.

PubMed

Conway, Kevin P; McGrain, Patrick

2016-10-14

Heavy metal music is distinguished for its deep sound and lyrical fixation with dark themes including war, destruction, doom, and misery. Such subjects permeate the music of Black Sabbath, the band generally considered the pioneers of heavy metal. One theme-substance use-is recurrent in Black Sabbath's songs and personal lives of its members. This study explored the band's relationship with substance use though a content analysis of all songs containing lyrics written and recorded in studio by Black Sabbath. The analysis included 156 songs across 19 albums recorded from 1970 to 2013. Three key findings emerged. First, a minority of songs (13%) contained substance references. Second, the songs with substance references were overwhelmingly (60%) negative, a pattern that increased over time. Third, despite many line-up changes over the band's 43-year period, every song referencing substance use except one featured vocalist Ozzy Osbourne and lyricist Geezer Butler. Contrary to the notion that heavy metal music glorifies or encourages substance use (Record Labeling, United States Senate, 1985), Black Sabbath's lyrics as a whole weave a cautionary tale of how persistent substance use can hijack free will, become the dominant focus of the affected individual, and produce myriad forms of human misery. The insidiousness of chronic substance use depicted by the lyrics mirrors findings from natural-history studies of individuals with substance use disorders and aligns with neurobiological heuristics of addiction.

Agrobacterium-delivered virulence protein VirE2 is trafficked inside host cells via a myosin XI-K–powered ER/actin network

PubMed Central

Yang, Qinghua; Li, Xiaoyang; Tu, Haitao; Pan, Shen Q.

2017-01-01

Agrobacterium tumefaciens causes crown gall tumors on various plants by delivering transferred DNA (T-DNA) and virulence proteins into host plant cells. Under laboratory conditions, the bacterium is widely used as a vector to genetically modify a wide range of organisms, including plants, yeasts, fungi, and algae. Various studies suggest that T-DNA is protected inside host cells by VirE2, one of the virulence proteins. However, it is not clear how Agrobacterium-delivered factors are trafficked through the cytoplasm. In this study, we monitored the movement of Agrobacterium-delivered VirE2 inside plant cells by using a split-GFP approach in real time. Agrobacterium-delivered VirE2 trafficked via the endoplasmic reticulum (ER) and F-actin network inside plant cells. During this process, VirE2 was aggregated as filamentous structures and was present on the cytosolic side of the ER. VirE2 movement was powered by myosin XI-K. Thus, exogenously produced and delivered VirE2 protein can use the endogenous host ER/actin network for movement inside host cells. The A. tumefaciens pathogen hijacks the conserved host infrastructure for virulence trafficking. Well-conserved infrastructure may be useful for Agrobacterium to target a wide range of recipient cells and achieve a high efficiency of transformation. PMID:28242680

Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen.

PubMed

Levin, Rebecca S; Hertz, Nicholas T; Burlingame, Alma L; Shokat, Kevan M; Mukherjee, Shaeri

2016-08-16

TGF-β activated kinase 1 (TAK1) is a critical signaling hub responsible for translating antigen binding signals to immune receptors for the activation of the AP-1 and NF-κB master transcriptional programs. Despite its importance, known substrates of TAK1 are limited to kinases of the MAPK and IKK families and include no direct effectors of biochemical processes. Here, we identify over 200 substrates of TAK1 using a chemical genetic kinase strategy. We validate phosphorylation of the dynamic switch II region of GTPase Rab1, a mediator of endoplasmic reticulum to Golgi vesicular transport, at T75 to be regulated by TAK1 in vivo. TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPase-activating protein (GAP) enzymes, and is exclusive to membrane-localized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. Previous studies established that the pathogen Legionella pneumophila is capable of hijacking Rab1 function through posttranslational modifications of the switch II region. Here, we present evidence that Rab1 is regulated by the host in a similar fashion, and that the innate immunity kinase TAK1 and Legionella effectors compete to regulate Rab1 by switch II modifications during infection.

Rice Dwarf Virus P2 Protein Hijacks Auxin Signaling by Directly Targeting the Rice OsIAA10 Protein, Enhancing Viral Infection and Disease Development

PubMed Central

Jin, Lian; Qin, Qingqing; Wang, Yu; Pu, Yingying; Liu, Lifang; Wen, Xing; Ji, Shaoyi; Wu, Jianguo; Wei, Chunhong; Li, Yi

2016-01-01

The phytohormone auxin plays critical roles in regulating myriads of plant growth and developmental processes. Microbe infection can disturb auxin signaling resulting in defects in these processes, but the underlying mechanisms are poorly understood. Auxin signaling begins with perception of auxin by a transient co-receptor complex consisting of an F-box transport inhibitor response 1/auxin signaling F-box (TIR1/AFB) protein and an auxin/indole-3-acetic acid (Aux/IAA) protein. Auxin binding to the co-receptor triggers ubiquitination and 26S proteasome degradation of the Aux/IAA proteins, leading to subsequent events, including expression of auxin-responsive genes. Here we report that Rice dwarf virus (RDV), a devastating pathogen of rice, causes disease symptoms including dwarfing, increased tiller number and short crown roots in infected rice as a result of reduced sensitivity to auxin signaling. The RDV capsid protein P2 binds OsIAA10, blocking the interaction between OsIAA10 and OsTIR1 and inhibiting 26S proteasome-mediated OsIAA10 degradation. Transgenic rice plants overexpressing wild-type or a dominant-negative (degradation-resistant) mutant of OsIAA10 phenocopy RDV symptoms are more susceptible to RDV infection; however, knockdown of OsIAA10 enhances the resistance of rice to RDV infection. Our findings reveal a previously unknown mechanism of viral protein reprogramming of a key step in auxin signaling initiation that enhances viral infection and pathogenesis. PMID:27606959

Hepatitis C, innate immunity and alcohol: friends or foes?

PubMed

Osna, Natalia A; Ganesan, Murali; Kharbanda, Kusum K

2015-02-05

Hepatitis C and alcohol are the most widespread causes of liver disease worldwide. Approximately 80% of patients with a history of hepatitis C and alcohol abuse develop chronic liver injury. Alcohol consumption in hepatitis C virus (HCV)-infected patients exacerbates liver disease leading to rapid progression of fibrosis, cirrhosis and even hepatocellular carcinoma. Hepatocytes are the main sites of HCV-infection and ethanol metabolism, both of which generate oxidative stress. Oxidative stress levels affect HCV replication and innate immunity, resulting in a greater susceptibility for HCV-infection and virus spread in the alcoholic patients. In this review paper, we analyze the effects of ethanol metabolism and other factors on HCV replication. In addition, we illustrate the mechanisms of how HCV hijacks innate immunity and how ethanol exposure regulates this process. We also clarify the effects of HCV and ethanol metabolism on interferon signaling-a crucial point for activation of anti-viral genes to protect cells from virus-and the role that HCV- and ethanol-induced impairments play in adaptive immunity which is necessary for recognition of virally-infected hepatocytes. In conclusion, ethanol exposure potentiates the suppressive effects of HCV on innate immunity, which activates viral spread in the liver and finally, leads to impairments in adaptive immunity. The dysregulation of immune response results in impaired elimination of HCV-infected cells, viral persistence, progressive liver damage and establishment of chronic infection that worsens the outcomes of chronic hepatitis C in alcoholic patients.

The critical protein interactions and structures that elicit growth deregulation in cancer and viral replication

PubMed Central

Ou, Horng D.; May, Andrew P.

2010-01-01

One of the greatest challenges in biomedicine is to define the critical targets and network interactions that are subverted to elicit growth deregulation in human cells. Understanding and developing rational treatments for cancer requires a definition of the key molecular targets and how they interact to elicit the complex growth deregulation phenotype. Viral proteins provide discerning and powerful probes to understand both how cells work and how they can be manipulated using a minimal number of components. The small DNA viruses have evolved to target inherent weaknesses in cellular protein interaction networks to hijack the cellular DNA and protein replication machinery. In the battle to escape the inevitability of senescence and programmed cell death, cancers have converged on similar mechanisms, through the acquisition and selection of somatic mutations that drive unchecked cellular replication in tumors. Understanding the dynamic mechanisms through which a minimal number of viral proteins promote host cells to undergo unscheduled and pathological replication is a powerful strategy to identify critical targets that are also disrupted in cancer. Viruses can therefore be used as tools to probe the system-wide protein-protein interactions and structures that drive growth deregulation in human cells. Ultimately this can provide a path for developing system context-dependent therapeutics. This review will describe ongoing experimental approaches using viruses to study pathways deregulated in cancer, with a particular focus on viral cellular protein-protein interactions and structures. PMID:21061422

Rewiring of cellular membrane homeostasis by picornaviruses.

PubMed

Belov, George A; Sztul, Elizabeth

2014-09-01

Viruses are obligatory intracellular parasites and utilize host elements to support key viral processes, including penetration of the plasma membrane, initiation of infection, replication, and suppression of the host's antiviral defenses. In this review, we focus on picornaviruses, a family of positive-strand RNA viruses, and discuss the mechanisms by which these viruses hijack the cellular machinery to form and operate membranous replication complexes. Studies aimed at revealing factors required for the establishment of viral replication structures identified several cellular-membrane-remodeling proteins and led to the development of models in which the virus used a preexisting cellular-membrane-shaping pathway "as is" for generating its replication organelles. However, as more data accumulate, this view is being increasingly questioned, and it is becoming clearer that viruses may utilize cellular factors in ways that are distinct from the normal functions of these proteins in uninfected cells. In addition, the proteincentric view is being supplemented by important new studies showing a previously unappreciated deep remodeling of lipid homeostasis, including extreme changes to phospholipid biosynthesis and cholesterol trafficking. The data on viral modifications of lipid biosynthetic pathways are still rudimentary, but it appears once again that the viruses may rewire existing pathways to generate novel functions. Despite remarkable progress, our understanding of how a handful of viral proteins can completely overrun the multilayered, complex mechanisms that control the membrane organization of a eukaryotic cell remains very limited. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Synergistic effects of ATP and RNA binding to human DEAD-box protein DDX1.

PubMed

Kellner, Julian N; Reinstein, Jochen; Meinhart, Anton

2015-03-11

RNA helicases of the DEAD-box protein family form the largest group of helicases. The human DEAD-box protein 1 (DDX1) plays an important role in tRNA and mRNA processing, is involved in tumor progression and is also hijacked by several virus families such as HIV-1 for replication and nuclear export. Although important in many cellular processes, the mechanism of DDX1's enzymatic function is unknown. We have performed equilibrium titrations and transient kinetics to determine affinities for nucleotides and RNA. We find an exceptional tight binding of DDX1 to adenosine diphosphate (ADP), one of the strongest affinities observed for DEAD-box helicases. ADP binds tighter by three orders of magnitude when compared to adenosine triphosphate (ATP), arresting the enzyme in a potential dead-end ADP conformation under physiological conditions. We thus suggest that a nucleotide exchange factor leads to DDX1 recycling. Furthermore, we find a strong cooperativity in binding of RNA and ATP to DDX1 that is also reflected in ATP hydrolysis. We present a model in which either ATP or RNA binding alone can partially shift the equilibrium from an 'open' to a 'closed'-state; this shift appears to be not further pronounced substantially even in the presence of both RNA and ATP as the low rate of ATP hydrolysis does not change. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Respect for Autonomy in Light of Neuropsychiatry.

PubMed

Müller, Sabine

2017-06-01

Bioethics needs an elaborated concept of autonomy based on empirical knowledge about the prerequisites of the capacity of autonomy. Whereas Beauchamp and Childress, and many other bioethicists have discussed social influences on the capacity of autonomy in depth, neurobiological influences have received less attention. A comprehensive concept of autonomy should consider both social and biological factors that can diminish the capacity of autonomy. This article focuses on neurobiological influences that can reduce the capacity of autonomy. The thesis of this article is that the integration of neuropsychiatric knowledge into the concept of autonomy is essential for (1) evaluating demands for harmful medical treatments which might be caused by a brain disease, and (2) deciding on involuntary treatments of patients who suffer from substantial lack of autonomy due to neuropsychiatric disorders. Diametrically opposed to such a comprehensive concept of the capacity of autonomy is the concept of 'liberty of illness'. In Germany, this concept is supported not only by anti-psychiatric groups but also by the Federal Constitutional Court. Several real cases demonstrate how the brain can be 'hijacked' by parasites, antibodies or technical devices. Applying the concept of 'liberty of illness' to persons whose decision-making capacity is severely affected by neuropsychiatric disorders is cynical. These patients neither chose their disease nor would refuse effective treatment if their will was not disturbed by the disease. Respect for autonomy should be understood as the positive obligation to save, support or restore the biological prerequisites of the capacity for autonomous decision-making. © 2017 John Wiley & Sons Ltd.

Polymeric mannosides prevent DC-SIGN-mediated cell-infection by cytomegalovirus.

PubMed

Brument, S; Cheneau, C; Brissonnet, Y; Deniaud, D; Halary, F; Gouin, S G

2017-09-20

Human cytomegalovirus (HCMV) is a beta-herpesvirus with a high prevalence in the population. HCMV is asymptomatic for immunocompetent adults but is a leading cause of morbidity for new born and immunocompromised patients. It was recently shown that the envelope glycoprotein B (gB) of HCMV interacts with the Dendritic Cell-Specific ICAM-3 Grabbing Non integrin (DC-SIGN) to infect the host. In this work we developed a set of DC-SIGN blockers based on mono-, di-, tetra and polyvalent mannosides. The multivalent mannosides were designed to interact with the carbohydrate recognition domains of DC-SIGN in a chelate or bind and recapture process, and represent the first chemical antiadhesives of HCMV reported so far. Polymeric dextrans coated with triazolylheptylmannoside (THM) ligands were highly potent, blocking the gB and DC-SIGN interaction at nanomolar concentrations. The compounds were further assessed for their ability to prevent the DC-SIGN mediated HCMV infection of dendritic cells. A dextran polymer coated with an average of 902 THM ligands showed an outstanding effect in blocking the HCMV trans-infection with IC 50 values down to the picomolar range (nanomolar when expressed in THM concentration). Each THM moiety on the polymer surpassed the antiadhesive effect of the methylmannoside reference by more than four orders of magnitude. The compound proved non-cytotoxic at the high concentration of 2 mM and therefore represents an interesting antiadhesive candidate against HCMV and potentially against other virus hijacking dendritic cells to infect the host.

Electron Tomography and Simulation of Baculovirus Actin Comet Tails Support a Tethered Filament Model of Pathogen Propulsion

PubMed Central

Mueller, Jan; Pfanzelter, Julia; Winkler, Christoph; Narita, Akihiro; Le Clainche, Christophe; Nemethova, Maria; Carlier, Marie-France; Maeda, Yuichiro; Welch, Matthew D.; Ohkawa, Taro; Schmeiser, Christian; Resch, Guenter P.; Small, J. Victor

2014-01-01

Several pathogens induce propulsive actin comet tails in cells they invade to disseminate their infection. They achieve this by recruiting factors for actin nucleation, the Arp2/3 complex, and polymerization regulators from the host cytoplasm. Owing to limited information on the structural organization of actin comets and in particular the spatial arrangement of filaments engaged in propulsion, the underlying mechanism of pathogen movement is currently speculative and controversial. Using electron tomography we have resolved the three-dimensional architecture of actin comet tails propelling baculovirus, the smallest pathogen yet known to hijack the actin motile machinery. Comet tail geometry was also mimicked in mixtures of virus capsids with purified actin and a minimal inventory of actin regulators. We demonstrate that propulsion is based on the assembly of a fishbone-like array of actin filaments organized in subsets linked by branch junctions, with an average of four filaments pushing the virus at any one time. Using an energy-minimizing function we have simulated the structure of actin comet tails as well as the tracks adopted by baculovirus in infected cells in vivo. The results from the simulations rule out gel squeezing models of propulsion and support those in which actin filaments are continuously tethered during branch nucleation and polymerization. Since Listeria monocytogenes, Shigella flexneri, and Vaccinia virus among other pathogens use the same common toolbox of components as baculovirus to move, we suggest they share the same principles of actin organization and mode of propulsion. PMID:24453943

Electron tomography and simulation of baculovirus actin comet tails support a tethered filament model of pathogen propulsion.

PubMed

Mueller, Jan; Pfanzelter, Julia; Winkler, Christoph; Narita, Akihiro; Le Clainche, Christophe; Nemethova, Maria; Carlier, Marie-France; Maeda, Yuichiro; Welch, Matthew D; Ohkawa, Taro; Schmeiser, Christian; Resch, Guenter P; Small, J Victor

2014-01-01

Several pathogens induce propulsive actin comet tails in cells they invade to disseminate their infection. They achieve this by recruiting factors for actin nucleation, the Arp2/3 complex, and polymerization regulators from the host cytoplasm. Owing to limited information on the structural organization of actin comets and in particular the spatial arrangement of filaments engaged in propulsion, the underlying mechanism of pathogen movement is currently speculative and controversial. Using electron tomography we have resolved the three-dimensional architecture of actin comet tails propelling baculovirus, the smallest pathogen yet known to hijack the actin motile machinery. Comet tail geometry was also mimicked in mixtures of virus capsids with purified actin and a minimal inventory of actin regulators. We demonstrate that propulsion is based on the assembly of a fishbone-like array of actin filaments organized in subsets linked by branch junctions, with an average of four filaments pushing the virus at any one time. Using an energy-minimizing function we have simulated the structure of actin comet tails as well as the tracks adopted by baculovirus in infected cells in vivo. The results from the simulations rule out gel squeezing models of propulsion and support those in which actin filaments are continuously tethered during branch nucleation and polymerization. Since Listeria monocytogenes, Shigella flexneri, and Vaccinia virus among other pathogens use the same common toolbox of components as baculovirus to move, we suggest they share the same principles of actin organization and mode of propulsion.

Fast Evolution and Lineage-Specific Gene Family Expansions of Aphid Salivary Effectors Driven by Interactions with Host-Plants.

PubMed

Boulain, Hélène; Legeai, Fabrice; Guy, Endrick; Morlière, Stéphanie; Douglas, Nadine E; Oh, Jonghee; Murugan, Marimuthu; Smith, Michael; Jaquiéry, Julie; Peccoud, Jean; White, Frank F; Carolan, James C; Simon, Jean-Christophe; Sugio, Akiko

2018-05-18

Effector proteins play crucial roles in plant-parasite interactions by suppressing plant defenses and hijacking plant physiological responses to facilitate parasite invasion and propagation. Although effector proteins have been characterized in many microbial plant pathogens, their nature and role in adaptation to host plants are largely unknown in insect herbivores. Aphids rely on salivary effector proteins injected into the host plants to promote phloem sap uptake. Therefore, gaining insight into the repertoire and evolution of aphid effectors is key to unveiling the mechanisms responsible for aphid virulence and host plant specialization. With this aim in mind, we assembled catalogues of putative effectors in the legume specialist aphid, Acyrthosiphon pisum, using transcriptomics and proteomics approaches. We identified 3603 candidate effector genes predicted to be expressed in A. pisum salivary glands (SGs), and 740 of which displayed up-regulated expression in SGs in comparison to the alimentary tract. A search for orthologs in 17 arthropod genomes revealed that SG-up-regulated effector candidates of A. pisum are enriched in aphid-specific genes and tend to evolve faster compared to the whole gene set. We also found that a large fraction of proteins detected in the A. pisum saliva belonged to three gene families, of which certain members show evidence consistent with positive selection. Overall, this comprehensive analysis suggests that the large repertoire of effector candidates in A. pisum constitutes a source of novelties promoting plant adaptation to legumes.

Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii

PubMed Central

Moynié, Lucile; Luscher, Alexandre; Rolo, Dora; Tortajada, Antoni; Weingart, Helge; Braun, Yvonne; Page, Malcolm G. P.; Naismith, James H.

2017-01-01

ABSTRACT The outer membrane of Gram-negative bacteria presents an efficient barrier to the permeation of antimicrobial molecules. One strategy pursued to circumvent this obstacle is to hijack transport systems for essential nutrients, such as iron. BAL30072 and MC-1 are two monobactams conjugated to a dihydroxypyridone siderophore that are active against Pseudomonas aeruginosa and Acinetobacter baumannii. Here, we investigated the mechanism of action of these molecules in A. baumannii. We identified two novel TonB-dependent receptors, termed Ab-PiuA and Ab-PirA, that are required for the antimicrobial activity of both agents. Deletion of either piuA or pirA in A. baumannii resulted in 4- to 8-fold-decreased susceptibility, while their overexpression in the heterologous host P. aeruginosa increased susceptibility to the two siderophore-drug conjugates by 4- to 32-fold. The crystal structures of PiuA and PirA from A. baumannii and their orthologues from P. aeruginosa were determined. The structures revealed similar architectures; however, structural differences between PirA and PiuA point to potential differences between their cognate siderophore ligands. Spontaneous mutants, selected upon exposure to BAL30072, harbored frameshift mutations in either the ExbD3 or the TonB3 protein of A. baumannii, forming the cytoplasmic-membrane complex providing the energy for the siderophore translocation process. The results of this study provide insight for the rational design of novel siderophore-drug conjugates against problematic Gram-negative pathogens. PMID:28137795

pelo Is Required for High Efficiency Viral Replication

PubMed Central

Wu, Xiurong; He, Wan-Ting; Tian, Shuye; Meng, Dan; Li, Yuanyue; Chen, Wanze; Li, Lisheng; Tian, Lili; Zhong, Chuan-Qi; Han, Felicia; Chen, Jianming; Han, Jiahuai

2014-01-01

Viruses hijack host factors for their high speed protein synthesis, but information about these factors is largely unknown. In searching for genes that are involved in viral replication, we carried out a forward genetic screen for Drosophila mutants that are more resistant or sensitive to Drosophila C virus (DCV) infection-caused death, and found a virus-resistant line in which the expression of pelo gene was deficient. Our mechanistic studies excluded the viral resistance of pelo deficient flies resulting from the known Drosophila anti-viral pathways, and revealed that pelo deficiency limits the high level synthesis of the DCV capsid proteins but has no or very little effect on the expression of some other viral proteins, bulk cellular proteins, and transfected exogenous genes. The restriction of replication of other types of viruses in pelo deficient flies was also observed, suggesting pelo is required for high level production of capsids of all kinds of viruses. We show that both pelo deficiency and high level DCV protein synthesis increase aberrant 80S ribosomes, and propose that the preferential requirement of pelo for high level synthesis of viral capsids is at least partly due to the role of pelo in dissociation of stalled 80S ribosomes and clearance of aberrant viral RNA and proteins. Our data demonstrated that pelo is a host factor that is required for high efficiency translation of viral capsids and targeting pelo could be a strategy for general inhibition of viral infection. PMID:24722736

Energetic cost of building a virus

PubMed Central

Mahmoudabadi, Gita; Milo, Ron; Phillips, Rob

2017-01-01

Viruses are incapable of autonomous energy production. Although many experimental studies make it clear that viruses are parasitic entities that hijack the molecular resources of the host, a detailed estimate for the energetic cost of viral synthesis is largely lacking. To quantify the energetic cost of viruses to their hosts, we enumerated the costs associated with two very distinct but representative DNA and RNA viruses, namely, T4 and influenza. We found that, for these viruses, translation of viral proteins is the most energetically expensive process. Interestingly, the costs of building a T4 phage and a single influenza virus are nearly the same. Due to influenza’s higher burst size, however, the overall cost of a T4 phage infection is only 2–3% of the cost of an influenza infection. The costs of these infections relative to their host’s estimated energy budget during the infection reveal that a T4 infection consumes about a third of its host’s energy budget, whereas an influenza infection consumes only ≈ 1%. Building on our estimates for T4, we show how the energetic costs of double-stranded DNA phages scale with the capsid size, revealing that the dominant cost of building a virus can switch from translation to genome replication above a critical size. Last, using our predictions for the energetic cost of viruses, we provide estimates for the strengths of selection and genetic drift acting on newly incorporated genetic elements in viral genomes, under conditions of energy limitation. PMID:28512219

Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma.

PubMed

Starrett, Gabriel J; Marcelus, Christina; Cantalupo, Paul G; Katz, Joshua P; Cheng, Jingwei; Akagi, Keiko; Thakuria, Manisha; Rabinowits, Guilherme; Wang, Linda C; Symer, David E; Pipas, James M; Harris, Reuben S; DeCaprio, James A

2017-01-03

Merkel cell polyomavirus is the primary etiological agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genomes of primary MCC tumors. Our study reveals that virus-associated tumors have minimally altered genomes compared to non-virus-associated tumors, which are dominated by UV-mediated mutations. Although virus-associated tumors contain relatively small mutation burdens, they exhibit a distinct mutation signature with observable transcriptionally biased kataegic events. In addition, viral integration sites overlap focal genome amplifications in virus-associated tumors, suggesting a potential mechanism for these events. Collectively, our studies indicate that Merkel cell polyomavirus is capable of hijacking cellular processes and driving tumorigenesis to the same severity as tens of thousands of somatic genome alterations. A variety of mutagenic processes that shape the evolution of tumors are critical determinants of disease outcome. Here, we sequenced the entire genome of virus-positive and virus-negative primary Merkel cell carcinomas (MCCs), revealing distinct mutation spectra and corresponding expression profiles. Our studies highlight the strong effect that Merkel cell polyomavirus has on the divergent development of viral MCC compared to the somatic alterations that typically drive nonviral tumorigenesis. A more comprehensive understanding of the distinct mutagenic processes operative in viral and nonviral MCCs has implications for the effective treatment of these tumors. Copyright © 2017 Starrett et al.

Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer

PubMed Central

Birge, R B; Boeltz, S; Kumar, S; Carlson, J; Wanderley, J; Calianese, D; Barcinski, M; Brekken, R A; Huang, X; Hutchins, J T; Freimark, B; Empig, C; Mercer, J; Schroit, A J; Schett, G; Herrmann, M

2016-01-01

Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics. PMID:26915293

Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer.

PubMed

Birge, R B; Boeltz, S; Kumar, S; Carlson, J; Wanderley, J; Calianese, D; Barcinski, M; Brekken, R A; Huang, X; Hutchins, J T; Freimark, B; Empig, C; Mercer, J; Schroit, A J; Schett, G; Herrmann, M

2016-06-01

Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics.

Mechanism of signal propagation in Physarum polycephalum.

PubMed

Alim, Karen; Andrew, Natalie; Pringle, Anne; Brenner, Michael P

2017-05-16

Complex behaviors are typically associated with animals, but the capacity to integrate information and function as a coordinated individual is also a ubiquitous but poorly understood feature of organisms such as slime molds and fungi. Plasmodial slime molds grow as networks and use flexible, undifferentiated body plans to forage for food. How an individual communicates across its network remains a puzzle, but Physarum polycephalum has emerged as a novel model used to explore emergent dynamics. Within P. polycephalum , cytoplasm is shuttled in a peristaltic wave driven by cross-sectional contractions of tubes. We first track P. polycephalum 's response to a localized nutrient stimulus and observe a front of increased contraction. The front propagates with a velocity comparable to the flow-driven dispersion of particles. We build a mathematical model based on these data and in the aggregate experiments and model identify the mechanism of signal propagation across a body: The nutrient stimulus triggers the release of a signaling molecule. The molecule is advected by fluid flows but simultaneously hijacks flow generation by causing local increases in contraction amplitude as it travels. The molecule is initiating a feedback loop to enable its own movement. This mechanism explains previously puzzling phenomena, including the adaptation of the peristaltic wave to organism size and P. polycephalum 's ability to find the shortest route between food sources. A simple feedback seems to give rise to P. polycephalum 's complex behaviors, and the same mechanism is likely to function in the thousands of additional species with similar behaviors.

Human T-lymphotropic virus proteins and post-translational modification pathways

PubMed Central

Bidoia, Carlo

2012-01-01

Cell life from the cell cycle to the signaling transduction and response to stimuli is finely tuned by protein post-translational modifications (PTMs). PTMs alter the conformation, the stability, the localization, and hence the pattern of interactions of the targeted protein. Cell pathways involve the activation of enzymes, like kinases, ligases and transferases, that, once activated, act on many proteins simultaneously, altering the state of the cell and triggering the processes they are involved in. Viruses enter a balanced system and hijack the cell, exploiting the potential of PTMs either to activate viral encoded proteins or to alter cellular pathways, with the ultimate consequence to perpetuate through their replication. Human T-lymphotropic virus type 1 (HTLV-1) is known to be highly oncogenic and associates with adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis and other inflammatory pathological conditions. HTLV-1 protein activity is controlled by PTMs and, in turn, viral activity is associated with the modulation of cellular pathways based on PTMs. More knowledge is acquired about the PTMs involved in the activation of its proteins, like Tax, Rex, p12, p13, p30, HTLV-I basic leucine zipper factor and Gag. However, more has to be understood at the biochemical level in order to counteract the associated fatal outcomes. This review will focus on known PTMs that directly modify HTLV-1 components and on enzymes whose activity is modulated by viral proteins. PMID:24175216

Entomopathogenicity and Biological Attributes of Himalayan Treasured Fungus Ophiocordyceps sinensis (Yarsagumba)

PubMed Central

Baral, Bikash

2017-01-01

Members of the entomophagous fungi are considered very crucial in the fungal domain relative to their natural phenomenon and economic perspectives; however, inadequate knowledge of their mechanisms of interaction keeps them lagging behind in parallel studies of fungi associated with agro-ecology, forest pathology and medical biology. Ophiocordyceps sinensis (syn. Cordyceps sinensis), an intricate fungus-caterpillar complex after it parasitizes the larva of the moth, is a highly prized medicinal fungus known widely for ages due to its peculiar biochemical assets. Recent technological innovations have significantly contributed a great deal to profiling the variable clinical importance of this fungus and other related fungi with similar medicinal potential. However, a detailed mechanism behind fungal pathogenicity and fungal-insect interactions seems rather ambiguous and is poorly justified, demanding special attention. The goal of the present review is to divulge an update on the published data and provides promising insights on different biological events that have remained underemphasized in previous reviews on fungal biology with relation to life-history trade-offs, host specialization and selection pressures. The infection of larvae by a fungus is not a unique event in Cordyceps; hence, other fungal species are also reviewed for effective comparison. Conceivably, the rationale and approaches behind the inheritance of pharmacological abilities acquired and stored within the insect framework at a time when they are completely hijacked and consumed by fungal parasites, and the molecular mechanisms involved therein, are clearly documented. PMID:29371523

Endophilins interact with Moloney murine leukemia virus Gag and modulate virion production

PubMed Central

Wang, Margaret Q; Kim, Wankee; Gao, Guangxia; Torrey, Ted A; Morse, Herbert C; De Camilli, Pietro; Goff, Stephen P

2004-01-01

Background The retroviral Gag protein is the central player in the process of virion assembly at the plasma membrane, and is sufficient to induce the formation and release of virus-like particles. Recent evidence suggests that Gag may co-opt the host cell's endocytic machinery to facilitate retroviral assembly and release. Results A search for novel partners interacting with the Gag protein of the Moloney murine leukemia virus (Mo-MuLV) via the yeast two-hybrid protein-protein interaction assay resulted in the identification of endophilin 2, a component of the machinery involved in clathrin-mediated endocytosis. We demonstrate that endophilin interacts with the matrix or MA domain of the Gag protein of Mo-MuLV, but not of human immunodeficiency virus, HIV. Both exogenously expressed and endogenous endophilin are incorporated into Mo-MuLV viral particles. Titration experiments suggest that the binding sites for inclusion of endophilin into viral particles are limited and saturable. Knock-down of endophilin with small interfering RNA (siRNA) had no effect on virion production, but overexpression of endophilin and, to a lesser extent, of several fragments of the protein, result in inhibition of Mo-MuLV virion production, but not of HIV virion production. Conclusions This study shows that endophilins interact with Mo-MuLV Gag and affect virion production. The findings imply that endophilin is another component of the large complex that is hijacked by retroviruses to promote virion production. PMID:14659004

Neurogenetic and epigenetic correlates of adolescent predisposition to and risk for addictive behaviors as a function of prefrontal cortex dysregulation.

PubMed

Blum, Kenneth; Febo, Marcelo; Smith, David E; Roy, A Kenison; Demetrovics, Zsolt; Cronjé, Frans J; Femino, John; Agan, Gozde; Fratantonio, James L; Pandey, Subhash C; Badgaiyan, Rajendra D; Gold, Mark S

2015-05-01

As addiction professionals, we are becoming increasingly concerned about preteenagers and young adults' involvement with substance abuse as a way of relieving stress and anger. The turbulent underdeveloped central nervous system, especially in the prefrontal cortex (PFC), provides impetus to not only continue important neuroimaging studies in both human and animal models, but also to encourage preventive measures and cautions embraced by governmental and social media outlets. It is well known that before people reach their 20s, PFC development is undergoing significant changes and, as such, hijacks appropriate decision making in this population. We are further proposing that early genetic testing for addiction risk alleles will offer important information that could potentially be utilized by their parents and caregivers prior to use of psychoactive drugs by these youth. Understandably, family history, parenting styles, and attachment may be modified by various reward genes, including the known bonding substances oxytocin/vasopressin, which effect dopaminergic function. Well-characterized neuroimaging studies continue to reflect region-specific differential responses to drugs and food (including other non-substance-addictive behaviors) via either "surfeit" or "deficit." With this in mind, we hereby propose a "reward deficiency solution system" that combines early genetic risk diagnosis, medical monitoring, and nutrigenomic dopamine agonist modalities to combat this significant global dilemma that is preventing our youth from leading normal productive lives, which will in turn make them happier.

Neurogenetic and Epigenetic Correlates of Adolescent Predisposition to and Risk for Addictive Behaviors as a Function of Prefrontal Cortex Dysregulation

PubMed Central

Febo, Marcelo; Smith, David E.; Roy, A. Kenison; Demetrovics, Zsolt; Cronjé, Frans J.; Femino, John; Agan, Gozde; Fratantonio, James L.; Pandey, Subhash C.; Badgaiyan, Rajendra D.; Gold, Mark S.

2015-01-01

Abstract As addiction professionals, we are becoming increasingly concerned about preteenagers and young adults' involvement with substance abuse as a way of relieving stress and anger. The turbulent underdeveloped central nervous system, especially in the prefrontal cortex (PFC), provides impetus to not only continue important neuroimaging studies in both human and animal models, but also to encourage preventive measures and cautions embraced by governmental and social media outlets. It is well known that before people reach their 20s, PFC development is undergoing significant changes and, as such, hijacks appropriate decision making in this population. We are further proposing that early genetic testing for addiction risk alleles will offer important information that could potentially be utilized by their parents and caregivers prior to use of psychoactive drugs by these youth. Understandably, family history, parenting styles, and attachment may be modified by various reward genes, including the known bonding substances oxytocin/vasopressin, which effect dopaminergic function. Well-characterized neuroimaging studies continue to reflect region-specific differential responses to drugs and food (including other non-substance-addictive behaviors) via either “surfeit” or “deficit.” With this in mind, we hereby propose a “reward deficiency solution system” that combines early genetic risk diagnosis, medical monitoring, and nutrigenomic dopamine agonist modalities to combat this significant global dilemma that is preventing our youth from leading normal productive lives, which will in turn make them happier. PMID:25919973

BMI predicts emotion-driven impulsivity and cognitive inflexibility in adolescents with excess weight.

PubMed

Delgado-Rico, Elena; Río-Valle, Jacqueline S; González-Jiménez, Emilio; Campoy, Cristina; Verdejo-García, Antonio

2012-08-01

Adolescent obesity is increasingly viewed as a brain-related dysfunction, whereby reward-driven urges for pleasurable foods "hijack" response selection systems, such that behavioral control progressively shifts from impulsivity to compulsivity. In this study, we aimed to examine the link between personality factors (sensitivity to reward (SR) and punishment (SP), BMI, and outcome measures of impulsivity vs. flexibility in--otherwise healthy--excessive weight adolescents. Sixty-three adolescents (aged 12-17) classified as obese (n = 26), overweight (n = 16), or normal weight (n = 21) participated in the study. We used psychometric assessments of the SR and SP motivational systems, impulsivity (using the UPPS-P scale), and neurocognitive measures with discriminant validity to dissociate inhibition vs. flexibility deficits (using the process-approach version of the Stroop test). We tested the relative contribution of age, SR/SP, and BMI on estimates of impulsivity and inhibition vs. switching performance using multistep hierarchical regression models. BMI significantly predicted elevations in emotion-driven impulsivity (positive and negative urgency) and inferior flexibility performance in adolescents with excess weight--exceeding the predictive capacity of SR and SP. SR was the main predictor of elevations in sensation seeking and lack of premeditation. These findings demonstrate that increases in BMI are specifically associated with elevations in emotion-driven impulsivity and cognitive inflexibility, supporting a dimensional path in which adolescents with excess weight increase their proneness to overindulge when under strong affective states, and their difficulties to switch or reverse habitual behavioral patterns.

HIV-1 tat protein recruits CIS to the cytoplasmic tail of CD127 to induce receptor ubiquitination and proteasomal degradation

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

Sugden, Scott, E-mail: scott.sugden@ircm.qc.ca

HIV-1 Tat protein down regulates expression of the IL-7 receptor alpha-chain (CD127) from the surface of CD8 T cells resulting in impaired T cell proliferation and cytolytic capacity. We have previously shown that soluble Tat protein is taken up by CD8 T cells and interacts with the cytoplasmic tail of CD127 to induce receptor degradation. The N-terminal domain of Tat interacts with CD127 while the basic domain directs CD127 to the proteasome. We have also shown that upon IL-7 binding to its receptor, CD127 is phosphorylated resulting in CIS-mediated proteasomal degradation. Here, we show that Tat mimics this process bymore » recruiting CIS to CD127 in the absence of IL-7 and receptor phosphorylation, leading to CD127 ubiquitination and degradation. Tat therefore acts as an adapter to induce cellular responses under conditions where they may not otherwise occur. Thusly, Tat reduces IL-7 signaling and impairs CD8 T cell survival and function. -- Highlights: •Soluble HIV-1 Tat decreases CD127 expression on CD8 T cells, causing dysfunction. •Tat induces CD127 ubiquitination without activating IL-7 signaling. •Tat binds CD127 and recruits the E3 ubiquitin ligase CIS via its basic domain. •Tat hijacks a normal cellular mechanism to degrade CD127 without IL-7 signaling.« less

Pathology and failure in the design and implementation of adaptive management

USGS Publications Warehouse

Allen, Craig R.; Gunderson, Lance H.

2011-01-01

The conceptual underpinnings for adaptive management are simple; there will always be inherent uncertainty and unpredictability in the dynamics and behavior of complex ecological systems as a result non-linear interactions among components and emergence, yet management decisions must still be made. The strength of adaptive management is in the recognition and confrontation of such uncertainty. Rather than ignore uncertainty, or use it to preclude management actions, adaptive management can foster resilience and flexibility to cope with an uncertain future, and develop safe to fail management approaches that acknowledge inevitable changes and surprises. Since its initial introduction, adaptive management has been hailed as a solution to endless trial and error approaches to complex natural resource management challenges. However, its implementation has failed more often than not. It does not produce easy answers, and it is appropriate in only a subset of natural resource management problems. Clearly adaptive management has great potential when applied appropriately. Just as clearly adaptive management has seemingly failed to live up to its high expectations. Why? We outline nine pathologies and challenges that can lead to failure in adaptive management programs. We focus on general sources of failures in adaptive management, so that others can avoid these pitfalls in the future. Adaptive management can be a powerful and beneficial tool when applied correctly to appropriate management problems; the challenge is to keep the concept of adaptive management from being hijacked for inappropriate use.

Chlamydia pneumoniae exploits adipocyte lipid chaperone FABP4 to facilitate fat mobilization and intracellular growth in murine adipocytes.

PubMed

Walenna, Nirwana Fitriani; Kurihara, Yusuke; Chou, Bin; Ishii, Kazunari; Soejima, Toshinori; Itoh, Ryota; Shimizu, Akinori; Ichinohe, Takeshi; Hiromatsu, Kenji

2018-01-01

Fatty acid-binding protein 4 (FABP4), a cytosolic lipid chaperone predominantly expressed in adipocytes and macrophages, modulates lipid fluxes, trafficking, signaling, and metabolism. Recent studies have demonstrated that FABP4 regulates metabolic and inflammatory pathways, and in mouse models its inhibition can improve type 2 diabetes mellitus and atherosclerosis. However, the role of FABP4 in bacterial infection, metabolic crosstalk between host and pathogen, and bacterial pathogenesis have not been studied. As an obligate intracellular pathogen, Chlamydia pneumoniae needs to obtain nutrients such as ATP and lipids from host cells. Here, we show that C. pneumoniae successfully infects and proliferates in murine adipocytes by inducing hormone sensitive lipase (HSL)-mediated lipolysis. Chemical inhibition or genetic manipulation of HSL significantly abrogated the intracellular growth of C. pneumoniae in adipocytes. Liberated free fatty acids were utilized to generate ATP via β-oxidation, which C. pneumoniae usurped for its replication. Strikingly, chemical inhibition or genetic silencing of FABP4 significantly abrogated C. pneumoniae infection-induced lipolysis and mobilization of liberated FFAs, resulting in reduced bacterial growth in adipocytes. Collectively, these results demonstrate that C. pneumoniae exploits host FABP4 to facilitate fat mobilization and intracellular replication in adipocytes. This work uncovers a novel strategy used by intracellular pathogens for acquiring energy via hijacking of the host lipid metabolism pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Using cyber vulnerability testing techniques to expose undocumented security vulnerabilities in DCS and SCADA equipment

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

Pollet, J.

2006-07-01

This session starts by providing an overview of typical DCS (Distributed Control Systems) and SCADA (Supervisory Control and Data Acquisition) architectures, and exposes cyber security vulnerabilities that vendors never admit, but are found through a comprehensive cyber testing process. A complete assessment process involves testing all of the layers and components of a SCADA or DCS environment, from the perimeter firewall all the way down to the end devices controlling the process, including what to look for when conducting a vulnerability assessment of real-time control systems. The following systems are discussed: 1. Perimeter (isolation from corporate IT or other non-criticalmore » networks) 2. Remote Access (third Party access into SCADA or DCS networks) 3. Network Architecture (switch, router, firewalls, access controls, network design) 4. Network Traffic Analysis (what is running on the network) 5. Host Operating Systems Hardening 6. Applications (how they communicate with other applications and end devices) 7. End Device Testing (PLCs, RTUs, DCS Controllers, Smart Transmitters) a. System Discovery b. Functional Discovery c. Attack Methodology i. DoS Tests (at what point does the device fail) ii. Malformed Packet Tests (packets that can cause equipment failure) iii. Session Hijacking (do anything that the operator can do) iv. Packet Injection (code and inject your own SCADA commands) v. Protocol Exploitation (Protocol Reverse Engineering / Fuzzing) This paper will provide information compiled from over five years of conducting cyber security testing on control systems hardware, software, and systems. (authors)« less

Brassinosteroids antagonize gibberellin- and salicylate-mediated root immunity in rice.

PubMed

De Vleesschauwer, David; Van Buyten, Evelien; Satoh, Kouji; Balidion, Johny; Mauleon, Ramil; Choi, Il-Ryong; Vera-Cruz, Casiana; Kikuchi, Shoshi; Höfte, Monica

2012-04-01

Brassinosteroids (BRs) are a unique class of plant steroid hormones that orchestrate myriad growth and developmental processes. Although BRs have long been known to protect plants from a suite of biotic and abiotic stresses, our understanding of the underlying molecular mechanisms is still rudimentary. Aiming to further decipher the molecular logic of BR-modulated immunity, we have examined the dynamics and impact of BRs during infection of rice (Oryza sativa) with the root oomycete Pythium graminicola. Challenging the prevailing view that BRs positively regulate plant innate immunity, we show that P. graminicola exploits BRs as virulence factors and hijacks the rice BR machinery to inflict disease. Moreover, we demonstrate that this immune-suppressive effect of BRs is due, at least in part, to negative cross talk with salicylic acid (SA) and gibberellic acid (GA) pathways. BR-mediated suppression of SA defenses occurred downstream of SA biosynthesis, but upstream of the master defense regulators NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 and OsWRKY45. In contrast, BR alleviated GA-directed immune responses by interfering at multiple levels with GA metabolism, resulting in indirect stabilization of the DELLA protein and central GA repressor SLENDER RICE1 (SLR1). Collectively, these data favor a model whereby P. graminicola coopts the plant BR pathway as a decoy to antagonize effectual SA- and GA-mediated defenses. Our results highlight the importance of BRs in modulating plant immunity and uncover pathogen-mediated manipulation of plant steroid homeostasis as a core virulence strategy.

Brassinosteroids Antagonize Gibberellin- and Salicylate-Mediated Root Immunity in Rice1[C][W][OA

PubMed Central

De Vleesschauwer, David; Van Buyten, Evelien; Satoh, Kouji; Balidion, Johny; Mauleon, Ramil; Choi, Il-Ryong; Vera-Cruz, Casiana; Kikuchi, Shoshi; Höfte, Monica

2012-01-01

Brassinosteroids (BRs) are a unique class of plant steroid hormones that orchestrate myriad growth and developmental processes. Although BRs have long been known to protect plants from a suite of biotic and abiotic stresses, our understanding of the underlying molecular mechanisms is still rudimentary. Aiming to further decipher the molecular logic of BR-modulated immunity, we have examined the dynamics and impact of BRs during infection of rice (Oryza sativa) with the root oomycete Pythium graminicola. Challenging the prevailing view that BRs positively regulate plant innate immunity, we show that P. graminicola exploits BRs as virulence factors and hijacks the rice BR machinery to inflict disease. Moreover, we demonstrate that this immune-suppressive effect of BRs is due, at least in part, to negative cross talk with salicylic acid (SA) and gibberellic acid (GA) pathways. BR-mediated suppression of SA defenses occurred downstream of SA biosynthesis, but upstream of the master defense regulators NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 and OsWRKY45. In contrast, BR alleviated GA-directed immune responses by interfering at multiple levels with GA metabolism, resulting in indirect stabilization of the DELLA protein and central GA repressor SLENDER RICE1 (SLR1). Collectively, these data favor a model whereby P. graminicola coopts the plant BR pathway as a decoy to antagonize effectual SA- and GA-mediated defenses. Our results highlight the importance of BRs in modulating plant immunity and uncover pathogen-mediated manipulation of plant steroid homeostasis as a core virulence strategy. PMID:22353574

Occipital Alpha and Gamma Oscillations Support Complementary Mechanisms for Processing Stimulus Value Associations.

PubMed

Marshall, Tom R; den Boer, Sebastiaan; Cools, Roshan; Jensen, Ole; Fallon, Sean James; Zumer, Johanna M

2018-01-01

Selective attention is reflected neurally in changes in the power of posterior neural oscillations in the alpha (8-12 Hz) and gamma (40-100 Hz) bands. Although a neural mechanism that allows relevant information to be selectively processed has its advantages, it may lead to lucrative or dangerous information going unnoticed. Neural systems are also in place for processing rewarding and punishing information. Here, we examine the interaction between selective attention (left vs. right) and stimulus's learned value associations (neutral, punished, or rewarded) and how they compete for control of posterior neural oscillations. We found that both attention and stimulus-value associations influenced neural oscillations. Whereas selective attention had comparable effects on alpha and gamma oscillations, value associations had dissociable effects on these neural markers of attention. Salient targets (associated with positive and negative outcomes) hijacked changes in alpha power-increasing hemispheric alpha lateralization when salient targets were attended, decreasing it when they were being ignored. In contrast, hemispheric gamma-band lateralization was specifically abolished by negative distractors. Source analysis indicated occipital generators of both attentional and value effects. Thus, posterior cortical oscillations support both the ability to selectively attend while at the same time retaining the ability to remain sensitive to valuable features in the environment. Moreover, the versatility of our attentional system to respond separately to salient from merely positively valued stimuli appears to be carried out by separate neural processes reflected in different frequency bands.

A Conserved Basal Transcription Factor Is Required for the Function of Diverse TAL Effectors in Multiple Plant Hosts.

PubMed

Huang, Renyan; Hui, Shugang; Zhang, Meng; Li, Pei; Xiao, Jinghua; Li, Xianghua; Yuan, Meng; Wang, Shiping

2017-01-01

Many Xanthomonas bacteria use transcription activator-like effector (TALE) proteins to activate plant disease susceptibility ( S ) genes, and this activation contributes to disease. We recently reported that rice basal transcription factor IIA gamma subunit, OsTFIIAγ5, is hijacked by TALE-carrying Xanthomonas oryzae infecting the plants. However, whether TFIIAγs are also involved in TALE-carrying Xanthomonas -caused diseases in other plants is unknown. Here, molecular and genetic approaches were used to investigate the role of TFIIAγs in other plants. We found that TFIIAγs are also used by TALE-carrying Xanthomonas to cause disease in other plants. The TALEs of Xanthomonas citri pv. citri ( Xcc ) causing canker in citrus and Xanthomonas campestris pv. vesicatoria ( Xcv ) causing bacterial spot in pepper and tomato interacted with corresponding host TFIIAγs as in rice. Transcriptionally suppressing TFIIAγ led to resistance to Xcc in citrus and Xcv in pepper and tomato. The 39th residue of OsTFIIAγ5 and citrus CsTFIIAγ is vital for TALE-dependent induction of plant S genes. As mutated OsTFIIAγ5 V 39E , CsTFIIAγ V 39E , pepper CaTFIIAγ V 39E , and tomato SlTFIIAγ V 39E also did not interact with TALEs to prevent disease. These results suggest that TALE-carrying bacteria share a common mechanism for infecting plants. Using TFIIAγ V 39E -type mutation could be a general strategy for improving resistance to TALE-carrying pathogens in crops.

Tomato leaf curl Yunnan virus-encoded C4 induces cell division through enhancing stability of Cyclin D 1.1 via impairing NbSKη -mediated phosphorylation in Nicotiana benthamiana

PubMed Central

Mei, Yuzhen; Yang, Xiuling; Huang, Changjun

2018-01-01

The whitefly-transmitted geminiviruses induce severe developmental abnormalities in plants. Geminivirus-encoded C4 protein functions as one of viral symptom determinants that could induce abnormal cell division. However, the molecular mechanism by which C4 contributes to cell division induction remains unclear. Here we report that tomato leaf curl Yunnan virus (TLCYnV) C4 interacts with a glycogen synthase kinase 3 (GSK3)/SHAGGY-like kinase, designed NbSKη, in Nicotiana benthamiana. Pro32, Asn34 and Thr35 of TLCYnV C4 are critical for its interaction with NbSKη and required for C4-induced typical symptoms. Interestingly, TLCYnV C4 directs NbSKη to the membrane and reduces the nuclear-accumulation of NbSKη. The relocalization of NbSKη impairs phosphorylation dependent degradation on its substrate-Cyclin D1.1 (NbCycD1;1), thereby increasing the accumulation level of NbCycD1;1 and inducing the cell division. Moreover, NbSKη-RNAi, 35S::NbCycD1;1 transgenic N. benthamiana plants have the similar phenotype as 35S::C4 transgenic N. benthamiana plants on callus-like tissue formation resulted from abnormal cell division induction. Thus, this study provides new insights into mechanism of how a viral protein hijacks NbSKη to induce abnormal cell division in plants. PMID:29293689

Complement System Part II: Role in Immunity

PubMed Central

Merle, Nicolas S.; Noe, Remi; Halbwachs-Mecarelli, Lise; Fremeaux-Bacchi, Veronique; Roumenina, Lubka T.

2015-01-01

The complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b–9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target. PMID:26074922

Lentiviral Nef Proteins Utilize PAK2-Mediated Deregulation of Cofilin as a General Strategy To Interfere with Actin Remodeling▿ †

PubMed Central

Stolp, Bettina; Abraham, Libin; Rudolph, Jochen M.; Fackler, Oliver T.

2010-01-01

Nef is an accessory protein and pathogenicity factor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) which elevates virus replication in vivo. We recently described for HIV type 1SF2 (HIV-1SF2) the potent interference of Nef with T-lymphocyte chemotaxis via its association with the cellular kinase PAK2. Mechanistic analysis revealed that this interaction results in deregulation of the actin-severing factor cofilin and thus blocks the chemokine-mediated actin remodeling required for cell motility. However, the efficiency of PAK2 association is highly variable among Nef proteins from different lentiviruses, prompting us to evaluate the conservation of this actin-remodeling/cofilin-deregulating mechanism. Based on the analysis of a total of 17 HIV-1, HIV-2, and SIV Nef proteins, we report here that inhibition of chemokine-induced actin remodeling as well as inactivation of cofilin are strongly conserved activities of lentiviral Nef proteins. Of note, even for Nef variants that display only marginal PAK2 association in vitro, these activities require the integrity of a PAK2 recruitment motif and the presence of endogenous PAK2. Thus, reduced in vitro affinity to PAK2 does not indicate limited functionality of Nef-PAK2 complexes in intact HIV-1 host cells. These results establish hijacking of PAK2 for deregulation of cofilin and inhibition of triggered actin remodeling as a highly conserved function of lentiviral Nef proteins, supporting the notion that PAK2 association may be critical for Nef's activity in vivo. PMID:20147394

Lentiviral Nef proteins utilize PAK2-mediated deregulation of cofilin as a general strategy to interfere with actin remodeling.

PubMed

Stolp, Bettina; Abraham, Libin; Rudolph, Jochen M; Fackler, Oliver T

2010-04-01

Nef is an accessory protein and pathogenicity factor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) which elevates virus replication in vivo. We recently described for HIV type 1(SF2) (HIV-1(SF2)) the potent interference of Nef with T-lymphocyte chemotaxis via its association with the cellular kinase PAK2. Mechanistic analysis revealed that this interaction results in deregulation of the actin-severing factor cofilin and thus blocks the chemokine-mediated actin remodeling required for cell motility. However, the efficiency of PAK2 association is highly variable among Nef proteins from different lentiviruses, prompting us to evaluate the conservation of this actin-remodeling/cofilin-deregulating mechanism. Based on the analysis of a total of 17 HIV-1, HIV-2, and SIV Nef proteins, we report here that inhibition of chemokine-induced actin remodeling as well as inactivation of cofilin are strongly conserved activities of lentiviral Nef proteins. Of note, even for Nef variants that display only marginal PAK2 association in vitro, these activities require the integrity of a PAK2 recruitment motif and the presence of endogenous PAK2. Thus, reduced in vitro affinity to PAK2 does not indicate limited functionality of Nef-PAK2 complexes in intact HIV-1 host cells. These results establish hijacking of PAK2 for deregulation of cofilin and inhibition of triggered actin remodeling as a highly conserved function of lentiviral Nef proteins, supporting the notion that PAK2 association may be critical for Nef's activity in vivo.

Wholly Rickettsia! Reconstructed Metabolic Profile of the Quintessential Bacterial Parasite of Eukaryotic Cells

PubMed Central

Driscoll, Timothy P.; Verhoeve, Victoria I.; Guillotte, Mark L.; Lehman, Stephanie S.; Rennoll, Sherri A.; Beier-Sexton, Magda; Rahman, M. Sayeedur; Azad, Abdu F.

2017-01-01

ABSTRACT Reductive genome evolution has purged many metabolic pathways from obligate intracellular Rickettsia (Alphaproteobacteria; Rickettsiaceae). While some aspects of host-dependent rickettsial metabolism have been characterized, the array of host-acquired metabolites and their cognate transporters remains unknown. This dearth of information has thwarted efforts to obtain an axenic Rickettsia culture, a major impediment to conventional genetic approaches. Using phylogenomics and computational pathway analysis, we reconstructed the Rickettsia metabolic and transport network, identifying 51 host-acquired metabolites (only 21 previously characterized) needed to compensate for degraded biosynthesis pathways. In the absence of glycolysis and the pentose phosphate pathway, cell envelope glycoconjugates are synthesized from three imported host sugars, with a range of additional host-acquired metabolites fueling the tricarboxylic acid cycle. Fatty acid and glycerophospholipid pathways also initiate from host precursors, and import of both isoprenes and terpenoids is required for the synthesis of ubiquinone and the lipid carrier of lipid I and O-antigen. Unlike metabolite-provisioning bacterial symbionts of arthropods, rickettsiae cannot synthesize B vitamins or most other cofactors, accentuating their parasitic nature. Six biosynthesis pathways contain holes (missing enzymes); similar patterns in taxonomically diverse bacteria suggest alternative enzymes that await discovery. A paucity of characterized and predicted transporters emphasizes the knowledge gap concerning how rickettsiae import host metabolites, some of which are large and not known to be transported by bacteria. Collectively, our reconstructed metabolic network offers clues to how rickettsiae hijack host metabolic pathways. This blueprint for growth determinants is an important step toward the design of axenic media to rescue rickettsiae from the eukaryotic cell. PMID:28951473

Role of addiction and stress neurobiology on food intake and obesity.

PubMed

Sinha, Rajita

2018-01-01

The US remains at the forefront of a global obesity epidemic with a significant negative impact on public health. While it is well known that a balance between energy intake and expenditure is homeostatically regulated to control weight, growing evidence points to multifactorial social, neurobehavioral and metabolic determinants of food intake that influence obesity risk. This review presents factors such as the ubiquitous presence of rewarding foods in the environment and increased salience of such foods that stimulate brain reward motivation and stress circuits to influence eating behaviors. These rewarding foods via conditioned and reinforcing effects stimulate not only metabolic, but also stress hormones, that, in turn, hijack the brain emotional (limbic) and motivational (striatal) pathways, to promote food craving and excessive food intake. Furthermore, the impact of high levels of stress and trauma and altered metabolic environment (e.g. higher weight, altered insulin sensitivity) on prefrontal cortical self-control processes that regulate emotional, motivational and visceral homeostatic mechanisms of food intake and obesity risk are also discussed. A heuristic framework is presented in which the interactive dynamic effects of neurobehavioral adaptations in metabolic, motivation and stress neurobiology may further support food craving, excessive food intake and weight gain in a complex feed-forward manner. Implications of such adaptations in brain addictive-motivational and stress pathways and their effects on excessive food intake and weight gain are discussed to highlight key questions that requires future research attention in order to better understand and address the growing obesity epidemic. Copyright © 2017 Elsevier B.V. All rights reserved.

Quantitative Analysis of Filament Branch Orientation in Listeria Actin Comet Tails.

PubMed

Jasnin, Marion; Crevenna, Alvaro H

2016-02-23

Several bacterial and viral pathogens hijack the host actin cytoskeleton machinery to facilitate spread and infection. In particular, Listeria uses Arp2/3-mediated actin filament nucleation at the bacterial surface to generate a branched network that will help propel the bacteria. However, the mechanism of force generation remains elusive due to the lack of high-resolution three-dimensional structural data on the spatial organization of the actin mother and daughter (i.e., branch) filaments within this network. Here, we have explored the three-dimensional structure of Listeria actin tails in Xenopus laevis egg extracts using cryo-electron tomography. We found that the architecture of Listeria actin tails is shared between those formed in cells and in cell extracts. Both contained nanoscopic bundles along the plane of the substrate, where the bacterium lies, and upright filaments (also called Z filaments), both oriented tangentially to the bacterial cell wall. Here, we were able to identify actin filament intersections, which likely correspond to branches, within the tails. A quantitative analysis of putative Arp2/3-mediated branches in the actin network showed that mother filaments lie on the plane of the substrate, whereas daughter filaments have random deviations out of this plane. Moreover, the analysis revealed that branches are randomly oriented with respect to the bacterial surface. Therefore, the actin filament network does not push directly toward the surface but rather accumulates, building up stress around the Listeria surface. Our results favor a mechanism of force generation for Listeria movement where the stress is released into propulsive motion. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder

PubMed Central

Voon, V; Brezing, C; Gallea, C; Hallett, M

2014-01-01

Background Conversion disorder is characterized by unexplained neurological symptoms presumed related to psychological issues. The main hypotheses to explain conversion paralysis, characterized by a lack of movement, include impairments in either motor intention or disruption of motor execution, and further, that hyperactive self-monitoring, limbic processing or top-down regulation from higher order frontal regions may interfere with motor execution. We have recently shown that conversion disorder with positive abnormal or excessive motor symptoms was associated with greater amygdala activity to arousing stimuli along with greater functional connectivity between the amgydala and supplementary motor area. Here we studied patients with such symptoms focusing on motor initiation. Methods Subjects performed either an internally or externally generated two-button action selection task in a functional MRI study. Results Eleven conversion disorder patients without major depression and 11 age- and gender-matched normal volunteers were assessed. During both internally and externally generated movement, conversion disorder patients relative to normal volunteers had lower left supplementary motor area (SMA) (implicated in motor initiation) and higher right amygdala, left anterior insula and bilateral posterior cingulate activity (implicated in assigning emotional salience). These findings were confirmed in a subgroup analysis of patients with tremor symptoms. During internally versus externally generated action in CD patients, the left SMA had lower functional connectivity with bilateral dorsolateral prefrontal cortices. Conclusion We propose a theory in which previously mapped conversion motor representations may in an arousing context hijack the voluntary action selection system which is both hypoactive and functionally disconnected from prefrontal top-down regulation. PMID:21935985

Functional anatomy of complement factor H.

PubMed

Makou, Elisavet; Herbert, Andrew P; Barlow, Paul N

2013-06-11

Factor H (FH) is a soluble regulator of the proteolytic cascade at the core of the evolutionarily ancient vertebrate complement system. Although FH consists of a single chain of similar protein modules, it has a demanding job description. Its chief role is to prevent complement-mediated injury to healthy host cells and tissues. This entails recognition of molecular patterns on host surfaces combined with control of one of nature's most dangerous examples of a positive-feedback loop. In this way, FH modulates, where and when needed, an amplification process that otherwise exponentially escalates the production of the pro-inflammatory, pro-phagocytic, and pro-cytolytic cleavage products of complement proteins C3 and C5. Mutations and single-nucleotide polymorphisms in the FH gene and autoantibodies against FH predispose individuals to diseases, including age-related macular degeneration, dense-deposit disease, and atypical hemolytic uremic syndrome. Moreover, deletions or variations of genes for FH-related proteins also influence the risk of disease. Numerous pathogens hijack FH and use it for self-defense. As reviewed herein, a molecular understanding of FH function is emerging. While its functional oligomeric status remains uncertain, progress has been achieved in characterizing its three-dimensional architecture and, to a lesser extent, its intermodular flexibility. Models are proposed, based on the reconciliation of older data with a wealth of recent evidence, in which a latent circulating form of FH is activated by its principal target, C3b tethered to a self-surface. Such models suggest hypotheses linking sequence variations to pathophysiology, but improved, more quantitative, functional assays and rigorous data analysis are required to test these ideas.

Evaluating apparent competition in limiting the recovery of an endangered ungulate.

PubMed

Johnson, Heather E; Hebblewhite, Mark; Stephenson, Thomas R; German, David W; Pierce, Becky M; Bleich, Vernon C

2013-01-01

Predation can disproportionately affect endangered prey populations when generalist predators are numerically linked to more abundant primary prey. Apparent competition, the term for this phenomenon, has been increasingly implicated in the declines of endangered prey populations. We examined the potential for apparent competition to limit the recovery of Sierra Nevada bighorn sheep (Ovis canadensis sierrae), an endangered subspecies under the US Endangered Species Act. Using a combination of location, demographic, and habitat data, we assessed whether cougar (Puma concolor) predation on endangered bighorn sheep was a consequence of their winter range overlap with abundant mule deer (Odocoileus hemionus). Consistent with the apparent competition hypothesis, bighorn sheep populations with higher spatial overlap with deer exhibited higher rates of cougar predation which had additive effects on adult survival. Bighorn sheep killed by cougars were primarily located within deer winter ranges, even though those areas constituted only a portion of the bighorn sheep winter ranges. We suspect that variation in sympatry between bighorn sheep and deer populations was largely driven by differences in habitat selection among bighorn sheep herds. Indeed, bighorn sheep herds that experienced the highest rates of predation and the greatest spatial overlap with deer also exhibited the strongest selection for low elevation habitat. Although predator-mediated apparent competition may limit some populations of bighorn sheep, it is not the primary factor limiting all populations, suggesting that the dynamics of different herds are highly idiosyncratic. Management plans for endangered species should consider the spatial distributions of key competitors and predators to reduce the potential for apparent competition to hijack conservation success.

ATG4B inhibitors with a benzotropolone core structure block autophagy and augment efficiency of chemotherapy in mice.

PubMed

Kurdi, Ammar; Cleenewerck, Matthias; Vangestel, Christel; Lyssens, Sophie; Declercq, Wim; Timmermans, Jean-Pierre; Stroobants, Sigrid; Augustyns, Koen; De Meyer, Guido R Y; Van Der Veken, Pieter; Martinet, Wim

2017-08-15

Autophagy is a cell survival mechanism hijacked by advanced tumors to endure a rough microenvironment. Late autophagy inhibitors such as (hydroxy)chloroquine have been used clinically to halt tumor progression with modest success. However, given the toxic nature of these compounds and their lack of specificity, novel targets should be considered. We recently identified a benzotropolone derivative that significantly inhibited the essential autophagy protein ATG4B. Therefore, we synthesized and tested additional benzotropolone compounds to identify a promising ATG4B inhibitor that impairs autophagy both in vitro and in vivo. A compound library containing 27 molecules with a benzotropolone backbone was synthesized and screened for inhibition of recombinant ATG4B. Depending on the benzotropolone compound, inhibition of recombinant ATG4B ranged from 3 to 82%. Active compounds were evaluated in cellular assays to confirm inhibition of ATG4B and suppression of autophagy. Seven compounds inhibited processing of the autophagy protein LC3 and autophagosome formation. Compound UAMC-2526 was selected for further in vivo use because of its fair plasma stability. This compound abolished autophagy both in nutrient-deprived GFP-LC3 mice and in CD1 -/- Foxn1nu mice bearing HT29 colorectal tumor xenografts. Moreover, addition of UAMC-2526 to the chemotherapy drug oxaliplatin significantly improved inhibition of tumor growth. Our data indicate that suppression of autophagy via ATG4B inhibition is a feasible strategy to augment existing chemotherapy efficacy and to halt tumor progression. Copyright © 2017 Elsevier Inc. All rights reserved.

Tailored chemokine receptor modification improves homing of adoptive therapy T cells in a spontaneous tumor model.

PubMed

Garetto, Stefano; Sardi, Claudia; Martini, Elisa; Roselli, Giuliana; Morone, Diego; Angioni, Roberta; Cianciotti, Beatrice Claudia; Trovato, Anna Elisa; Franchina, Davide Giuseppe; Castino, Giovanni Francesco; Vignali, Debora; Erreni, Marco; Marchesi, Federica; Rumio, Cristiano; Kallikourdis, Marinos

2016-07-12

In recent years, tumor Adoptive Cell Therapy (ACT), using administration of ex vivo-enhanced T cells from the cancer patient, has become a promising therapeutic strategy. However, efficient homing of the anti-tumoral T cells to the tumor or metastatic site still remains a substantial hurdle. Yet the tumor site itself attracts both tumor-promoting and anti-tumoral immune cell populations through the secretion of chemokines. We attempted to identify these chemokines in a model of spontaneous metastasis, in order to "hijack" their function by expressing matching chemokine receptors on the cytotoxic T cells used in ACT, thus allowing us to enhance the recruitment of these therapeutic cells. Here we show that this enabled the modified T cells to preferentially home into spontaneous lymph node metastases in the TRAMP model, as well as in an inducible tumor model, E.G7-OVA. Due to the improved homing, the modified CD8+ T cells displayed an enhanced in vivo protective effect, as seen by a significant delay in E.G7-OVA tumor growth. These results offer a proof of principle for the tailored application of chemokine receptor modification as a means of improving T cell homing to the target tumor, thus enhancing ACT efficacy. Surprisingly, we also uncover that the formation of the peri-tumoral fibrotic capsule, which has been shown to impede T cell access to tumor, is partially dependent on host T cell presence. This finding, which would be impossible to observe in immunodeficient model studies, highlights possible conflicting roles that T cells may play in a therapeutic context.

Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences for Human Disease

PubMed Central

Goriely, Anne; Wilkie, Andrew O.M.

2012-01-01

Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term “paternal age effect” (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time—explaining the observed paternal age effect associated with these disorders—and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition. PMID:22325359

Cognitive biases in binge eating disorder: the hijacking of decision making.

PubMed

Voon, Valerie

2015-12-01

Binge eating disorder (BED) is the most common of eating disorders and is characterized by excessive, out-of-control, rapid food intake. This review focuses on cognitive impairments in BED, which represent an endophenotype that mediates brain function and behavior. Here we focus on reviewing impulsivity, compulsivity, attentional biases to food cues, and executive function. Behavioral regulation in BED appears to be influenced by the context of motivationally salient food cues and the degree of obesity. Deficits in delay discounting and risk taking under ambiguity are impaired in obesity irrespective of BED status. However, in BED subjects with milder obesity, greater risk seeking under explicit probabilistic risk is observed to monetary rewards, whereas this shifts to risk aversion and enhanced delay discounting in more severe obesity. Relative to non-BED obese subjects, BED is characterized by enhanced behavioral inflexibility or compulsivity across multiple domains, with subjects selecting the same choices despite change in relevance (set shifting), being no longer rewarding (habit formation), or irrespective of outcome (perseveration). The context of food cues was associated with multiple attentional and early and late inhibitory impairments and enhanced memory bias, although BED patients also have generalized cognitive interference in working memory. These findings may help explain the phenotype of binge eating. Motivationally salient food cues provoke attentional and memory biases along with impairing response inhibitory processes. Those with BED are also more susceptible to cognitive interference and have impaired decisional impulsivity, with the tendency to inflexibly stick with the same choices irrespective of changes in context. These findings suggest critical cognitive domains that may guide therapeutic interventions.

Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

PubMed Central

Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF

2013-01-01

Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

Long Non-coding RNAs (LncRNA) Regulated by Transforming Growth Factor (TGF) β

PubMed Central

Richards, Edward J.; Zhang, Gu; Li, Zhu-Peng; Permuth-Wey, Jennifer; Challa, Sridevi; Li, Yajuan; Kong, William; Dan, Su; Bui, Marilyn M.; Coppola, Domenico; Mao, Wei-Min; Sellers, Thomas A.; Cheng, Jin Q.

2015-01-01

Long noncoding RNAs (lncRNAs) are emerging as key regulators in various biological processes. Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by tumor cells to depart from the primary tumor site, invade surrounding tissue, and establish distant metastases. Transforming growth factor β (TGFβ) signaling has been shown to be a major inducer of EMT and to facilitate breast cancer metastasis. However, the role of lncRNAs in this process remains largely unknown. Here we report a genome-wide lncRNA profile in mouse mammary epithelial NMuMG cells upon TGFβ induction of EMT. Among 10,802 lncRNAs profiled, over 600 were up-regulated and down-regulated during the EMT, respectively. Furthermore, we identify that lncRNA-HIT (HOXA transcript induced by TGFβ) mediates TGFβ function, i.e. depletion of lncRNA-HIT inhibits TGFβ-induced migration, invasion, and EMT in NMuMG. LncRNA-HIT is also significantly elevated in the highly metastatic 4T1 cells. Knockdown of lncRNA-HIT in 4T1 results in decrease of cell migration, invasion, tumor growth, and metastasis. E-cadherin was identified as a major target of lncRNA-HIT. Moreover, lncRNA-HIT is conserved in humans and elevated expression associates with more invasive human primary breast carcinoma. Collectively, these data suggest that a subset of lncRNAs such as lncRNA-HIT play a significant role in regulation of EMT and breast cancer invasion and metastasis, and could be potential therapeutic targets in breast cancers. PMID:25605728

Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder.

PubMed

Voon, Valerie; Brezing, Christina; Gallea, Cecile; Hallett, Mark

2011-11-01

Conversion disorder (CD) is characterized by unexplained neurological symptoms presumed related to psychological issues. The main hypotheses to explain conversion paralysis, characterized by a lack of movement, include impairments in either motor intention or disruption of motor execution, and further, that hyperactive self-monitoring, limbic processing or top-down regulation from higher order frontal regions may interfere with motor execution. We have recently shown that CD with positive abnormal or excessive motor symptoms was associated with greater amygdala activity to arousing stimuli along with greater functional connectivity between the amygdala and supplementary motor area. Here we studied patients with such symptoms focusing on motor initiation. Subjects performed either an internally or externally generated 2-button action selection task in a functional MRI study. Eleven CD patients without major depression and 11 age- and gender-matched normal volunteers were assessed. During both internally and externally generated movement, conversion disorder patients relative to normal volunteers had lower left supplementary motor area (SMA) (implicated in motor initiation) and higher right amygdala, left anterior insula, and bilateral posterior cingulate activity (implicated in assigning emotional salience). These findings were confirmed in a subgroup analysis of patients with tremor symptoms. During internally versus externally generated action in CD patients, the left SMA had lower functional connectivity with bilateral dorsolateral prefrontal cortices. We propose a theory in which previously mapped conversion motor representations may in an arousing context hijack the voluntary action selection system, which is both hypoactive and functionally disconnected from prefrontal top-down regulation. Copyright © 2011 Movement Disorder Society.

Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii.

PubMed

Moynié, Lucile; Luscher, Alexandre; Rolo, Dora; Pletzer, Daniel; Tortajada, Antoni; Weingart, Helge; Braun, Yvonne; Page, Malcolm G P; Naismith, James H; Köhler, Thilo

2017-04-01

The outer membrane of Gram-negative bacteria presents an efficient barrier to the permeation of antimicrobial molecules. One strategy pursued to circumvent this obstacle is to hijack transport systems for essential nutrients, such as iron. BAL30072 and MC-1 are two monobactams conjugated to a dihydroxypyridone siderophore that are active against Pseudomonas aeruginosa and Acinetobacter baumannii Here, we investigated the mechanism of action of these molecules in A. baumannii We identified two novel TonB-dependent receptors, termed Ab -PiuA and Ab -PirA, that are required for the antimicrobial activity of both agents. Deletion of either piuA or pirA in A. baumannii resulted in 4- to 8-fold-decreased susceptibility, while their overexpression in the heterologous host P. aeruginosa increased susceptibility to the two siderophore-drug conjugates by 4- to 32-fold. The crystal structures of PiuA and PirA from A. baumannii and their orthologues from P. aeruginosa were determined. The structures revealed similar architectures; however, structural differences between PirA and PiuA point to potential differences between their cognate siderophore ligands. Spontaneous mutants, selected upon exposure to BAL30072, harbored frameshift mutations in either the ExbD3 or the TonB3 protein of A. baumannii , forming the cytoplasmic-membrane complex providing the energy for the siderophore translocation process. The results of this study provide insight for the rational design of novel siderophore-drug conjugates against problematic Gram-negative pathogens. Copyright © 2017 American Society for Microbiology.

A critique of neoliberalism with fierceness: queer youth of color creating dialogues of resistance.

PubMed

Grady, Jonathan; Marquez, Rigoberto; McLaren, Peter

2012-01-01

As a form of deregulated capitalism that has run amok, commodifying all that is in its path, and as a cultural means of commodifying Black and brown bodies, neoliberalism has taken a serious toll on the lives of working-class queer youth of color. Although it has hijacked spaces of cultural representation and material production, neoliberal capitalism is far from transparent. Through resistance, activism and performance queer youth of color have now started to shape a critique of oppressive structures, neoliberal policies, and pedagogical practices that are critical of their intersecting identities. This article examines neoliberalism's impact on education, focusing on educational policy and how these policies have affected queer youth of color in the urban centers of our major cities. This article also considers the contributions made by educators writing from the perspective of critical pedagogy in addressing the plight of queer youth of color in U.S. schools while employing the example of the dance group, Innovation, as way of addressing the havoc of neoliberalism in the lives of queer youth of color through performance and activism. This group has not only transformed notions of gender, race, class and sexuality that challenge major tenants of neoliberalism, but has also served as potent sites for the development of a critical pedagogy for working-class queer youth of color. Through sites of resistance rooted in progressive struggle, queer youth of color must be enabled by critical transformative intellectuals committed to encouraging youth to critically evaluate and challenge ideologies while displaying an allegiance to egalitarianism.

Retroviruses Hijack Chromatin Loops to Drive Oncogene Expression and Highlight the Chromatin Architecture around Proto-Oncogenic Loci

PubMed Central

Pattison, Jillian M.; Wright, Jason B.; Cole, Michael D.

2015-01-01

The majority of the genome consists of intergenic and non-coding DNA sequences shown to play a major role in different gene regulatory networks. However, the specific potency of these distal elements as well as how these regions exert function across large genomic distances remains unclear. To address these unresolved issues, we closely examined the chromatin architecture around proto-oncogenic loci in the mouse and human genomes to demonstrate a functional role for chromatin looping in distal gene regulation. Using cell culture models, we show that tumorigenic retroviral integration sites within the mouse genome occur near existing large chromatin loops and that this chromatin architecture is maintained within the human genome as well. Significantly, as mutagenesis screens are not feasible in humans, we demonstrate a way to leverage existing screens in mice to identify disease relevant human enhancers and expose novel disease mechanisms. For instance, we characterize the epigenetic landscape upstream of the human Cyclin D1 locus to find multiple distal interactions that contribute to the complex cis-regulation of this cell cycle gene. Furthermore, we characterize a novel distal interaction upstream of the Cyclin D1 gene which provides mechanistic evidence for the abundant overexpression of Cyclin D1 occurring in multiple myeloma cells harboring a pathogenic translocation event. Through use of mapped retroviral integrations and translocation breakpoints, our studies highlight the importance of chromatin looping in oncogene expression, elucidate the epigenetic mechanisms crucial for distal cis-regulation, and in one particular instance, explain how a translocation event drives tumorigenesis through upregulation of a proto-oncogene. PMID:25799187

Life without double-headed non-muscle myosin II motor proteins

PubMed Central

Betapudi, Venkaiah

2014-01-01

Non-muscle myosin II motor proteins (myosin IIA, myosin IIB, and myosin IIC) belong to a class of molecular motor proteins that are known to transduce cellular free-energy into biological work more efficiently than man-made combustion engines. Nature has given a single myosin II motor protein for lower eukaryotes and multiple for mammals but none for plants in order to provide impetus for their life. These specialized nanomachines drive cellular activities necessary for embryogenesis, organogenesis, and immunity. However, these multifunctional myosin II motor proteins are believed to go awry due to unknown reasons and contribute for the onset and progression of many autosomal-dominant disorders, cataract, deafness, infertility, cancer, kidney, neuronal, and inflammatory diseases. Many pathogens like HIV, Dengue, hepatitis C, and Lymphoma viruses as well as Salmonella and Mycobacteria are now known to take hostage of these dedicated myosin II motor proteins for their efficient pathogenesis. Even after four decades since their discovery, we still have a limited knowledge of how these motor proteins drive cell migration and cytokinesis. We need to enrich our current knowledge on these fundamental cellular processes and develop novel therapeutic strategies to fix mutated myosin II motor proteins in pathological conditions. This is the time to think how to relieve the hijacked myosins from pathogens in order to provide a renewed impetus for patients' life. Understanding how to steer these molecular motors in proliferating and differentiating stem cells will improve stem cell based-therapeutics development. Given the plethora of cellular activities non-muscle myosin motor proteins are involved in, their importance is apparent for human life. PMID:25072053

Opiate Drugs with Abuse Liability Hijack the Endogenous Opioid System to Disrupt Neuronal and Glial Maturation in the Central Nervous System.

PubMed

Hauser, Kurt F; Knapp, Pamela E

2017-01-01

The endogenous opioid system, comprised of multiple opioid neuropeptide and receptor gene families, is highly expressed by developing neural cells and can significantly influence neuronal and glial maturation. In many central nervous system (CNS) regions, the expression of opioid peptides and receptors occurs only transiently during development, effectively disappearing with subsequent maturation only to reemerge under pathologic conditions, such as with inflammation or injury. Opiate drugs with abuse liability act to modify growth and development by mimicking the actions of endogenous opioids. Although typically mediated by μ-opioid receptors, opiate drugs can also act through δ- and κ-opioid receptors to modulate growth in a cell-type, region-specific, and developmentally regulated manner. Opioids act as biological response modifiers and their actions are highly contextual, plastic, modifiable, and influenced by other physiological processes or pathophysiological conditions, such as neuro-acquired immunodeficiency syndrome. To date, most studies have considered the acute effects of opiates on cellular maturation. For example, activating opioid receptors typically results in acute growth inhibition in both neurons and glia. However, with sustained opioid exposure, compensatory factors become operative, a concept that has been largely overlooked during CNS maturation. Accordingly, this article surveys prior studies on the effects of opiates on CNS maturation, and also suggests new directions for future research in this area. Identifying the cellular and molecular mechanisms underlying the adaptive responses to chronic opiate exposure (e.g., tolerance) during maturation is crucial toward understanding the consequences of perinatal opiate exposure on the CNS.

Exosomes carring gag/env of ALV-J possess negative effect on immunocytes.

PubMed

Wang, Guihua; Wang, Zhenzhen; Zhuang, Pingping; Zhao, Xiaomin; Cheng, Ziqiang

2017-11-01

J subgroup avian leukosis virus (ALV-J) is an exogenous retrovirus of avian. A key feature of ALV-J infection is leading to severe immunosuppressive characteristic of diseases. Viral components of retrovirus were reported closely associated with immunosuppression, and several similarities between exosomes and retrovirus preparations have lead to the hypotheses of retrovirus hijacker exosomes pathway. In this study, we purified exosomes from DF-1 cells infected and uninfected by ALV-J. Electron microscopy and mass spectrometry (MS) analysis showed that ALV-J not only increased the production of exosomes from ALV-J infected DF-1 cells (Exo-J) but also stimulated some proteins expression, especially ALV-J components secreted in exosomes. Immunosuppressive domain peptide (ISD) of envelope subunit transmembrane (TM) and gag of ALV-J were secreted in Exo-J. It has been reported that HIV gag was budded from endosome-like domains of the T cell plasma membrane. But env protein was first detected in exosomes from retrovirus infected cells. We found that Exo-J caused negative effects on splenocytes in a dose-dependant manner by flow cytometric analysis. And low dose of Exo-J activated immune activity of splenocytes, while high dose possessed immunosuppressive properties. Interestingly, Exo-J has no significant effects on the immunosuppression induced by ALV-J, and the immunosuppressive effects induced by Exo-J lower than that by ALV-J. Taken together, our data indicated that Exo-J supplied a microenvironment for the replication and transformation of ALV-J. Copyright © 2017. Published by Elsevier Ltd.

Regulation of HTLV-1 Tax Stability, Cellular Trafficking and NF-κB Activation by the Ubiquitin-Proteasome Pathway

PubMed Central

Lavorgna, Alfonso; Harhaj, Edward William

2014-01-01

Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%–5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T-cell proliferation and cell survival. The Tax oncoprotein promotes T-cell transformation, in part via constitutive activation of the NF-κB transcription factor; however, the underlying mechanisms remain unknown. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Emerging studies indicate that Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-κB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine 63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. In addition to NF-κB signaling, mono- and polyubiquitination of Tax also regulate its subcellular trafficking and stability. Here, we review recent advances in the diverse roles of ubiquitin in Tax function and how Tax usurps the ubiquitin-proteasome pathway to promote oncogenesis. PMID:25341660

HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression

PubMed Central

Redmond, Catherine J.; Dooley, Katharine E.; Fu, Haiqing; Gillison, Maura L.; Akagi, Keiko; Symer, David E.; Aladjem, Mirit I.

2018-01-01

Integration of human papillomavirus (HPV) genomes into cellular chromatin is common in HPV-associated cancers. Integration is random, and each site is unique depending on how and where the virus integrates. We recently showed that tandemly integrated HPV16 could result in the formation of a super-enhancer-like element that drives transcription of the viral oncogenes. Here, we characterize the chromatin landscape and genomic architecture of this integration locus to elucidate the mechanisms that promoted de novo super-enhancer formation. Using next-generation sequencing and molecular combing/fiber-FISH, we show that ~26 copies of HPV16 are integrated into an intergenic region of chromosome 2p23.2, interspersed with 25 kb of amplified, flanking cellular DNA. This interspersed, co-amplified viral-host pattern is frequent in HPV-associated cancers and here we designate it as Type III integration. An abundant viral-cellular fusion transcript encoding the viral E6/E7 oncogenes is expressed from the integration locus and the chromatin encompassing both the viral enhancer and a region in the adjacent amplified cellular sequences is strongly enriched in the super-enhancer markers H3K27ac and Brd4. Notably, the peak in the amplified cellular sequence corresponds to an epithelial-cell-type specific enhancer. Thus, HPV16 integration generated a super-enhancer-like element composed of tandem interspersed copies of the viral upstream regulatory region and a cellular enhancer, to drive high levels of oncogene expression. PMID:29364907

The human phosphotyrosine signaling network: Evolution and hotspots of hijacking in cancer

PubMed Central

Li, Lei; Tibiche, Chabane; Fu, Cong; Kaneko, Tomonori; Moran, Michael F.; Schiller, Martin R.; Li, Shawn Shun-Cheng; Wang, Edwin

2012-01-01

Phosphotyrosine (pTyr) signaling, which plays a central role in cell–cell and cell–environment interactions, has been considered to be an evolutionary innovation in multicellular metazoans. However, neither the emergence nor the evolution of the human pTyr signaling system is currently understood. Tyrosine kinase (TK) circuits, each of which consists of a TK writer, a kinase substrate, and a related reader, such as Src homology (SH) 2 domains and pTyr-binding (PTB) domains, comprise the core machinery of the pTyr signaling network. In this study, we analyzed the evolutionary trajectories of 583 literature-derived and 50,000 computationally predicted human TK circuits in 19 representative eukaryotic species and assigned their evolutionary origins. We found that human TK circuits for intracellular pTyr signaling originated largely from primitive organisms, whereas the inter- or extracellular signaling circuits experienced significant expansion in the bilaterian lineage through the “back-wiring” of newly evolved kinases to primitive substrates and SH2/PTB domains. Conversely, the TK circuits that are involved in tissue-specific signaling evolved mainly in vertebrates by the back-wiring of vertebrate substrates to primitive kinases and SH2/PTB domains. Importantly, we found that cancer signaling preferentially employs the pTyr sites, which are linked to more TK circuits. Our work provides insights into the evolutionary paths of the human pTyr signaling circuits and suggests the use of a network approach for cancer intervention through the targeting of key pTyr sites and their associated signaling hubs in the network. PMID:22194470

Therapeutic dormancy to delay postsurgical glioma recurrence: the past, present and promise of focal hypothermia.

PubMed

Wion, Didier

2017-07-01

Surgery precedes both radiotherapy and chemotherapy as the first-line therapy for glioma. However, despite multimodal treatment, most glioma patients die from local recurrence in the resection margin. Glioma surgery is inherently lesional, and the response of brain tissue to surgery includes hemostasis, angiogenesis, reactive gliosis and inflammation. Unfortunately, these processes are also associated with tumorigenic side-effects. An increasing amount of evidence indicates that the response to a surgery-related brain injury is hijacked by residual glioma cells and participates in the local regeneration of tumor tissues at the resection margin. Inducing therapeutic hypothermia in the brain has long been used to treat the secondary damage, such as neuroinflammation and edema, that are caused by accidental traumatic brain injuries. There is compelling evidence to suggest that inducing therapeutic hypothermia at the resection margin would delay the local recurrence of glioma by (i) limiting cell proliferation, (ii) disrupting the pathological connection between inflammation and glioma recurrence, and (iii) limiting the consequences of the functional heterogeneity and complexity inherent to the tumor ecosystem. While the global whole-body cooling methods that are currently used to treat stroke in clinical practice may not adequately treat the resection margin, the future lies in implantable focal microcooling devices similar to those under development for the treatment of epilepsy. Preclinical and clinical strategies to evaluate focal hypothermia must be implemented to prevent glioma recurrence in the resection margin. Placing the resection margin in a state of hibernation may potentially provide such a long-awaited therapeutic breakthrough.

Epidermal Growth Factor Receptor-PI3K Signaling Controls Cofilin Activity To Facilitate Herpes Simplex Virus 1 Entry into Neuronal Cells

PubMed Central

Zheng, Kai; Xiang, Yangfei; Wang, Xiao; Wang, Qiaoli; Zhong, Meigong; Wang, Shaoxiang; Wang, Xiaoyan; Fan, Jianglin; Kitazato, Kaio; Wang, Yifei

2014-01-01

ABSTRACT Herpes simplex virus type 1 (HSV-1) establishes latency in neurons and can cause severe disseminated infection with neurological impairment and high mortality. This neurodegeneration is thought to be tightly associated with virus-induced cytoskeleton disruption. Currently, the regulation pattern of the actin cytoskeleton and the involved molecular mechanisms during HSV-1 entry into neurons remain unclear. Here, we demonstrate that the entry of HSV-1 into neuronal cells induces biphasic remodeling of the actin cytoskeleton and an initial inactivation followed by the subsequent activation of cofilin, a member of the actin depolymerizing factor family that is critical for actin reorganization. The disruption of F-actin dynamics or the modulation of cofilin activity by mutation, knockdown, or overexpression affects HSV-1 entry efficacy and virus-mediated cell ruffle formation. Binding of the HSV-1 envelope initiates the epidermal growth factor receptor (EGFR)-phosphatidylinositide 3-kinase (PI3K) signaling pathway, which leads to virus-induced early cofilin phosphorylation and F-actin polymerization. Moreover, the extracellular signal-regulated kinase (ERK) kinase and Rho-associated, coiled-coil-containing protein kinase 1 (ROCK) are recruited as downstream mediators of the HSV-1-induced cofilin inactivation pathway. Inhibitors specific for those kinases significantly reduce the virus infectivity without affecting virus binding to the target cells. Additionally, lipid rafts are clustered to promote EGFR-associated signaling cascade transduction. We propose that HSV-1 hijacks cofilin to initiate infection. These results could promote a better understanding of the pathogenesis of HSV-1-induced neurological diseases. PMID:24425731

Instant transformation of learned repulsion into motivational "wanting".

PubMed

Robinson, Mike J F; Berridge, Kent C

2013-02-18

Learned cues for pleasant reward often elicit desire, which, in addicts, may become compulsive. According to the dominant view in addiction neuroscience and reinforcement modeling, such desires are the simple products of learning, coming from a past association with reward outcome. We demonstrate that cravings are more than merely the products of accumulated pleasure memories-even a repulsive learned cue for unpleasantness can become suddenly desired via the activation of mesocorticolimbic circuitry. Rats learned repulsion toward a Pavlovian cue (a briefly-inserted metal lever) that always predicted an unpleasant Dead Sea saltiness sensation. Yet, upon first reencounter in a novel sodium-depletion state to promote mesocorticolimbic reactivity (reflected by elevated Fos activation in ventral tegmentum, nucleus accumbens, ventral pallidum, and the orbitofrontal prefrontal cortex), the learned cue was instantly transformed into an attractive and powerful motivational magnet. Rats jumped and gnawed on the suddenly attractive Pavlovian lever cue, despite never having tasted intense saltiness as anything other than disgusting. Instant desire transformation of a learned cue contradicts views that Pavlovian desires are essentially based on previously learned values (e.g., prediction error or temporal difference models). Instead desire is recomputed at reencounter by integrating Pavlovian information with the current brain/physiological state. This powerful brain transformation reverses strong learned revulsion into avid attraction. When applied to addiction, related mesocorticolimbic transformations (e.g., drugs or neural sensitization) of cues for already-pleasant drug experiences could create even more intense cravings. This cue/state transformation helps define what it means to say that addiction hijacks brain limbic circuits of natural reward. Copyright © 2013 Elsevier Ltd. All rights reserved.

A Tripartite Neurocognitive Model of Internet Gaming Disorder

PubMed Central

Wei, Lei; Zhang, Shuyue; Turel, Ofir; Bechara, Antoine; He, Qinghua

2017-01-01

Playing Internet games has emerged as a growing in prevalence leisure activity. In some cases, excess gaming can lead to addiction-like symptoms and aversive outcomes that may be seen by some as manifestations of a behavioral addiction. Even though agreement regarding the pathologizing of excessive video gaming is not yet achieved and perhaps because the field requires more research, many works have examined the antecedents and outcomes of what is termed internet gaming disorder (IGD). In this article, we aim at summarizing perspectives and findings related to the neurocognitive processes that may underlie IGD and map such findings onto the triadic-system that governs behavior and decision-making, the deficits in which have been shown to be associated with many addictive disorders. This tripartite system model includes the following three brain systems: (1) the impulsive system, which often mediates fast, automatic, unconscious, and habitual behaviors; (2) the reflective system, which mediates deliberating, planning, predicting future outcomes of selected behaviors, and exerting inhibitory control; and (3) the interoceptive awareness system, which generates a state of craving through the translation of somatic signals into a subjective state of drive. We suggest that IGD formation and maintenance can be associated with (1) a hyperactive “impulsive” system; (2) a hypoactive “reflective” system, as exacerbated by (3) an interoceptive awareness system that potentiates the activity of the impulsive system, and/or hijacks the goal-driven cognitive resources needed for the normal operation of the reflective system. Based on this review, we propose ways to improve the therapy and treatment of IGD and reduce the risk of relapse among recovering IGD populations. PMID:29312016

Cannabinoid modulation of drug reward and the implications of marijuana legalization.

PubMed

Covey, Dan P; Wenzel, Jennifer M; Cheer, Joseph F

2015-12-02

Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana's illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana's psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction. Copyright © 2014 Elsevier B.V. All rights reserved.

Reclaiming hijacked phagosomes: Hybrid nano-in-micro encapsulated MIAP peptide ensures host directed therapy by specifically augmenting phagosome-maturation and apoptosis in TB infected macrophage cells.

PubMed

Sharma, Ankur; Vaghasiya, Kalpesh; Gupta, Pushpa; Gupta, Umesh Datta; Verma, Rahul Kumar

2018-01-30

TB-Superbugs have emerged as one of the most challenging global health threat due to the decrease in effectiveness of conventional antibiotics. Meanwhile, Host defense peptides (HDP) have evolved as an alternative to classical therapeutics with lesser susceptibility of resistance. We describe the potential of nano-encapsulated synthetic Magainin-I analog peptide (MIAP) as Host Directed Therapy against TB. Micron-sized inhalable platform "Porous Nanoparticle Aggregates Particles (PNAP)" with nano-scale physiognomies were developed to improve the delivery of MIAP-peptide to the lungs and enhance its stability. This particle engineering enabled more control over aerodynamic characteristics and bioactive release. Antimicrobial and mechanistic studies were carried out against virulent H37Rv TB bacteria. These MIAP-PNAP nano-assemblies demonstrated dose and time dependent antibacterial action against virulent M.tb for at least 96 h, with up to ∼3.03-log CFU reduction in numbers of viable bacteria compared to untreated group. These MIAP-PNAP at concentration of 50 μM and above showed significant antibacterial effects on M.tb after 48-96 h of incubation. Mechanistically, MIAP nano-formulation enhanced host defense mechanism by averting bacteria-induced inhibition of phagosomal-lysosome fusion (Lysostracker) and apoptosis (Annexin-FITC) as shown by confocal microscopy and flow-cytometry. Encapsulated MIAP may serve for adjunctive host-directed TB therapy which may also synergizes the efficacy of standard anti-TB drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Cyclomodulins in Urosepsis Strains of Escherichia coli▿

PubMed Central

Dubois, Damien; Delmas, Julien; Cady, Anne; Robin, Frédéric; Sivignon, Adeline; Oswald, Eric; Bonnet, Richard

2010-01-01

Determinants of urosepsis in Escherichia coli remain incompletely defined. Cyclomodulins (CMs) are a growing functional family of toxins that hijack the eukaryotic cell cycle. Four cyclomodulin types are actually known in E. coli: cytotoxic necrotizing factors (CNFs), cycle-inhibiting factor (Cif), cytolethal distending toxins (CDTs), and the pks-encoded toxin. In the present study, the distribution of CM-encoding genes and the functionality of these toxins were investigated in 197 E. coli strains isolated from patients with community-acquired urosepsis (n = 146) and from uninfected subjects (n = 51). This distribution was analyzed in relation to the phylogenetic background, clinical origin, and antibiotic resistance of the strains. It emerged from this study that strains harboring the pks island and the cnf1 gene (i) were strongly associated with the B2 phylogroup (P, <0.001), (ii) frequently harbored both toxin-encoded genes in phylogroup B2 (33%), and (iii) were predictive of a urosepsis origin (P, <0.001 to 0.005). However, the prevalences of the pks island among phylogroup B2 strains, in contrast to those of the cnf1 gene, were not significantly different between fecal and urosepsis groups, suggesting that the pks island is more important for the colonization process and the cnf1 gene for virulence. pks- or cnf1-harboring strains were significantly associated with susceptibility to antibiotics (amoxicillin, cotrimoxazole, and quinolones [P, <0.001 to 0.043]). Otherwise, only 6% and 1% of all strains harbored the cdtB and cif genes, respectively, with no particular distribution by phylogenetic background, antimicrobial susceptibility, or clinical origin. PMID:20375237

Life without double-headed non-muscle myosin II motor proteins

NASA Astrophysics Data System (ADS)

Betapudi, Venkaiah

2014-07-01

Non-muscle myosin II motor proteins (myosin IIA, myosin IIB, and myosin IIC) belong to a class of molecular motor proteins that are known to transduce cellular free-energy into biological work more efficiently than man-made combustion engines. Nature has given a single myosin II motor protein for lower eukaryotes and multiple for mammals but none for plants in order to provide impetus for their life. These specialized nanomachines drive cellular activities necessary for embryogenesis, organogenesis, and immunity. However, these multifunctional myosin II motor proteins are believed to go awry due to unknown reasons and contribute for the onset and progression of many autosomal-dominant disorders, cataract, deafness, infertility, cancer, kidney, neuronal, and inflammatory diseases. Many pathogens like HIV, Dengue, hepatitis C, and Lymphoma viruses as well as Salmonella and Mycobacteria are now known to take hostage of these dedicated myosin II motor proteins for their efficient pathogenesis. Even after four decades since their discovery, we still have a limited knowledge of how these motor proteins drive cell migration and cytokinesis. We need to enrich our current knowledge on these fundamental cellular processes and develop novel therapeutic strategies to fix mutated myosin II motor proteins in pathological conditions. This is the time to think how to relieve the hijacked myosins from pathogens in order to provide a renewed impetus for patients’ life. Understanding how to steer these molecular motors in proliferating and differentiating stem cells will improve stem cell based-therapeutics development. Given the plethora of cellular activities non-muscle myosin motor proteins are involved in, their importance is apparent for human life.

Chemotactic Cues for NOTCH1-Dependent Leukemia

PubMed Central

Piovan, Erich; Tosello, Valeria; Amadori, Alberto; Zanovello, Paola

2018-01-01

The NOTCH signaling pathway is a conserved signaling cascade that regulates many aspects of development and homeostasis in multiple organ systems. Aberrant activity of this signaling pathway is linked to the initiation and progression of several hematological malignancies, exemplified by T-cell acute lymphoblastic leukemia (T-ALL). Interestingly, frequent non-mutational activation of NOTCH1 signaling has recently been demonstrated in B-cell chronic lymphocytic leukemia (B-CLL), significantly extending the pathogenic significance of this pathway in B-CLL. Leukemia patients often present with high-blood cell counts, diffuse disease with infiltration of the bone marrow, secondary lymphoid organs, and diffusion to the central nervous system (CNS). Chemokines are chemotactic cytokines that regulate migration of cells between tissues and the positioning and interactions of cells within tissue. Homeostatic chemokines and their receptors have been implicated in regulating organ-specific infiltration, but may also directly and indirectly modulate tumor growth. Recently, oncogenic NOTCH1 has been shown to regulate infiltration of leukemic cells into the CNS hijacking the CC-chemokine ligand 19/CC-chemokine receptor 7 chemokine axis. In addition, a crucial role for the homing receptor axis CXC-chemokine ligand 12/CXC-chemokine receptor 4 has been demonstrated in leukemia maintenance and progression. Moreover, the CCL25/CCR9 axis has been implicated in the homing of leukemic cells into the gut, particularly in the presence of phosphatase and tensin homolog tumor suppressor loss. In this review, we summarize the latest developments regarding the role of NOTCH signaling in regulating the chemotactic microenvironmental cues involved in the generation and progression of T-ALL and compare these findings to B-CLL. PMID:29666622

Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination

PubMed Central

Mortensen, Franziska; Schneider, Daniel; Barbic, Tanja; Sladewska-Marquardt, Anna; Kühnle, Simone; Marx, Andreas; Scheffner, Martin

2015-01-01

Deregulation of the ubiquitin ligase E6 associated protein (E6AP) encoded by the UBE3A gene has been associated with three different clinical pictures. Hijacking of E6AP by the E6 oncoprotein of distinct human papillomaviruses (HPV) contributes to the development of cervical cancer, whereas loss of E6AP expression or function is the cause of Angelman syndrome, a neurodevelopmental disorder, and increased expression of E6AP has been involved in autism spectrum disorders. Although these observations indicate that the activity of E6AP has to be tightly controlled, only little is known about how E6AP is regulated at the posttranslational level. Here, we provide evidence that the hydrophobic patch of ubiquitin comprising Leu-8 and Ile-44 is important for E6AP-mediated ubiquitination, whereas it does not affect the catalytic properties of the isolated catalytic HECT domain of E6AP. Furthermore, we show that the HPV E6 oncoprotein rescues the disability of full-length E6AP to use a respective hydrophobic patch mutant of ubiquitin for ubiquitination and that it stimulates E6AP-mediated ubiquitination of Ring1B, a known substrate of E6AP, in vitro and in cells. Based on these data, we propose that E6AP exists in at least two different states, an active and a less active or latent one, and that the activity of E6AP is controlled by noncovalent interactions with ubiquitin and allosteric activators such as the HPV E6 oncoprotein. PMID:26216987

Chlamydia trachomatis Is Responsible for Lipid Vacuolation in the Amniotic Epithelium of Fetal Gastroschisis.

PubMed

Feldkamp, Marcia L; Ward, Diane M; Pysher, Theodore J; Chambers, Christina T

2017-07-17

Vacuolated amniotic epithelium with lipid droplets in gastroschisis placentas is an unusual finding. Mass spectrometry of lipid droplets identified triglycerides, ester-linked to an unusual pattern of fatty acids. We hypothesize that these findings result from a Chlamydia trachomatis infection during the periconceptional period. The rising incidence of chlamydia infections has paralleled the increasing prevalence of gastroschisis among women less than 25 years of age. Histologically, young women are at greatest risk for a chlamydia infection due to their immature columnar epithelium, the preferential site for attachment of Chlamydia trachomatis infectious particle (elementary body). Chlamydia trachomatis survive in an inclusion, relying on its host to acquire essential nutrients, amino acids, and nucleotides for survival and replication. If essential nutrients are not available, the bacteria cannot replicate and may be trafficked to the lysosome for degradation or remain quiescent, within the inclusion, subverting innate immunologic clearance. Chlamydiae synthesize several lipids (phosphatidylethanolamine, phosphatidylserine, and phosphoatidylglycerol); however, their lipid content reveal eukaryotic lipids (sphingomyelin, cholesterol, phosphatidylcholine, and phosphatidylinositol), evidence that chlamydiae "hijack" host lipids for expansion and replication. The abnormal amniotic epithelial findings are supported by experimental evidence of the trafficking of host lipids into the chlamydiae inclusion. If not lethal, what harm will elementary bodies inflict to the developing embryo? Do these women have a greater pro-inflammatory response to an environmental exposure, whether cigarette smoking, change in partner, or a pathogen? Testing the hypothesis that Chlamydia trachomatis is responsible for amniotic epithelium vacuoles will be a critical first step. Birth Defects Research 109:1003-1010, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

PubMed Central

2016-01-01

SUMMARY The HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle. PMID:27357278

Decisions and desire.

PubMed

Morse, Gardiner

2006-01-01

When we make decisions, we're not always in charge. One moment we hotheadedly let our emotions get the better of us; the next, we're paralyzed by uncertainty. Then we'll pull a brilliant decision out of thin air--and wonder how we did it. Though we may have no idea how decision making happens, neuroscientists peering deep into our brains are beginning to get the picture. What they're finding may not be what you want to hear, but it's worth listening. We have dog brains, basically, with human cortexes stuck on top. By watching the brain in action as it deliberates and decides, neuroscientists are finding that not a second goes by that our animal brains aren't conferring with our modern cortexes to influence their choices. Scientists have discovered, for example, that the "reward" circuits in the brain that activate in response to cocaine, chocolate, sex, and music also find pleasure in the mere anticipation of making money--or getting revenge. And the "aversion" circuits that react to the threat of physical pain also respond with disgust when we feel cheated by a partner. In this article, HBR senior editor Gardiner Morse describes the experiments that illuminate the aggressive participation of our emotion-driven animal brains in decision making. This research also shows that our emotional brains needn't always operate beneath our radar. While our dog brains sometimes hijack our higher cognitive functions to drive bad, or at least illogical, decisions, they play an important part in rational decision making as well. The more we understand about how we make decisions, the better we can manage them.

HIV-1 Triggers WAVE2 Phosphorylation in Primary CD4 T Cells and Macrophages, Mediating Arp2/3-dependent Nuclear Migration*

PubMed Central

Spear, Mark; Guo, Jia; Turner, Amy; Yu, Dongyang; Wang, Weifeng; Meltzer, Beatrix; He, Sijia; Hu, Xiaohua; Shang, Hong; Kuhn, Jeffrey; Wu, Yuntao

2014-01-01

The human immunodeficiency virus type 1 (HIV-1) initiates receptor signaling and early actin dynamics during viral entry. This process is required for viral infection of primary targets such as resting CD4 T cells. WAVE2 is a component of a multiprotein complex linking receptor signaling to dynamic remodeling of the actin cytoskeleton. WAVE2 directly activates Arp2/3, leading to actin nucleation and filament branching. Although several bacterial and viral pathogens target Arp2/3 for intracellular mobility, it remains unknown whether HIV-1 actively modulates the Arp2/3 complex through virus-mediated receptor signal transduction. Here we report that HIV-1 triggers WAVE2 phosphorylation at serine 351 through gp120 binding to the chemokine coreceptor CXCR4 or CCR5 during entry. This phosphorylation event involves both Gαi-dependent and -independent pathways, and is conserved both in X4 and R5 viral infection of resting CD4 T cells and primary macrophages. We further demonstrate that inhibition of WAVE2-mediated Arp2/3 activity through stable shRNA knockdown of Arp3 dramatically diminished HIV-1 infection of CD4 T cells, preventing viral nuclear migration. Inhibition of Arp2/3 through a specific inhibitor, CK548, also drastically inhibited HIV-1 nuclear migration and infection of CD4 T cells. Our results suggest that Arp2/3 and the upstream regulator, WAVE2, are essential co-factors hijacked by HIV for intracellular migration, and may serve as novel targets to prevent HIV transmission. PMID:24415754

HIV-1 triggers WAVE2 phosphorylation in primary CD4 T cells and macrophages, mediating Arp2/3-dependent nuclear migration.

PubMed

Spear, Mark; Guo, Jia; Turner, Amy; Yu, Dongyang; Wang, Weifeng; Meltzer, Beatrix; He, Sijia; Hu, Xiaohua; Shang, Hong; Kuhn, Jeffrey; Wu, Yuntao

2014-03-07

The human immunodeficiency virus type 1 (HIV-1) initiates receptor signaling and early actin dynamics during viral entry. This process is required for viral infection of primary targets such as resting CD4 T cells. WAVE2 is a component of a multiprotein complex linking receptor signaling to dynamic remodeling of the actin cytoskeleton. WAVE2 directly activates Arp2/3, leading to actin nucleation and filament branching. Although several bacterial and viral pathogens target Arp2/3 for intracellular mobility, it remains unknown whether HIV-1 actively modulates the Arp2/3 complex through virus-mediated receptor signal transduction. Here we report that HIV-1 triggers WAVE2 phosphorylation at serine 351 through gp120 binding to the chemokine coreceptor CXCR4 or CCR5 during entry. This phosphorylation event involves both Gαi-dependent and -independent pathways, and is conserved both in X4 and R5 viral infection of resting CD4 T cells and primary macrophages. We further demonstrate that inhibition of WAVE2-mediated Arp2/3 activity through stable shRNA knockdown of Arp3 dramatically diminished HIV-1 infection of CD4 T cells, preventing viral nuclear migration. Inhibition of Arp2/3 through a specific inhibitor, CK548, also drastically inhibited HIV-1 nuclear migration and infection of CD4 T cells. Our results suggest that Arp2/3 and the upstream regulator, WAVE2, are essential co-factors hijacked by HIV for intracellular migration, and may serve as novel targets to prevent HIV transmission.

ε/ζ systems: their role in resistance, virulence, and their potential for antibiotic development.

PubMed

Mutschler, Hannes; Meinhart, Anton

2011-12-01

Cell death in bacteria can be triggered by activation of self-inflicted molecular mechanisms. Pathogenic bacteria often make use of suicide mechanisms in which the death of individual cells benefits survival of the population. Important elements for programmed cell death in bacteria are proteinaceous toxin-antitoxin systems. While the toxin generally resides dormant in the bacterial cytosol in complex with its antitoxin, conditions such as impaired de novo synthesis of the antitoxin or nutritional stress lead to antitoxin degradation and toxin activation. A widespread toxin-antitoxin family consists of the ε/ζ systems, which are distributed over plasmids and chromosomes of various pathogenic bacteria. In its inactive state, the bacteriotoxic ζ toxin protein is inhibited by its cognate antitoxin ε. Upon degradation of ε, the ζ toxin is released allowing this enzyme to poison bacterial cell wall synthesis, which eventually triggers autolysis. ε/ζ systems ensure stable plasmid inheritance by inducing death in plasmid-deprived offspring cells. In contrast, chromosomally encoded ε/ζ systems were reported to contribute to virulence of pathogenic bacteria, possibly by inducing autolysis in individual cells under stressful conditions. The capability of toxin-antitoxin systems to kill bacteria has made them potential targets for new therapeutic compounds. Toxin activation could be hijacked to induce suicide of bacteria. Likewise, the unique mechanism of ζ toxins could serve as template for new drugs. Contrarily, inhibition of virulence-associated ζ toxins might attenuate infections. Here we provide an overview of ε/ζ toxin-antitoxin family and its potential role in the development of new therapeutic approaches in microbial defense.

Pathogen exploitation of an abscisic acid- and jasmonate-inducible MAPK phosphatase and its interception by Arabidopsis immunity.

PubMed

Mine, Akira; Berens, Matthias L; Nobori, Tatsuya; Anver, Shajahan; Fukumoto, Kaori; Winkelmüller, Thomas M; Takeda, Atsushi; Becker, Dieter; Tsuda, Kenichi

2017-07-11

Phytopathogens promote virulence by, for example, exploiting signaling pathways mediated by phytohormones such as abscisic acid (ABA) and jasmonate (JA). Some plants can counteract pathogen virulence by invoking a potent form of immunity called effector-triggered immunity (ETI). Here, we report that ABA and JA mediate inactivation of the immune-associated MAP kinases (MAPKs), MPK3 and MPK6, in Arabidopsis thaliana ABA induced expression of genes encoding the protein phosphatases 2C (PP2Cs), HAI1 , HAI2 , and HAI3 through ABF/AREB transcription factors. These three HAI PP2Cs interacted with MPK3 and MPK6 and were required for ABA-mediated MPK3/MPK6 inactivation and immune suppression. The bacterial pathogen Pseudomonas syringae pv. tomato ( Pto ) DC3000 activates ABA signaling and produces a JA-mimicking phytotoxin, coronatine (COR), that promotes virulence. We found that Pto DC3000 induces HAI1 through COR-mediated activation of MYC2, a master transcription factor in JA signaling. HAI1 dephosphorylated MPK3 and MPK6 in vitro and was necessary for COR-mediated suppression of MPK3/MPK6 activation and immunity. Intriguingly, upon ETI activation, A. thaliana plants overcame the HAI1-dependent virulence of COR by blocking JA signaling. Finally, we showed conservation of induction of HAI PP2Cs by ABA and JA in other Brassicaceae species. Taken together, these results suggest that ABA and JA signaling pathways, which are hijacked by the bacterial pathogen, converge on the HAI PP2Cs that suppress activation of the immune-associated MAPKs. Also, our data unveil interception of JA-signaling activation as a host counterstrategy against the bacterial suppression of MAPKs during ETI.

The serpin saga; development of a new class of virus derived anti-inflammatory protein immunotherapeutics.

PubMed

Lucas, Alexandra; Liu, Liying; Dai, Erbin; Bot, Ilze; Viswanathan, Kasinath; Munuswamy-Ramunujam, Ganesh; Davids, Jennifer A; Bartee, Mee Y; Richardson, Jakob; Christov, Alexander; Wang, Hao; Macaulay, Colin; Poznansky, Mark; Zhong, Robert; Miller, Leslie; Biessen, Erik; Richardson, Mary; Sullivan, Collin; Moyer, Richard; Hatton, Mark; Lomas, David A; McFadden, Grant

2009-01-01

Serine proteinase inhibitors, also called serpins, are an ancient grouping of proteins found in primitive organisms from bacteria, protozoa and horseshoe crabs and thus likely present at the time of the dinosaurs, up to all mammals living today. The innate or inflammatory immune system is also an ancient metazoan regulatory system, providing the first line of defense against infection or injury. The innate inflammatory defense response evolved long before acquired, antibody dependent immunity. Viruses have developed highly effective stratagems that undermine and block a wide variety of host inflammatory and immune responses. Some of the most potent of these immune modifying strategies utilize serpins that have also been developed over millions of years, including the hijacking by some viruses for defense against host immune attacks. Serpins represent up to 2-10 percent of circulating plasma proteins, regulating actions as wide ranging as thrombosis, inflammation, blood pressure control and even hormone transport. Targeting serpin-regulated immune or inflammatory pathways makes evolutionary sense for viral defense and many of these virus-derived inhibitory proteins have proven to be highly effective, working at very low concentrations--even down to the femptomolar to picomolar range. We are studying these viral anti-inflammatory proteins as a new class of immunomodulatory therapeutic agents derived from their native viral source. One such viral serpin, Serp-1 is now in clinical trial (conducted by VIRON Therapeutics, Inc.) for acute unstable coronary syndromes (unstable angina and small heart attacks), representing a 'first in class' therapeutic study. Several other viral serpins are also currently under investigation as anti-inflammatory or anti-immune therapeutics. This chapter describes these original studies and the ongoing analysis of viral serpins as a new class of virus-derived immunotherapeutic.

Setting the Alarm: Word Emotional Attributes Require Consolidation to be Operational.

PubMed

Dumay, Nicolas; Sharma, Dinkar; Kellen, Nora; Abdelrahim, Sarah

2018-01-25

Demonstrations of emotional Stroop in conditioned made-up words are flawed because of the lack of task ensuring similar word encoding across conditions. Here, participants were trained on associations between made-up words (e.g., 'drott') and pictures with an alarming or neutral content (e.g., 'a dead sheep' vs. 'a munching cow') in a situation that required attention to both ends of each association. To test whether word emotional attributes need to consolidate before they can hijack attention, one set of associations was learned seven days before the test, whereas the other set was learned either six hrs or immediately before the test. The novel words' ability to evoke their emotional attributes was assessed by using both Stroop and an auditory analogue called pause detection. Matching words and pictures was harder for alarming associations. However, similar learning rate and forgetting at seven days were observed for both types of associations. Pause detection revealed no emotion effect for same-day (i.e., unconsolidated) associations, but robust interference for seven-day-old (i.e., consolidated) alarming associations. Attention capture was found in the emotional Stroop as well, though only when trial n-1 referred to a same-day association. This task also showed stronger response repetition priming (independently of emotion) when trials n and n-1 both tapped into seven-day-old associations. Word emotional attributes hence take between six hrs and seven days to be operational. Moreover, age interactions between consecutive trials can be used to gauge implicitly the indirect (relational) episodic associations that develop in the meantime between the memories of individual items. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Co-evolution of insect proteases and plant protease inhibitors.

PubMed

Jongsma, Maarten A; Beekwilder, Jules

2011-08-01

Plants are at the basis of the food chain, but there is no such thing as a "free lunch" for herbivores. To promote reproductive success, plants evolved multi-layered defensive tactics to avoid or discourage herbivory. To the detriment of plants, herbivores, in turn, evolved intricate strategies to find, eat, and successfully digest essential plant parts to raise their own offspring. In this battle the digestive tract is the arena determining final victory or defeat as measured by growth or starvation of the herbivore. Earlier, specific molecular opponents were identified as proteases and inhibitors: digestive proteases of herbivores evolved structural motifs to occlude plant protease inhibitors, or alternatively, the insects evolved proteases capable of specifically degrading the host plant inhibitors. In response plant inhibitors evolved hyper-variable and novel protein folds to remain active against potential herbivores. At the level of protease regulation in herbivorous insects, it was shown that inhibition-insensitive digestive proteases are up-regulated when sensitive proteases are inhibited. The way this regulation operates in mammals is known as negative feedback by gut-luminal factors, so-called 'monitor peptides' that are sensitive to the concentration of active enzymes. We propose that regulation of gut enzymes by endogenous luminal factors has been an open invitation to plants to "hijack" this regulation by evolving receptor antagonists, although yet these plant factors have not been identified. In future research the question of the co-evolution of insect proteases and plant inhibitors should, therefore, be better approached from a systems level keeping in mind that evolution is fundamentally opportunistic and that the plant's fitness is primarily improved by lowering the availability of essential amino acids to an herbivore by any available mechanism.

Mental Imagery and Post-Traumatic Stress Disorder: A Neuroimaging and Experimental Psychopathology Approach to Intrusive Memories of Trauma

PubMed Central

Clark, Ian A.; Mackay, Clare E.

2015-01-01

This hypothesis and theory paper presents a pragmatic framework to help bridge the clinical presentation and neuroscience of intrusive memories following psychological trauma. Intrusive memories are a hallmark symptom of post-traumatic stress disorder (PTSD). However, key questions, including those involving etiology, remain. In particular, we know little about the brain mechanisms involved in why only some moments of the trauma return as intrusive memories while others do not. We first present an overview of the patient experience of intrusive memories and the neuroimaging studies that have investigated intrusive memories in PTSD patients. Next, one mechanism of how to model intrusive memories in the laboratory, the trauma film paradigm, is examined. In particular, we focus on studies combining the trauma film paradigm with neuroimaging. Stemming from the clinical presentation and our current understanding of the processes involved in intrusive memories, we propose a framework in which an intrusive memory comprises five component parts; autobiographical (trauma) memory, involuntary recall, negative emotions, attention hijacking, and mental imagery. Each component part is considered in turn, both behaviorally and from a brain imaging perspective. A mapping of these five components onto our understanding of the brain is described. Unanswered questions that exist in our understanding of intrusive memories are considered using the proposed framework. Overall, we suggest that mental imagery is key to bridging the experience, memory, and intrusive recollection of the traumatic event. Further, we suggest that by considering the brain mechanisms involved in the component parts of an intrusive memory, in particular mental imagery, we may be able to aid the development of a firmer bridge between patients’ experiences of intrusive memories and the clinical neuroscience behind them. PMID:26257660

Extensive in silico analysis of Mimivirus coded Rab GTPase homolog suggests a possible role in virion membrane biogenesis.

PubMed

Zade, Amrutraj; Sengupta, Malavi; Kondabagil, Kiran

2015-01-01

Rab GTPases are the key regulators of intracellular membrane trafficking in eukaryotes. Many viruses and intracellular bacterial pathogens have evolved to hijack the host Rab GTPase functions, mainly through activators and effector proteins, for their benefit. Acanthamoeba polyphaga mimivirus (APMV) is one of the largest viruses and belongs to the monophyletic clade of nucleo-cytoplasmic large DNA viruses (NCLDV). The inner membrane lining is integral to the APMV virion structure. APMV assembly involves extensive host membrane modifications, like vesicle budding and fusion, leading to the formation of a membrane sheet that is incorporated into the virion. Intriguingly, APMV and all group I members of the Mimiviridae family code for a putative Rab GTPase protein. APMV is the first reported virus to code for a Rab GTPase (encoded by R214 gene). Our thorough in silico analysis of the subfamily specific (SF) region of Mimiviridae Rab GTPase sequences suggests that they are related to Rab5, a member of the group II Rab GTPases, of lower eukaryotes. Because of their high divergence from the existing three isoforms, A, B, and C of the Rab5-family, we suggest that Mimiviridae Rabs constitute a new isoform, Rab5D. Phylogenetic analysis indicated probable horizontal acquisition from a lower eukaryotic ancestor followed by selection and divergence. Furthermore, interaction network analysis suggests that vps34 (a Class III PI3K homolog, coded by APMV L615), Atg-8 and dynamin (host proteins) are recruited by APMV Rab GTPase during capsid assembly. Based on these observations, we hypothesize that APMV Rab plays a role in the acquisition of inner membrane during virion assembly.

RNA splicing and splicing regulator changes in prostate cancer pathology.

PubMed

Munkley, Jennifer; Livermore, Karen; Rajan, Prabhakar; Elliott, David J

2017-09-01

Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA. ST6GALNAC1 encodes a sialyltransferase that catalyses the synthesis of the cancer-associated sTn antigen important for cell mobility. Genetic rearrangements occurring early in prostate cancer development place ERG oncogene expression under the control of the androgen-regulated TMPRSS2 promoter to hijack cell behaviour. This TMPRSS2-ERG fusion gene shows different patterns of alternative splicing in invasive versus localised prostate cancer. Alternative AR mRNA isoforms play a key role in the generation of prostate cancer drug resistance, by providing a mechanism through which prostate cancer cells can grow in limited serum androgen concentrations. A number of splicing regulator proteins change expression patterns in prostate cancer and may help drive key stages of disease progression. Up-regulation of SRRM4 establishes neuronal splicing patterns in neuroendocrine prostate cancer. The splicing regulators Sam68 and Tra2β increase expression in prostate cancer. The SR protein kinase SRPK1 that modulates the activity of SR proteins is up-regulated in prostate cancer and has already given encouraging results as a potential therapeutic target in mouse models.

The molecular basis of targeting protein kinases in cancer therapeutics.

PubMed

Tsai, Chung-Jung; Nussinov, Ruth

2013-08-01

In this paper, we provide an overview of targeted anticancer therapies with small molecule kinase inhibitors. First, we discuss why a single constitutively active kinase emanating from a variety of aberrant genetic alterations is capable of transforming a normal cell, leading it to acquire the hallmarks of a cancer cell. To draw attention to the fact that kinase inhibition in targeted cancer therapeutics differs from conventional cytotoxic chemotherapy, we exploit a conceptual framework explaining why suppressed kinase activity will selectively kill only the so-called oncogene 'addicted' cancer cell, while sparing the healthy cell. Second, we introduce the protein kinase superfamily in light of its common active conformation with precisely positioned structural elements, and the diversified auto-inhibitory conformations among the kinase families. Understanding the detailed activation mechanism of individual kinases is essential to relate the observed oncogenic alterations to the elevated constitutively active state, to identify the mechanism of consequent drug resistance, and to guide the development of the next-generation inhibitors. To clarify the vital importance of structural guidelines in studies of oncogenesis, we explain how somatic mutations in EGFR result in kinase constitutive activation. Third, in addition to the common theme of secondary (acquired) mutations that prevent drug binding from blocking a signaling pathway which is hijacked by the aberrant activated kinase, we discuss scenarios of drug resistance and relapse by compensating lesions that bypass the inactivated pathway in a vertical or horizontal fashion. Collectively, these suggest that the future challenge of cancer therapy with small molecule kinase inhibitors will rely on the discovery of distinct combinations of optimized drugs to target individual subtypes of different cancers. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hepatitis C Virus Proteins Interact with the Endosomal Sorting Complex Required for Transport (ESCRT) Machinery via Ubiquitination To Facilitate Viral Envelopment

PubMed Central

Barouch-Bentov, Rina; Neveu, Gregory; Xiao, Fei; Beer, Melanie; Bekerman, Elena; Schor, Stanford; Campbell, Joseph; Boonyaratanakornkit, Jim; Lindenbach, Brett; Lu, Albert; Jacob, Yves

2016-01-01

ABSTRACT Enveloped viruses commonly utilize late-domain motifs, sometimes cooperatively with ubiquitin, to hijack the endosomal sorting complex required for transport (ESCRT) machinery for budding at the plasma membrane. However, the mechanisms underlying budding of viruses lacking defined late-domain motifs and budding into intracellular compartments are poorly characterized. Here, we map a network of hepatitis C virus (HCV) protein interactions with the ESCRT machinery using a mammalian-cell-based protein interaction screen and reveal nine novel interactions. We identify HRS (hepatocyte growth factor-regulated tyrosine kinase substrate), an ESCRT-0 complex component, as an important entry point for HCV into the ESCRT pathway and validate its interactions with the HCV nonstructural (NS) proteins NS2 and NS5A in HCV-infected cells. Infectivity assays indicate that HRS is an important factor for efficient HCV assembly. Specifically, by integrating capsid oligomerization assays, biophysical analysis of intracellular viral particles by continuous gradient centrifugations, proteolytic digestion protection, and RNase digestion protection assays, we show that HCV co-opts HRS to mediate a late assembly step, namely, envelopment. In the absence of defined late-domain motifs, K63-linked polyubiquitinated lysine residues in the HCV NS2 protein bind the HRS ubiquitin-interacting motif to facilitate assembly. Finally, ESCRT-III and VPS/VTA1 components are also recruited by HCV proteins to mediate assembly. These data uncover involvement of ESCRT proteins in intracellular budding of a virus lacking defined late-domain motifs and a novel mechanism by which HCV gains entry into the ESCRT network, with potential implications for other viruses. PMID:27803188

The hitchhiker's guide to Europe: the infection dynamics of an ongoing Wolbachia invasion and mitochondrial selective sweep in Rhagoletis cerasi.

PubMed

Schuler, Hannes; Köppler, Kirsten; Daxböck-Horvath, Sabine; Rasool, Bilal; Krumböck, Susanne; Schwarz, Dietmar; Hoffmeister, Thomas S; Schlick-Steiner, Birgit C; Steiner, Florian M; Telschow, Arndt; Stauffer, Christian; Arthofer, Wolfgang; Riegler, Markus

2016-04-01

Wolbachia is a maternally inherited and ubiquitous endosymbiont of insects. It can hijack host reproduction by manipulations such as cytoplasmic incompatibility (CI) to enhance vertical transmission. Horizontal transmission of Wolbachia can also result in the colonization of new mitochondrial lineages. In this study, we present a 15-year-long survey of Wolbachia in the cherry fruit fly Rhagoletis cerasi across Europe and the spatiotemporal distribution of two prevalent strains, wCer1 and wCer2, and associated mitochondrial haplotypes in Germany. Across most of Europe, populations consisted of either 100% singly (wCer1) infected individuals with haplotype HT1, or 100% doubly (wCer1&2) infected individuals with haplotype HT2, differentiated only by a single nucleotide polymorphism. In central Germany, singly infected populations were surrounded by transitional populations, consisting of both singly and doubly infected individuals, sandwiched between populations fixed for wCer1&2. Populations with fixed infection status showed perfect association of infection and mitochondria, suggesting a recent CI-driven selective sweep of wCer2 linked with HT2. Spatial analysis revealed a range expansion for wCer2 and a large transition zone in which wCer2 splashes appeared to coalesce into doubly infected populations. Unexpectedly, the transition zone contained a large proportion (22%) of wCer1&2 individuals with HT1, suggesting frequent intraspecific horizontal transmission. However, this horizontal transmission did not break the strict association between infection types and haplotypes in populations outside the transition zone, suggesting that this horizontally acquired Wolbachia infection may be transient. Our study provides new insights into the rarely studied Wolbachia invasion dynamics in field populations. © 2016 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd.

Phytoplasma Effector SAP54 Hijacks Plant Reproduction by Degrading MADS-box Proteins and Promotes Insect Colonization in a RAD23-Dependent Manner

PubMed Central

MacLean, Allyson M.; Orlovskis, Zigmunds; Kowitwanich, Krissana; Zdziarska, Anna M.; Angenent, Gerco C.; Immink, Richard G. H.; Hogenhout, Saskia A.

2014-01-01

Pathogens that rely upon multiple hosts to complete their life cycles often modify behavior and development of these hosts to coerce them into improving pathogen fitness. However, few studies describe mechanisms underlying host coercion. In this study, we elucidate the mechanism by which an insect-transmitted pathogen of plants alters floral development to convert flowers into vegetative tissues. We find that phytoplasma produce a novel effector protein (SAP54) that interacts with members of the MADS-domain transcription factor (MTF) family, including key regulators SEPALLATA3 and APETALA1, that occupy central positions in the regulation of floral development. SAP54 mediates degradation of MTFs by interacting with proteins of the RADIATION SENSITIVE23 (RAD23) family, eukaryotic proteins that shuttle substrates to the proteasome. Arabidopsis rad23 mutants do not show conversion of flowers into leaf-like tissues in the presence of SAP54 and during phytoplasma infection, emphasizing the importance of RAD23 to the activity of SAP54. Remarkably, plants with SAP54-induced leaf-like flowers are more attractive for colonization by phytoplasma leafhopper vectors and this colonization preference is dependent on RAD23. An effector that targets and suppresses flowering while simultaneously promoting insect herbivore colonization is unprecedented. Moreover, RAD23 proteins have, to our knowledge, no known roles in flower development, nor plant defence mechanisms against insects. Thus SAP54 generates a short circuit between two key pathways of the host to alter development, resulting in sterile plants, and promotes attractiveness of these plants to leafhopper vectors helping the obligate phytoplasmas reproduce and propagate (zombie plants). PMID:24714165

HIV-1 Vpr modulates macrophage metabolic pathways: a SILAC-based quantitative analysis.

PubMed

Barrero, Carlos A; Datta, Prasun K; Sen, Satarupa; Deshmane, Satish; Amini, Shohreh; Khalili, Kamel; Merali, Salim

2013-01-01

Human immunodeficiency virus type 1 encoded viral protein Vpr is essential for infection of macrophages by HIV-1. Furthermore, these macrophages are resistant to cell death and are viral reservoir. However, the impact of Vpr on the macrophage proteome is yet to be comprehended. The goal of the present study was to use a stable-isotope labeling by amino acids in cell culture (SILAC) coupled with mass spectrometry-based proteomics approach to characterize the Vpr response in macrophages. Cultured human monocytic cells, U937, were differentiated into macrophages and transduced with adenovirus construct harboring the Vpr gene. More than 600 proteins were quantified in SILAC coupled with LC-MS/MS approach, among which 136 were significantly altered upon Vpr overexpression in macrophages. Quantified proteins were selected and clustered by biological functions, pathway and network analysis using Ingenuity computational pathway analysis. The proteomic data illustrating increase in abundance of enzymes in the glycolytic pathway (pentose phosphate and pyruvate metabolism) was further validated by western blot analysis. In addition, the proteomic data demonstrate down regulation of some key mitochondrial enzymes such as glutamate dehydrogenase 2 (GLUD2), adenylate kinase 2 (AK2) and transketolase (TKT). Based on these observations we postulate that HIV-1 hijacks the macrophage glucose metabolism pathway via the Vpr-hypoxia inducible factor 1 alpha (HIF-1 alpha) axis to induce expression of hexokinase (HK), glucose-6-phosphate dehyrogenase (G6PD) and pyruvate kinase muscle type 2 (PKM2) that facilitates viral replication and biogenesis, and long-term survival of macrophages. Furthermore, dysregulation of mitochondrial glutamate metabolism in macrophages can contribute to neurodegeneration via neuroexcitotoxic mechanisms in the context of NeuroAIDS.

Long non-coding RNAs (LncRNA) regulated by transforming growth factor (TGF) β: LncRNA-hit-mediated TGFβ-induced epithelial to mesenchymal transition in mammary epithelia.

PubMed

Richards, Edward J; Zhang, Gu; Li, Zhu-Peng; Permuth-Wey, Jennifer; Challa, Sridevi; Li, Yajuan; Kong, William; Dan, Su; Bui, Marilyn M; Coppola, Domenico; Mao, Wei-Min; Sellers, Thomas A; Cheng, Jin Q

2015-03-13

Long noncoding RNAs (lncRNAs) are emerging as key regulators in various biological processes. Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by tumor cells to depart from the primary tumor site, invade surrounding tissue, and establish distant metastases. Transforming growth factor β (TGFβ) signaling has been shown to be a major inducer of EMT and to facilitate breast cancer metastasis. However, the role of lncRNAs in this process remains largely unknown. Here we report a genome-wide lncRNA profile in mouse mammary epithelial NMuMG cells upon TGFβ induction of EMT. Among 10,802 lncRNAs profiled, over 600 were up-regulated and down-regulated during the EMT, respectively. Furthermore, we identify that lncRNA-HIT (HOXA transcript induced by TGFβ) mediates TGFβ function, i.e. depletion of lncRNA-HIT inhibits TGFβ-induced migration, invasion, and EMT in NMuMG. LncRNA-HIT is also significantly elevated in the highly metastatic 4T1 cells. Knockdown of lncRNA-HIT in 4T1 results in decrease of cell migration, invasion, tumor growth, and metastasis. E-cadherin was identified as a major target of lncRNA-HIT. Moreover, lncRNA-HIT is conserved in humans and elevated expression associates with more invasive human primary breast carcinoma. Collectively, these data suggest that a subset of lncRNAs such as lncRNA-HIT play a significant role in regulation of EMT and breast cancer invasion and metastasis, and could be potential therapeutic targets in breast cancers. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

A Pooled Sequencing Approach Identifies a Candidate Meiotic Driver in Drosophila

PubMed Central

Wei, Kevin H.-C.; Reddy, Hemakumar M.; Rathnam, Chandramouli; Lee, Jimin; Lin, Deanna; Ji, Shuqing; Mason, James M.; Clark, Andrew G.; Barbash, Daniel A.

2017-01-01

Meiotic drive occurs when a selfish element increases its transmission frequency above the Mendelian ratio by hijacking the asymmetric divisions of female meiosis. Meiotic drive causes genomic conflict and potentially has a major impact on genome evolution, but only a few drive loci of large effect have been described. New methods to reliably detect meiotic drive are therefore needed, particularly for discovering moderate-strength drivers that are likely to be more prevalent in natural populations than strong drivers. Here, we report an efficient method that uses sequencing of large pools of backcross (BC1) progeny to test for deviations from Mendelian segregation genome-wide with single-nucleotide polymorphisms (SNPs) that distinguish the parental strains. We show that meiotic drive can be detected by a characteristic pattern of decay in distortion of SNP frequencies, caused by recombination unlinking the driver from distal loci. We further show that control crosses allow allele-frequency distortion caused by meiotic drive to be distinguished from distortion resulting from developmental effects. We used this approach to test whether chromosomes with extreme telomere-length differences segregate at Mendelian ratios, as telomeric regions are a potential hotspot for meiotic drive due to their roles in meiotic segregation and multiple observations of high rates of telomere sequence evolution. Using four different pairings of long and short telomere strains, we find no evidence that extreme telomere-length variation causes meiotic drive in Drosophila. However, we identify one candidate meiotic driver in a centromere-linked region that shows an ∼8% increase in transmission frequency, corresponding to a ∼54:46 segregation ratio. Our results show that candidate meiotic drivers of moderate strength can be readily detected and localized in pools of BC1 progeny. PMID:28258181

An auto-inhibitory helix in CTP:phosphocholine cytidylyltransferase hijacks the catalytic residue and constrains a pliable, domain-bridging helix pair

PubMed Central

Ramezanpour, Mohsen; Lee, Jaeyong; Taneva, Svetla G.; Tieleman, D. Peter; Cornell, Rosemary B.

2018-01-01

The activity of CTP:phosphocholine cytidylyltransferase (CCT), a key enzyme in phosphatidylcholine synthesis, is regulated by reversible interactions of a lipid-inducible amphipathic helix (domain M) with membrane phospholipids. When dissociated from membranes, a portion of the M domain functions as an auto-inhibitory (AI) element to suppress catalysis. The AI helix from each subunit binds to a pair of α helices (αE) that extend from the base of the catalytic dimer to create a four-helix bundle. The bound AI helices make intimate contact with loop L2, housing a key catalytic residue, Lys122. The impacts of the AI helix on active-site dynamics and positioning of Lys122 are unknown. Extensive MD simulations with and without the AI helix revealed that backbone carbonyl oxygens at the point of contact between the AI helix and loop L2 can entrap the Lys122 side chain, effectively competing with the substrate, CTP. In silico, removal of the AI helices dramatically increased αE dynamics at a predicted break in the middle of these helices, enabling them to splay apart and forge new contacts with loop L2. In vitro cross-linking confirmed the reorganization of the αE element upon membrane binding of the AI helix. Moreover, when αE bending was prevented by disulfide engineering, CCT activation by membrane binding was thwarted. These findings suggest a novel two-part auto-inhibitory mechanism for CCT involving capture of Lys122 and restraint of the pliable αE helices. We propose that membrane binding enables bending of the αE helices, bringing the active site closer to the membrane surface. PMID:29519816

World commercial aircraft accidents: 1st edition, 1946--1991

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

Kimura, C.Y.

1992-02-01

This report is a compilation of all accidents world-wide involving aircraft in commercial service which resulted in the loss of the airframe or one or more fatality, or both. This information has been gathered in order to present a complete inventory of commercial aircraft accidents. Events involving military action, sabotage, terrorist bombings, hijackings, suicides, and industrial ground accidents are included within this list. This report is organized into six chapters. The first chapter is the introduction. The second chapter contains the compilation of accidents involving world commercial jet aircraft from 1952 to 1991. The third chapter presents a compilation ofmore » accidents involving world commercial turboprop aircraft from 1952 to 1991. The fourth chapter presents a compilation of accidents involving world commercial pistonprop aircraft with four or more engines from 1946 to 1991. Each accident compilation or database in chapters two, three and four is presented in chronological order. Each accident is presented with information the following categories: date of accident, airline or operator and its flight number (if known), type of flight, type of aircraft and model, aircraft registration number, construction number/manufacturers serial number, aircraft damage resulting from accident, accident flight phase, accident location, number of fatalities, number of occupants, references used to compile the information, and finally cause, remarks, or description (brief) of the accident. The fifth chapter presents a list of all commercial aircraft accidents for all aircraft types with 100 or more fatalities in order of decreasing number of fatalities. Chapter six presents the commercial aircraft accidents for all aircraft types by flight phase. Future editions of this report will have additional follow-on chapters which will present other studies still in preparation at the time this edition was being prepared.« less

Intracellular bacteria interfere with dendritic cell functions: role of the type I interferon pathway.

PubMed

Gorvel, Laurent; Textoris, Julien; Banchereau, Romain; Ben Amara, Amira; Tantibhedhyangkul, Wiwit; von Bargen, Kristin; Ka, Mignane B; Capo, Christian; Ghigo, Eric; Gorvel, Jean-Pierre; Mege, Jean-Louis

2014-01-01

Dendritic cells (DCs) orchestrate host defenses against microorganisms. In infectious diseases due to intracellular bacteria, the inefficiency of the immune system to eradicate microorganisms has been attributed to the hijacking of DC functions. In this study, we selected intracellular bacterial pathogens with distinct lifestyles and explored the responses of monocyte-derived DCs (moDCs). Using lipopolysaccharide as a control, we found that Orientia tsutsugamushi, the causative agent of scrub typhus that survives in the cytosol of target cells, induced moDC maturation, as assessed by decreased endocytosis activity, the ability to induce lymphocyte proliferation and the membrane expression of phenotypic markers. In contrast, Coxiella burnetii, the agent of Q fever, and Brucella abortus, the agent of brucellosis, both of which reside in vacuolar compartments, only partly induced the maturation of moDCs, as demonstrated by a phenotypic analysis. To analyze the mechanisms used by C. burnetii and B. abortus to alter moDC activation, we performed microarray and found that C. burnetii and B. abortus induced a specific signature consisting of TLR4, TLR3, STAT1 and interferon response genes. These genes were down-modulated in response to C. burnetii and B. abortus but up-modulated in moDCs activated by lipopolysaccharide and O. tsutsugamushi. This transcriptional alteration was associated with the defective interferon-β production. This study demonstrates that intracellular bacteria specifically affect moDC responses and emphasizes how C. burnetii and B. abortus interfere with moDC activation and the antimicrobial immune response. We believe that comparing infection by several bacterial species may be useful for defining new pathways and biomarkers and for developing new treatment strategies.

DISCOIDIN DOMAIN RECEPTOR TYROSINE KINASES: NEW PLAYERS IN CANCER PROGRESSION

PubMed Central

Valiathan, Rajeshwari R.; Marco, Marta; Leitinger, Birgit; Kleer, Celina G.; Fridman, Rafael

2012-01-01

Almost all human cancers display dysregulated expression and/or function of one or more receptor tyrosine kinases (RTKs). The strong causative association between altered RTK function and cancer progression has translated into novel therapeutic strategies that target these cell surface receptors in the treatment of cancer. Yet, the full spectrum of RTKs that may alter the oncogenic process is not completely understood. Accumulating evidence suggests that a unique set of RTKs known as the Discoidin Domain Receptors (DDRs) play a role in cancer progression by regulating the interactions of tumor cells with their surrounding collagen matrix. The DDRs are the only RTKs that specifically bind to, and are activated by collagen. Hence, the DDRs are part of the signaling networks that translate information from the extracellular matrix thereby acting as key regulators of cell-matrix interactions. Under physiological conditions, DDRs control cell and tissue homeostasis by acting as collagen sensors, transducing signals that regulate cell polarity, tissue morphogenesis, and cell differentiation. In cancer, DDRs are hijacked by tumor cells to disrupt normal cell-matrix communication and initiate pro-migratory and pro-invasive programs. Importantly, several cancer types exhibit DDR mutations, which are thought to alter receptor function and contribute to cancer progression. Other evidence suggests that the actions of DDRs in cancer are complex, either promoting or suppressing tumor cell behavior in a DDR type/isoform specific and context dependent manner. Thus, there is still a considerable gap in our knowledge of DDR actions in cancer tissues. This review summarizes the current knowledge on DDR expression and function in cancer and discusses the potential implications of DDRs in cancer biology. It is hoped that this effort will encourage more research into these poorly understood but unique RTKs, which have the potential of becoming novel therapeutics targets in cancer. PMID:22366781

Localization and Sub-Cellular Shuttling of HTLV-1 Tax with the miRNA Machinery

PubMed Central

Van Duyne, Rachel; Guendel, Irene; Klase, Zachary; Narayanan, Aarthi; Coley, William; Jaworski, Elizabeth; Roman, Jessica; Popratiloff, Anastas; Mahieux, Renaud; Kehn-Hall, Kylene; Kashanchi, Fatah

2012-01-01

The innate ability of the human cell to silence endogenous retroviruses through RNA sequences encoding microRNAs, suggests that the cellular RNAi machinery is a major means by which the host mounts a defense response against present day retroviruses. Indeed, cellular miRNAs target and hybridize to specific sequences of both HTLV-1 and HIV-1 viral transcripts. However, much like the variety of host immune responses to retroviral infection, the virus itself contains mechanisms that assist in the evasion of viral inhibition through control of the cellular RNAi pathway. Retroviruses can hijack both the enzymatic and catalytic components of the RNAi pathway, in some cases to produce novel viral miRNAs that can either assist in active viral infection or promote a latent state. Here, we show that HTLV-1 Tax contributes to the dysregulation of the RNAi pathway by altering the expression of key components of this pathway. A survey of uninfected and HTLV-1 infected cells revealed that Drosha protein is present at lower levels in all HTLV-1 infected cell lines and in infected primary cells, while other components such as DGCR8 were not dramatically altered. We show colocalization of Tax and Drosha in the nucleus in vitro as well as coimmunoprecipitation in the presence of proteasome inhibitors, indicating that Tax interacts with Drosha and may target it to specific areas of the cell, namely, the proteasome. In the presence of Tax we observed a prevention of primary miRNA cleavage by Drosha. Finally, the changes in cellular miRNA expression in HTLV-1 infected cells can be mimicked by the add back of Drosha or the addition of antagomiRs against the cellular miRNAs which are downregulated by the virus. PMID:22808228

Analyzing Cyber-Physical Threats on Robotic Platforms.

PubMed

Ahmad Yousef, Khalil M; AlMajali, Anas; Ghalyon, Salah Abu; Dweik, Waleed; Mohd, Bassam J

2018-05-21

Robots are increasingly involved in our daily lives. Fundamental to robots are the communication link (or stream) and the applications that connect the robots to their clients or users. Such communication link and applications are usually supported through client/server network connection. This networking system is amenable of being attacked and vulnerable to the security threats. Ensuring security and privacy for robotic platforms is thus critical, as failures and attacks could have devastating consequences. In this paper, we examine several cyber-physical security threats that are unique to the robotic platforms; specifically the communication link and the applications. Threats target integrity, availability and confidential security requirements of the robotic platforms, which use MobileEyes/arnlServer client/server applications. A robot attack tool (RAT) was developed to perform specific security attacks. An impact-oriented approach was adopted to analyze the assessment results of the attacks. Tests and experiments of attacks were conducted in simulation environment and physically on the robot. The simulation environment was based on MobileSim; a software tool for simulating, debugging and experimenting on MobileRobots/ActivMedia platforms and their environments. The robot platform PeopleBot TM was used for physical experiments. The analysis and testing results show that certain attacks were successful at breaching the robot security. Integrity attacks modified commands and manipulated the robot behavior. Availability attacks were able to cause Denial-of-Service (DoS) and the robot was not responsive to MobileEyes commands. Integrity and availability attacks caused sensitive information on the robot to be hijacked. To mitigate security threats, we provide possible mitigation techniques and suggestions to raise awareness of threats on the robotic platforms, especially when the robots are involved in critical missions or applications.