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Find video protocols related to scientific articles indexed in Pubmed.
A critical role for mTORC1 in erythropoiesis and anemia.
Elife
PUBLISHED: 09-04-2014
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Red blood cells (RBC) must coordinate their rate of growth and proliferation with the availability of nutrients, such as iron, but the signaling mechanisms that link the nutritional state to RBC growth are incompletely understood. We performed a screen for cell types that have high levels of signaling through mTORC1, a protein kinase that couples nutrient availability to cell growth. This screen revealed that reticulocytes show high levels of phosphorylated ribosomal protein S6, a downstream target of mTORC1. We found that mTORC1 activity in RBCs is regulated by dietary iron and that genetic activation or inhibition of mTORC1 results in macrocytic or microcytic anemia, respectively. Finally, ATP competitive mTOR inhibitors reduced RBC proliferation and were lethal after treatment with phenylhydrazine, an inducer of hemolysis. These results identify the mTORC1 pathway as a critical regulator of RBC growth and proliferation and establish that perturbations in this pathway result in anemia.
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Processes of incremental message planning during conversation.
Psychon Bull Rev
PUBLISHED: 08-28-2014
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Speaking begins with the formulation of an intended preverbal message and linguistic encoding of this information. The transition from thought to speech occurs incrementally, with cascading planning at subsequent levels of production. In this article, we aim to specify the mechanisms that support incremental message preparation. We contrast two hypotheses about the mechanisms responsible for incorporating message-level information into a linguistic plan. According to the Initial Preparation view, messages can be encoded as fluent utterances if all information is ready before speaking begins. By contrast, on the Continuous Incrementality view, messages can be continually prepared and updated throughout the production process, allowing for fluent production even if new information is added to the message while speaking is underway. Testing these hypotheses, eye-tracked speakers in two experiments produced unscripted, conjoined noun phrases with modifiers. Both experiments showed that new message elements can be incrementally incorporated into the utterance even after articulation begins, consistent with a Continuous Incrementality view of message planning, in which messages percolate to linguistic encoding immediately as that information becomes available in the mind of the speaker. We conclude by discussing the functional role of incremental message planning in conversational speech and the situations in which this continuous incremental planning would be most likely to be observed.
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Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA.
Ann. Rheum. Dis.
PUBLISHED: 08-12-2014
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To determine whether there is an additive effect of anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) on the number and size of bone erosions in patients with rheumatoid arthritis (RA) METHODS: 242 patients with RA received high-resolution peripheral quantitative CT (HR-pQCT) scans of the metacarpophalangeal joints. Demographic and disease-specific parameters including ACPA and RF levels were recorded from all patients. Erosion numbers and their size were assessed in 238 patients at 714 individual joints (MCP 2, 3 and 4) and 5712 sites (each 4 quadrants in metacarpal heads and phalangeal bases). The volume of erosions was calculated by a semiellipsoid formula.
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Evaluating a model linking assessed parent factors to four domains of youth risky driving.
Accid Anal Prev
PUBLISHED: 05-07-2014
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Motor vehicle collisions are the leading cause of death in youth aged 15-19. Research has consistently shown that driver education programs do not result in safer youth driving. Indeed, the biggest predictor of collisions involving youth is parental history of collisions. The current study examined how parental modeling of and teaching about risky driving behaviors related to youth practices within four domains of risky driving (aggressive, substance use, distracted, moving violations), and evaluated whether the Prototype-Willingness Model explains links from parent to teen driving practices. Participants (N=432) were undergraduate students (mean age 18 years, age range 17-22 years) who had obtained their G2 driver's license within the past year; the G2 driver's license allows youth to drive alone on all municipal roads, with some restrictions on their blood alcohol level and the number of passengers they can carry. Results revealed that parental modeling was more predictive than parental teaching for all domains of risky driving examined. Youth whose parents modeled risky driving behaviors were found to be more likely to have engaged in those risky driving behaviors in the past, as well as to be more willing to engage in the behaviors in the future. The Prototype-Willingness Model was not a good fit to explain these relations. Findings from this study highlight the role parents play in the development of youth risky driving practices.
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Adjusting conceptual pacts in three-party conversation.
J Exp Psychol Learn Mem Cogn
PUBLISHED: 04-07-2014
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During conversation, partners develop representations of jointly known information--the common ground--and use this knowledge to guide subsequent linguistic exchanges. Extensive research on 2-party conversation has offered key insights into this process, in particular, its partner-specificity: Common ground that is shared with 1 partner is not always assumed to be shared with other partners. Conversation often involves multiple pairs of individuals who differ in common ground. Yet, little is known about common ground processes in multi-party conversation. Here, we take a 1st step toward understanding this problem by examining situations in which simple dyadic representations of common ground might cause difficulty--situations in which dialogue partners develop shared labels (entrained terms), and then a 3rd (naïve) party joins the conversation. Experiment 1 examined unscripted, task-based conversation in which 2 partners entrained on terms. At test, speakers referenced game-pieces in a dialogue with their partner, or in a 3-party conversation including a new, naïve listener. Speakers were sensitive to the 3rd party, using longer, disfluent expressions when additionally addressing the new partner. By contrast, analysis of listener eye-fixations did not suggest sensitivity. Experiment 2 provided a stronger test of sensitivity and revealed that listeners do cancel expectations for terms that had been entrained before when a 3rd, naïve party joins the conversation. These findings shed light on the mechanisms underlying common ground, showing that rather than a unitary construct, common ground is flexibly adapted to the needs of a naïve 3rd party.
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Urinary MCP1 and Microalbumin increase prior to onset of Azotemia in mice with polycystic kidney disease.
Comp. Med.
PUBLISHED: 03-29-2014
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Urinary biomarkers may offer a more sensitive and less invasive means to monitor kidney disease than traditional blood chemistry biomarkers such as creatinine. CD1(pcy/pcy) (pcy) mice have a slowly progressive disease phenotype that resembles human autosomal dominant polycystic kidney disease with renal cyst formation and inflammation. Previous reports suggest that dietary protein restriction may slow disease progression in mice and humans with polycystic kidney disease. Accordingly, we fed pcy mice either a standard chow (22.5% protein) or a protein-restricted (11.5% soy-based protein) diet from weaning until 34 wk of age. Every 6 wk we measured markers of kidney disease, including serum creatinine, BUN, and serum albumin as well as urinary monocyte chemoattractant protein 1 (MCP1), microalbumin, and specific gravity. Progression of kidney disease was equivalent for both diet groups despite dietary protein restriction. Urinary biomarkers proved useful for early detection of disease, in that urinary microalbumin was elevated as early as 22 wk of age and urinary MCP1 was increased by 28 wk of age, whereas increases in serum creatinine and BUN were detected later (at 34 wk of age) in both diet groups. Thus, urinary microalbumin and MCP1 analyses provided earlier, noninvasive indicators for detection of kidney disease and disease progression in pcy mice than did serum creatinine and BUN.
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Talker-specific learning in amnesia: Insight into mechanisms of adaptive speech perception.
Cortex
PUBLISHED: 01-24-2014
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A hallmark of human speech perception is the ability to comprehend speech quickly and effortlessly despite enormous variability across talkers. However, current theories of speech perception do not make specific claims about the memory mechanisms involved in this process. To examine whether declarative memory is necessary for talker-specific learning, we tested the ability of amnesic patients with severe declarative memory deficits to learn and distinguish the accents of two unfamiliar talkers by monitoring their eye-gaze as they followed spoken instructions. Analyses of the time-course of eye fixations showed that amnesic patients rapidly learned to distinguish these accents and tailored perceptual processes to the voice of each talker. These results demonstrate that declarative memory is not necessary for this ability and points to the involvement of non-declarative memory mechanisms. These results are consistent with findings that other social and accommodative behaviors are preserved in amnesia and contribute to our understanding of the interactions of multiple memory systems in the use and understanding of spoken language.
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The influence of partner-specific memory associations on picture naming: a failure to replicate horton (2007).
PLoS ONE
PUBLISHED: 01-01-2014
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The results of two experiments by Horton (2007) show that speakers name a pictured object faster when in the presence of another person with whom the speaker has previously associated that object name. The first of those two experiments (Horton, 2007, Experiment 1) is the focus of the present research. This paper presents the results of three experiments designed to replicate and extend Horton's (2007) Experiment 1. The original findings were not replicated. These findings do not support the hypothesis that partner-specific memory associations facilitate object naming.
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Do adults show a curse of knowledge in false-belief reasoning? A robust estimate of the true effect size.
PLoS ONE
PUBLISHED: 01-01-2014
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Seven experiments use large sample sizes to robustly estimate the effect size of a previous finding that adults are more likely to commit egocentric errors in a false-belief task when the egocentric response is plausible in light of their prior knowledge. We estimate the true effect size to be less than half of that reported in the original findings. Even though we found effects in the same direction as the original, they were substantively smaller; the original study would have had less than 33% power to detect an effect of this magnitude. The influence of plausibility on the curse of knowledge in adults appears to be small enough that its impact on real-life perspective-taking may need to be reevaluated.
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Limitations on adaptation to foreign accents.
J Mem Lang
PUBLISHED: 09-10-2013
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Although foreign accents can be highly dissimilar to native speech, existing research suggests that listeners readily adapt to foreign accents after minimal exposure. However, listeners often report difficulty understanding non-native accents, and the time-course and specificity of adaptation remain unclear. Across five experiments, we examined whether listeners could use a newly learned feature of a foreign accent to eliminate lexical competitors during online speech perception. Participants heard the speech of a native English speaker and a native speaker of Québec French who, in English, pronounces /i/ as [i] (e.g., weak as wick) before all consonants except voiced fricatives. We examined whether listeners could learn to eliminate a shifted /i/-competitor (e.g., weak) when interpreting the accented talker produce an unshifted word (e.g., wheeze). In four experiments, adaptation was strikingly limited, though improvement across the course of the experiment and with stimulus variations indicates learning was possible. In a fifth experiment, adaptation was not improved when a native English talker produced the critical vowel shift, demonstrating that the limitation is not simply due to the fact the accented talker was non-native. These findings suggest that although listeners can arrive at the correct interpretation of a foreign accent, this process can pose significant difficulty.
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LMX1B is essential for the maintenance of differentiated podocytes in adult kidneys.
J. Am. Soc. Nephrol.
PUBLISHED: 08-29-2013
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Mutations of the LMX1B gene cause nail-patella syndrome, a rare autosomal-dominant disorder affecting the development of the limbs, eyes, brain, and kidneys. The characterization of conventional Lmx1b knockout mice has shown that LMX1B regulates the development of podocyte foot processes and slit diaphragms, but studies using podocyte-specific Lmx1b knockout mice have yielded conflicting results regarding the importance of LMX1B for maintaining podocyte structures. In order to address this question, we generated inducible podocyte-specific Lmx1b knockout mice. One week of Lmx1b inactivation in adult mice resulted in proteinuria with only minimal foot process effacement. Notably, expression levels of slit diaphragm and basement membrane proteins remained stable at this time point, and basement membrane charge properties also did not change, suggesting that alternative mechanisms mediate the development of proteinuria in these mice. Cell biological and biophysical experiments with primary podocytes isolated after 1 week of Lmx1b inactivation indicated dysregulation of actin cytoskeleton organization, and time-resolved DNA microarray analysis identified the genes encoding actin cytoskeleton-associated proteins, including Abra and Arl4c, as putative LMX1B targets. Chromatin immunoprecipitation experiments in conditionally immortalized human podocytes and gel shift assays showed that LMX1B recognizes AT-rich binding sites (FLAT elements) in the promoter regions of ABRA and ARL4C, and knockdown experiments in zebrafish support a model in which LMX1B and ABRA act in a common pathway during pronephros development. Our report establishes the importance of LMX1B in fully differentiated podocytes and argues that LMX1B is essential for the maintenance of an appropriately structured actin cytoskeleton in podocytes.
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Identification of novel inhibitors of nonreplicating Mycobacterium tuberculosis using a carbon starvation model.
ACS Chem. Biol.
PUBLISHED: 08-13-2013
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During Mycobacterium tuberculosis infection, a population of bacteria is thought to exist in a nonreplicating state, refractory to antibiotics, which may contribute to the need for prolonged antibiotic therapy. The identification of inhibitors of the nonreplicating state provides tools that can be used to probe this hypothesis and the physiology of this state. The development of such inhibitors also has the potential to shorten the duration of antibiotic therapy required. Here we describe the development of a novel nonreplicating assay amenable to high-throughput chemical screening coupled with secondary assays that use carbon starvation as the in vitro model. Together these assays identify compounds with activity against replicating and nonreplicating M. tuberculosis as well as compounds that inhibit the transition from nonreplicating to replicating stages of growth. Using these assays we successfully screened over 300,000 compounds and identified 786 inhibitors of nonreplicating M. tuberculosis In order to understand the relationship among different nonreplicating models, we tested 52 of these molecules in a hypoxia model, and four different chemical scaffolds in a stochastic persister model, and a streptomycin-dependent model. We found that compounds display varying levels of activity in different models for the nonreplicating state, suggesting important differences in bacterial physiology between models. Therefore, chemical tools identified in this assay may be useful for determining the relevance of different nonreplicating in vitro models to in vivo M. tuberculosis infection. Given our current limited understanding, molecules that are active across multiple models may represent more promising candidates for further development.
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Hippocampal contributions to language: evidence of referential processing deficits in amnesia.
J Exp Psychol Gen
PUBLISHED: 08-12-2013
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A growing body of work suggests the hippocampus contributes to a variety of cognitive domains beyond its traditional role in memory. We propose that the hippocampus, in its capacity for relational binding, representational flexibility, and online maintenance and integration of multimodal relational representations, is a key contributor to language processing. Here we test the hypothesis that the online interpretation of pronouns is hippocampus-dependent. We combined eye tracking with neuropsychological methods, where participants (4 patients with bilateral hippocampal damage and severe declarative memory impairment, 4 patients with ventromedial prefrontal cortex [vmPFC] damage, and healthy comparison participants) viewed a scene while listening to short dialogues introducing 2 characters; for example, Melissa is playing violin for Debbie/Danny as the sun is shining overhead. She is wearing a blue/purple dress. Consistent with previous work, analysis of eye gaze showed that younger and older healthy comparison participants and the vmPFC patients rapidly identified the intended referent of the pronoun when gender uniquely identified the referent, and when it did not, they showed a preference to interpret the pronoun as referring to the first-mentioned character. By contrast, hippocampal patients, while exhibiting a similar gender effect, exhibited significant disruptions in their ability to use information about which character had been mentioned first to interpret the pronoun. This finding suggests that the hippocampus plays a role in maintaining and integrating information even over a very short discourse history. These observed disruptions in referential processing demonstrate how promiscuously the hallmark processing features of the hippocampus are used in service of a variety of cognitive domains including language.
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Ways of looking ahead: hierarchical planning in language production.
Cognition
PUBLISHED: 07-22-2013
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It is generally assumed that language production proceeds incrementally, with chunks of linguistic structure planned ahead of speech. Extensive research has examined the scope of language production and suggests that the size of planned chunks varies across contexts (Ferreira & Swets, 2002; Wagner & Jescheniak, 2010). By contrast, relatively little is known about the structure of advance planning, specifically whether planning proceeds incrementally according to the surface structure of the utterance, or whether speakers plan according to the hierarchical relationships between utterance elements. In two experiments, we examine the structure and scope of lexical planning in language production using a picture description task. Analyses of speech onset times and word durations show that speakers engage in hierarchical planning such that structurally dependent lexical items are planned together and that hierarchical planning occurs for both direct and indirect dependencies.
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Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 06-24-2013
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Infection with the bacterial pathogen Mycobacterium tuberculosis imposes an enormous burden on global public health. New antibiotics are urgently needed to combat the global tuberculosis pandemic; however, the development of new small molecules is hindered by a lack of validated drug targets. Here, we describe the identification of a 4,6-diaryl-5,7-dimethyl coumarin series that kills M. tuberculosis by inhibiting fatty acid degradation protein D32 (FadD32), an enzyme that is required for biosynthesis of cell-wall mycolic acids. These substituted coumarin inhibitors directly inhibit the acyl-acyl carrier protein synthetase activity of FadD32. They effectively block bacterial replication both in vitro and in animal models of tuberculosis, validating FadD32 as a target for antibiotic development that works in the same pathway as the established antibiotic isoniazid. Targeting new steps in well-validated biosynthetic pathways in antitubercular therapy is a powerful strategy that removes much of the usual uncertainty surrounding new targets and in vivo clinical efficacy, while circumventing existing resistance to established targets.
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What is the context of prediction?
Behav Brain Sci
PUBLISHED: 06-24-2013
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We agree with Pickering & Garrods (P&Gs) claim that theories of language processing must address the interconnection of language production and comprehension. However, we have two concerns: First, the central notion of context when predicting what another person will say is underspecified. Second, it is not clear that P&Gs dual-mechanism model captures the data better than a single-mechanism model would.
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Persistent bacterial infections, antibiotic tolerance, and the oxidative stress response.
Virulence
PUBLISHED: 04-05-2013
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Certain bacterial pathogens are able to evade the host immune system and persist within the human host. The consequences of persistent bacterial infections potentially include increased morbidity and mortality from the infection itself as well as an increased risk of dissemination of disease. Eradication of persistent infections is difficult, often requiring prolonged or repeated courses of antibiotics. During persistent infections, a population or subpopulation of bacteria exists that is refractory to traditional antibiotics, possibly in a non-replicating or metabolically altered state. This review highlights the clinical significance of persistent infections and discusses different in vitro models used to investigate the altered physiology of bacteria during persistent infections. We specifically focus on recent work establishing increased protection against oxidative stress as a key element of the altered physiologic state across different in vitro models and pathogens.
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Developmental role for endocannabinoid signaling in regulating glucose metabolism and growth.
Diabetes
PUBLISHED: 02-19-2013
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Treatment of ob/ob (obese) mice with a cannabinoid receptor 1 (Cnr1) antagonist reduces food intake, suggesting a role for endocannabinoid signaling in leptin action. We further evaluated the role of endocannabinoid signaling by analyzing the phenotype of Cnr1 knockout ob/ob mice. Double mutant animals show a more severe growth retardation than ob/ob mice with similar levels of adiposity and reduced IGF-I levels without alterations of growth hormone (GH) levels. The double mutant mice are also significantly more glucose intolerant than ob/ob mice. This is in contrast to treatment of ob/ob mice with a Cnr1 antagonist that had no effect on glucose metabolism, suggesting a possible requirement for endocannabinoid signaling during development for normal glucose homeostasis. Double mutant animals also showed similar leptin sensitivity as ob/ob mice, suggesting that there are developmental changes that compensate for the loss of Cnr1 signaling. These data establish a role for Cnr1 during development and suggest that compensatory changes during development may mitigate the requirement for Cnr1 in mediating the effects of leptin. The data also suggest a developmental role for Cnr1 to promote growth, regulate the GH/IGF-I axis, and improve ?-cell function and glucose homeostasis in the setting of leptin deficiency.
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MITEs in the promoters of effector genes allow prediction of novel virulence genes in Fusarium oxysporum.
BMC Genomics
PUBLISHED: 02-11-2013
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The plant-pathogenic fungus Fusarium oxysporum f.sp.lycopersici (Fol) has accessory, lineage-specific (LS) chromosomes that can be transferred horizontally between strains. A single LS chromosome in the Fol4287 reference strain harbors all known Fol effector genes. Transfer of this pathogenicity chromosome confers virulence to a previously non-pathogenic recipient strain. We hypothesize that expression and evolution of effector genes is influenced by their genomic context.
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Catabolic and anabolic periarticular bone changes in patients with rheumatoid arthritis: a computed tomography study on the role of age, disease duration and bone markers.
Arthritis Res. Ther.
PUBLISHED: 01-18-2013
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The aim of this study was to determine the factors, including markers of bone resorption and bone formation, which determine catabolic and anabolic periarticular bone changes in patients with rheumatoid arthritis (RA).
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How do I remember that I know you know that I know?
Psychol Sci
PUBLISHED: 11-28-2011
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Communication is aided greatly when speakers and listeners take advantage of mutually shared knowledge (i.e., common ground). How such information is represented in memory is not well known. Using a neuropsychological-psycholinguistic approach to real-time language understanding, we investigated the ability to form and use common ground during conversation in memory-impaired participants with hippocampal amnesia. Analyses of amnesics eye fixations as they interpreted their partners utterances about a set of objects demonstrated successful use of common ground when the amnesics had immediate access to common-ground information, but dramatic failures when they did not. These findings indicate a clear role for declarative memory in maintenance of common-ground representations. Even when amnesics were successful, however, the eye movement record revealed subtle deficits in resolving potential ambiguity among competing intended referents; this finding suggests that declarative memory may be critical to more basic aspects of the on-line resolution of linguistic ambiguity.
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In vivo expression profile of the antiviral restriction factor and tumor-targeting antigen CD317/BST-2/HM1.24/tetherin in humans.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 08-01-2011
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Human CD317 is an intrinsic immunity factor that restricts the release of enveloped viruses, including the major pathogens HIV and Lassa virus, from infected cells in culture. Its importance for infection control in humans is unclear, due in part to its incompletely defined in vivo expression pattern. CD317 also has been proposed as a selective target for immunotherapy of multiple myeloma. To provide a framework for studies of the biological functions, regulation, and therapeutic potential of CD317, we performed microarray-based expression profiling in 468 tissue samples from 25 healthy organs from more than 210 patients. We found that CD317 protein was expressed to varying degrees in all organs tested and detected in a number of specialized cell types, including hepatocytes, pneumocytes, ducts of major salivary glands, pancreas and kidney, Paneth cells, epithelia, Leydig cells, plasma cells, bone marrow stromal cells, monocytes, and vascular endothelium. Although many of these cell types are in vivo targets for pathogenic viruses, restriction by CD317 or virus-encoded antagonists has been documented in only some of them. Limited cell type-dependent coexpression of CD317 with the IFN biomarker MxA in vivo and lack of responsive stimulation in organ explants suggest that interferons may only partially regulate CD317. This in vivo expression profiling sheds light on the biology and species-specificity of CD317, identifies multiple thus far unknown interaction sites of viruses with this restriction factor, and refutes the concept of its restricted constitutive expression and primary IFN inducibility. CD317s widespread expression calls into question its suitability as a target for immunotherapy.
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Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion.
Ann. Rheum. Dis.
PUBLISHED: 05-27-2011
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To investigate whether bone erosions in patients with rheumatoid arthritis (RA) show evidence of repair.
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Kindlin-3-mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption.
J. Cell Biol.
PUBLISHED: 02-28-2011
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The blood cell-specific kindlin-3 protein is required to activate leukocyte and platelet integrins. In line with this function, mutations in the KINDLIN-3 gene in man cause immunodeficiency and severe bleeding. Some patients also suffer from osteopetrosis, but the underlying mechanism leading to abnormal bone turnover is unknown. Here we show that kindlin-3-deficient mice develop severe osteopetrosis because of profound adhesion and spreading defects in bone-resorbing osteoclasts. Mechanistically, loss of kindlin-3 impairs the activation of ?1, ?2, and ?3 integrin classes expressed on osteoclasts, which in turn abrogates the formation of podosomes and sealing zones required for bone resorption. In agreement with these findings, genetic ablation of all integrin classes abolishes the development of podosomes, mimicking kindlin-3 deficiency. Although loss of single integrin classes gives rise to podosomes, their resorptive activity is impaired. These findings show that osteoclasts require their entire integrin repertoire to be regulated by kindlin-3 to orchestrate bone homeostasis.
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Pathogenomics of fungal plant parasites: what have we learnt about pathogenesis?
Curr. Opin. Plant Biol.
PUBLISHED: 01-28-2011
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Members of the kingdom fungi comprise numerous plant pathogens, including the causal agents of many agriculturally relevant plant diseases such as rust, powdery mildew, rice blast and cereal head blight. Data from recent sequencing projects provide deep insight into the genomes of a range of fungi that infect different organs of monocotyledonous or dicotyledonous hosts and that have diverse pathogenic lifestyles. These studies have revealed that, similar to sequenced phytopathogenic oomycetes, these plant parasites possess very plastic and dynamic genomes, which typically encode several hundred candidate secreted effector proteins that can be highly divergent even among related species. A new insight is the presence of lineage-specific genes on mobile and partly dispensable chromosomes that are transferred intraspecifically and possibly interspecifically, thereby constituting pathogenicity and host range determinants. Convergent lifestyle-specific adaptations have shaped the parasite genomes to maximize pathogenic success according to the different infection strategies employed.
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HIV-1 Vpu blocks recycling and biosynthetic transport of the intrinsic immunity factor CD317/tetherin to overcome the virion release restriction.
MBio
PUBLISHED: 01-01-2011
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The intrinsic immunity factor CD317 (BST-2/HM1.24/tetherin) imposes a barrier to HIV-1 release at the cell surface that can be overcome by the viral protein Vpu. Expression of Vpu results in a reduction of CD317 surface levels; however, the mechanism of this Vpu activity and its contribution to the virological antagonism are incompletely understood. Here, we characterized the influence of Vpu on major CD317 trafficking pathways using quantitative antibody-based endocytosis and recycling assays as well as a microinjection/microscopy-based kinetic de novo expression approach. We report that HIV-1 Vpu inhibited both the anterograde transport of newly synthesized CD317 and the recycling of CD317 to the cell surface, while the kinetics of CD317 endocytosis remained unaffected. Vpu trapped trafficking CD317 molecules at the trans-Golgi network, where the two molecules colocalized. The subversion of both CD317 transport pathways was dependent on the highly conserved diserine S52/S56 motif of Vpu; however, it did not require recruitment of the diserine motif interactor and substrate adaptor of the SCF-E3 ubiquitin ligase complex, ?-TrCP. Treatment of cells with the malaria drug primaquine resulted in a CD317 trafficking defect that mirrored that induced by Vpu. Importantly, primaquine could functionally replace Vpu as a CD317 antagonist and rescue HIV-1 particle release.
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Genome expansion and gene loss in powdery mildew fungi reveal tradeoffs in extreme parasitism.
Science
PUBLISHED: 12-15-2010
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Powdery mildews are phytopathogens whose growth and reproduction are entirely dependent on living plant cells. The molecular basis of this life-style, obligate biotrophy, remains unknown. We present the genome analysis of barley powdery mildew, Blumeria graminis f.sp. hordei (Blumeria), as well as a comparison with the analysis of two powdery mildews pathogenic on dicotyledonous plants. These genomes display massive retrotransposon proliferation, genome-size expansion, and gene losses. The missing genes encode enzymes of primary and secondary metabolism, carbohydrate-active enzymes, and transporters, probably reflecting their redundancy in an exclusively biotrophic life-style. Among the 248 candidate effectors of pathogenesis identified in the Blumeria genome, very few (less than 10) define a core set conserved in all three mildews, suggesting that most effectors represent species-specific adaptations.
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Reactions of a ?-diketiminate zinc hydride complex with heterocumulenes.
Chem. Commun. (Camb.)
PUBLISHED: 09-01-2010
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The ?-diketiminate zinc hydride MesnacnacZnH (1) reacts with CO(2), C(Ni-Pr)(2) and t-BuNCO at ambient temperature with insertion into the Zn-H bond and subsequent formation of the corresponding formato (2), formamido (3) and formamidinato (4) complexes.
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"Please keep an eye on your younger sister": sibling supervision and young childrens risk of unintentional injury.
Inj. Prev.
PUBLISHED: 08-30-2010
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Parental supervision reduces young childrens risk of unintentional injuries, but supervision by older siblings has been shown to increase risk. The current study explored how this differential risk of injury may arise.
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Endogenous CD317/Tetherin limits replication of HIV-1 and murine leukemia virus in rodent cells and is resistant to antagonists from primate viruses.
J. Virol.
PUBLISHED: 08-11-2010
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Human CD317 (BST-2/tetherin) is an intrinsic immunity factor that blocks the release of retroviruses, filoviruses, herpesviruses, and arenaviruses. It is unclear whether CD317 expressed endogenously in rodent cells has the capacity to interfere with the replication of the retroviral rodent pathogen murine leukemia virus (MLV) or, in the context of small-animal model development, contributes to the well-established late-phase restriction of human immunodeficiency virus type 1 (HIV-1). Here, we show that small interfering RNA (siRNA)-mediated knockdown of CD317 relieved a virion release restriction and markedly enhanced the egress of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) in rat cells, including primary macrophages. Moreover, rodent CD317 potently inhibited MLV release, and siRNA-mediated depletion of CD317 in a mouse T-cell line resulted in the accelerated spread of MLV. Several virus-encoded antagonists have recently been reported to overcome the restriction imposed by human or monkey CD317, including HIV-1 Vpu, envelope glycoproteins of HIV-2 and Ebola virus, Kaposis sarcoma-associated herpesvirus K5, and SIV Nef. In contrast, both rat and mouse CD317 showed a high degree of resistance to these viral antagonists. These data suggest that CD317 is a broadly acting and conserved mediator of innate control of retroviral infection and pathogenesis that restricts the release of retroviruses and lentiviruses in rodents. The high degree of resistance of the rodent CD317 restriction factors to antagonists from primate viruses has implications for HIV-1 small-animal model development and may guide the design of novel antiviral interventions.
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Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors.
J. Virol.
PUBLISHED: 03-17-2010
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Proteolytic cleavage of the influenza virus surface glycoprotein hemagglutinin (HA) by host cell proteases is crucial for infectivity and virus spread. The proteases HAT (human airway trypsin-like protease) and TMPRSS2 (transmembrane protease serine S1 member 2) known to be present in the human airways were previously identified as proteases that cleave HA. We studied subcellular localization of HA cleavage and cleavage inhibition of seasonal influenza virus A/Memphis/14/96 (H1N1) and pandemic virus A/Hamburg/5/2009 (H1N1) in MDCK cells that express HAT and TMPRSS2 under doxycycline-induced transcriptional activation. We made the following observations: (i) HA is cleaved by membrane-bound TMPRSS2 and HAT and not by soluble forms released into the supernatant; (ii) HAT cleaves newly synthesized HA before or during the release of progeny virions and HA of incoming viruses prior to endocytosis at the cell surface, whereas TMPRSS2 cleaves newly synthesized HA within the cell and is not able to support the proteolytic activation of HA of incoming virions; and (iii) cleavage activation of HA and virus spread in TMPRSS2- and HAT-expressing cells can be suppressed by peptide mimetic protease inhibitors. The further development of these inhibitors could lead to new drugs for influenza treatment.
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Sibling supervision and young childrens risk of injury: a comparison of mothers and older siblings reactions to risk taking by a younger child in the family.
Soc Sci Med
PUBLISHED: 02-11-2010
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Although parental supervision is associated with reduced risk of injury to young children, supervision by older siblings has been shown to increase this risk. The current study, conducted in Guelph, Canada, explored how this differential risk of injury may arise. It compares the supervision behaviors of mothers to those of their older children when each was the designated supervisor of a young child, shown on a videotape to engage in no risk, risk, and rule violation behaviors in a home situation. The mothers and older child supervisors were told to imagine the toddler on the videotape was the young child in their own family, and to stop the tape and speak to the child whenever they would in real life. Results indicated that supervisees were allowed to engage in more risk behaviors when supervised by older siblings than by mothers. Sibling supervisors reacted to risk behaviors with more prohibitions, whereas mothers adopted a teaching orientation and gave more explanations and directions in response to risk behaviors by the supervisee. Implications for injury prevention and directions for future research are discussed.
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The role of executive function in perspective taking during online language comprehension.
Psychon Bull Rev
PUBLISHED: 10-10-2009
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During conversation, interlocutors build on the set of shared beliefs known as common ground. Although there is general agreement that interlocutors maintain representations of common ground, there is no consensus regarding whether common-ground representations constrain initial language interpretation processes. Here, I propose that executive functioning--specifically, failures in inhibition control--can account for some occasional insensitivities to common-ground information. The present article presents the results of an experiment that demonstrates that individual differences in inhibition control determine the degree to which addressees successfully inhibit perspective-inappropriate interpretations of temporary referential ambiguities in their partners speech. Whether mentioned information was grounded or not also played a role, suggesting that addressees may show sensitivity to common ground only when it is established collaboratively. The results suggest that, in conversation, perspective information routinely guides online language processing and that occasional insensitivities to perspective can be attributed partly to difficulties in inhibiting perspective-inappropriate interpretations.
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Partner-specific interpretation of maintained referential precedents during interactive dialog.
J Mem Lang
PUBLISHED: 08-14-2009
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In dialog settings, conversational partners converge on similar names for referents. These lexically entrained terms (Garrod & Anderson, 1987) are part of the common ground between the particular individuals who established the entrained term (Brennan & Clark, 1996), and are thought to be encoded in memory with a partner-specific cue. Thus far, analyses of the time-course of interpretation suggest that partner-specific information may not constrain the initial interpretation of referring expressions (Kronmüller & Barr, 2007; Barr & Keysar, 2002). However, these studies used non-interactive paradigms, which may limit the use of partner-specific representations. This article presents the results of three eye-tracking experiments. Experiment 1a used an interactive conversation methodology in which the experimenter and participant jointly established entrained terms for various images. On critical trials, the same experimenter, or a new experimenter described a critical image using an entrained term, or a new term. The results demonstrated an early, on-line partner-specific effect for interpretation of entrained terms, as well as preliminary evidence for an early, partner-specific effect for new terms. Experiment 1b used a non-interactive paradigm in which participants completed the same task by listening to image descriptions recorded during Experiment 1a; the results showed that partner-specific effects were eliminated. Experiment 2 replicated the partner-specific findings of Experiment 1a with an interactive paradigm and scenes that contained previously unmentioned images. The results suggest that partner-specific interpretation is most likely to occur in interactive dialog settings; the number of critical trials and stimulus characteristics may also play a role. The results are consistent with a large body of work demonstrating that the language processing system uses a rich source of contextual and pragmatic representations to guide on-line processing decisions.
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Leptin-mediated changes in hepatic mitochondrial metabolism, structure, and protein levels.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 07-21-2009
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Leptin reduces body weight in ob/ob mice by decreasing food intake and increasing energy expenditure; however, the mechanisms by which it does the latter are not known. Here we report that 30% of the weight loss induced by leptin treatment of ob/ob mice is due to changes in energy expenditure. In assessing leptins effects on specific tissues, we found that hepatic basal metabolic rate was paradoxically decreased 1.7-fold with leptin treatment, which was the result of a 1.6-fold reduction in mitochondrial volume density and altered substrate oxidation kinetics. The altered kinetics were associated with a decrease in protein levels of 2 mitochondrial respiratory chain components--cytochrome c oxidase subunit VIa and cytochrome c oxidase subunit IV. In addition to reduced hepatic metabolism, there was reduced long chain fatty acid production and a 2.5-fold increase in hepatic lipid export, both of which explain the reduced steatosis in leptin-treated animals. These data help clarify the role of the liver in leptin-mediated weight loss and define the mechanisms by which leptin alters hepatic metabolism and corrects steatosis.
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Kindlin-3 is required for beta2 integrin-mediated leukocyte adhesion to endothelial cells.
Nat. Med.
PUBLISHED: 01-05-2009
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Integrin activation is essential for the function of all blood cells, including platelets and leukocytes. The blood cell-specific FERM domain protein Kindlin-3 is required for the activation of the beta1 and beta3 integrins on platelets. Impaired activation of beta1, beta2 and beta3 integrins on platelets and leukocytes is the hallmark of a rare autosomal recessive leukocyte adhesion deficiency syndrome in humans called LAD-III, characterized by severe bleeding and impaired adhesion of leukocytes to inflamed endothelia. Here we show that Kindlin-3 also binds the beta2 integrin cytoplasmic domain and is essential for neutrophil binding and spreading on beta2 integrin-dependent ligands such as intercellular adhesion molecule-1 and the complement C3 activation product iC3b. Moreover, loss of Kindlin-3 expression abolished firm adhesion and arrest of neutrophils on activated endothelial cells in vitro and in vivo, whereas selectin-mediated rolling was unaffected. Thus, Kindlin-3 is essential to activate the beta1, beta2 and beta3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice.
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The molecular basis of leukocyte recruitment and its deficiencies.
Mol. Immunol.
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The innate immune system responds to inflammation, infection and injury by recruiting neutrophils and other leukocytes. These cells are able to leave the intravascular compartment in a process called leukocyte recruitment. This process involves several distinct steps: selectin-mediated rolling, firm adhesion via integrins, postarrest modifications including adhesion strengthening and leukocyte crawling and finally transmigration into tissue. Genetic defects affecting the different steps of the cascade can result in severe impairment in leukocyte recruitment. So far, three leukocyte adhesion deficiencies (LAD I-III) have been described in humans. These LADs are rare autosomal recessive inherited disorders and, although clinically distinct, exhibit several common features including recurrent bacterial infections and leukocytosis. In LAD-I, mutations within the ?2-integrin gene result in a severe defect in ?2 integrin-mediated firm leukocyte adhesion. Defects in the posttranslational fucosylation of selectin ligands dramatically reduce leukocyte rolling and lead to LAD-II. Finally, LAD-III, also known as LAD-I variant, is caused by impaired integrin activation due to mutations within the kindlin-3 gene. This review provides an overview on the molecular basis of leukocyte adhesion and its deficiencies.
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Molecular profiling of activated neurons by phosphorylated ribosome capture.
Cell
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The mammalian brain is composed of thousands of interacting neural cell types. Systematic approaches to establish the molecular identity of functional populations of neurons would advance our understanding of neural mechanisms controlling behavior. Here, we show that ribosomal protein S6, a structural component of the ribosome, becomes phosphorylated in neurons activated by a wide range of stimuli. We show that these phosphorylated ribosomes can be captured from mouse brain homogenates, thereby enriching directly for the mRNAs expressed in discrete subpopulations of activated cells. We use this approach to identify neurons in the hypothalamus regulated by changes in salt balance or food availability. We show that galanin neurons are activated by fasting and that prodynorphin neurons restrain food intake during scheduled feeding. These studies identify elements of the neural circuit that controls food intake and illustrate how the activity-dependent capture of cell-type-specific transcripts can elucidate the functional organization of a complex tissue.
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SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells.
Nat. Med.
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Unlike activated CD4(+) T cells, resting CD4(+) T cells are highly resistant to productive HIV-1 infection. Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4(+) T cells. SAMHD1 is abundantly expressed in resting CD4(+) T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4(+) T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4(+) T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutières syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4(+) T cells in vivo. Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.
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Bone anabolic changes progress in psoriatic arthritis patients despite treatment with methotrexate or tumour necrosis factor inhibitors.
Ann. Rheum. Dis.
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To investigate whether methotrexate or tumour necrosis factor inhibitors (TNFi) affect osteophyte formation in patients with psoriatic arthritis (PsA).
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Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals.
Proc. Natl. Acad. Sci. U.S.A.
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During Mycobacterium tuberculosis infection, a population of bacteria likely becomes refractory to antibiotic killing in the absence of genotypic resistance, making treatment challenging. We describe an in vitro model capable of yielding a phenotypically antibiotic-tolerant subpopulation of cells, often called persisters, within populations of Mycobacterium smegmatis and M. tuberculosis. We find that persisters are distinct from the larger antibiotic-susceptible population, as a small drop in dissolved oxygen (DO) saturation (20%) allows for their survival in the face of bactericidal antibiotics. In contrast, if high levels of DO are maintained, all cells succumb, sterilizing the culture. With increasing evidence that bactericidal antibiotics induce cell death through the production of reactive oxygen species (ROS), we hypothesized that the drop in DO decreases the concentration of ROS, thereby facilitating persister survival, and maintenance of high DO yields sufficient ROS to kill persisters. Consistent with this hypothesis, the hydroxyl-radical scavenger thiourea, when added to M. smegmatis cultures maintained at high DO levels, rescues the persister population. Conversely, the antibiotic clofazimine, which increases ROS via an NADH-dependent redox cycling pathway, successfully eradicates the persister population. Recent work suggests that environmentally induced antibiotic tolerance of bulk populations may result from enhanced antioxidant capabilities. We now show that the small persister subpopulation within a larger antibiotic-susceptible population also shows differential susceptibility to antibiotic-induced hydroxyl radicals. Furthermore, we show that stimulating ROS production can eradicate persisters, thus providing a potential strategy to managing persistent infections.
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Interleukin-6 receptor blockade induces limited repair of bone erosions in rheumatoid arthritis: a micro CT study.
Ann. Rheum. Dis.
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Interleukin-6 receptor (IL-6R) blockade improves the signs and symptoms of rheumatoid arthritis (RA) and retards bone damage. Whether IL-6R blockade allows repair of existing bone erosions is so far unclear.
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Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening.
ACS Chem. Biol.
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Despite the urgent need for new antitubercular drugs, few are on the horizon. To combat the problem of emerging drug resistance, structurally unique chemical entities that inhibit new targets will be required. Here we describe our investigations using whole cell screening of a diverse collection of small molecules as a methodology for identifying novel inhibitors that target new pathways for Mycobacterium tuberculosis drug discovery. We find that conducting primary screens using model mycobacterial species may limit the potential for identifying new inhibitors with efficacy against M. tuberculosis. In addition, we confirm the importance of developing in vitro assay conditions that are reflective of in vivo biology for maximizing the proportion of hits from whole cell screening that are likely to have activity in vivo. Finally, we describe the identification and characterization of two novel inhibitors that target steps in M. tuberculosis cell wall biosynthesis. The first is a novel benzimidazole that targets mycobacterial membrane protein large 3 (MmpL3), a proposed transporter for cell wall mycolic acids. The second is a nitro-triazole that inhibits decaprenylphosphoryl-?-D-ribose 2-epimerase (DprE1), an epimerase required for cell wall biosynthesis. These proteins are both among the small number of new targets that have been identified by forward chemical genetics using resistance generation coupled with genome sequencing. This suggests that methodologies currently employed for screening and target identification may lead to a bias in target discovery and that alternative methods should be explored.
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Influence of perspective and goals on reference production in conversation.
Psychon Bull Rev
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We examined the extent to which speakers take into consideration the addressees perspective in language production. Previous research on this process had revealed clear deficits (Horton & Keysar, Cognition 59:91-117, 1996; Wardlow Lane & Ferreira, Journal of Experimental Psychology: Learning, Memory, and Cognition 34:1466-1481, 2008). Here, we evaluated a new hypothesis--that the relevance of the addressees perspective depends on the speakers goals. In two experiments, Korean speakers described a target object in situations in which the perspective status of a competitor object (e.g., a large plate when describing a smaller plate) was manipulated. In Experiment 1, we examined whether speakers would use scalar-modified expressions even when the competitor was hidden from the addressee. The results demonstrated that information from both the speakers and the addressees perspectives influenced production. In Experiment 2, we examined whether utterance goals modulate this process. The results indicated that when a speaker makes a request, the addressees perspective has a stronger influence than it does when the speaker informs the addressee. These results suggest that privileged knowledge does shape language use, but crucially, that the degree to which the addressees perspective is considered is shaped by the relevance of the addressees perspective to the utterance goals.
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Transcriptome analysis of enriched Golovinomyces orontii haustoria by deep 454 pyrosequencing.
Fungal Genet. Biol.
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Powdery mildews are phytopathogenic ascomycetes that have an obligate biotrophic lifestyle and establish intimate relationships with their plant hosts. A crucial aspect of this plant-fungus interaction is the formation of specialized fungal infection structures termed haustoria. Although located within the cell boundaries of plant epidermal cells, haustoria remain separated from the plant cytoplasm by a host plasma membrane derivative, the extrahaustorial membrane. Haustoria are thought to represent pivotal sites of nutrient uptake and effector protein delivery. We enriched haustorial complexes from Arabidopsis thaliana plants infected with the powdery mildew fungus Golovinomyces orontii and performed in-depth transcriptome analysis by 454-based pyrosequencing of haustorial cDNAs. We assembled 7077 expressed sequence tag (EST) contigs with greater than 5-fold average coverage and analyzed these with regard to the respective predicted protein functions. We found that transcripts coding for gene products with roles in protein turnover, detoxification of reactive oxygen species and fungal pathogenesis are abundant in the haustorial EST contigs, while surprisingly transcripts encoding presumptive nutrient transporters were not highly represented in the haustorial cDNA library. A substantial proportion (?38%) of transcripts coding for predicted secreted proteins comprises effector candidates. Our data provide valuable insights into the transcriptome of the key infection structure of a model obligate biotrophic phytopathogen.
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The hippocampus and the flexible use and processing of language.
Front Hum Neurosci
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Fundamental to all human languages is an unlimited expressive capacity and creative flexibility that allow speakers to rapidly generate novel and complex utterances. In turn, listeners interpret language "on-line," incrementally integrating multiple sources of information as words unfold over time. A challenge for theories of language processing has been to understand how speakers and listeners generate, gather, integrate, and maintain representations in service of language processing. We propose that many of the processes by which we use language place high demands on and receive contributions from the hippocampal declarative memory system. The hippocampal declarative memory system is long known to support relational binding and representational flexibility. Recent findings demonstrate that these same functions are engaged during the real-time processes that support behavior in-the-moment. Such findings point to the hippocampus as a potentially key contributor to cognitive functions that require on-line integration of multiple sources of information, such as on-line language processing. Evidence supporting this view comes from findings that individuals with hippocampal amnesia show deficits in the use of language flexibly and on-line. We conclude that the relational binding and representational flexibility afforded by the hippocampal declarative memory system positions the hippocampus as a key contributor to language use and processing.
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Interaction of a Blumeria graminis f. sp. hordei effector candidate with a barley ARF-GAP suggests host vesicle trafficking is a fungal pathogenicity target.
Mol. Plant Pathol.
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Filamentous phytopathogens such as fungi and oomycetes secrete effector proteins to establish successful interactions with their plant hosts. In contrast to oomycetes, little is known about effector functions in true fungi. We used a bioinformatic pipeline to identify effector candidates (BECs) from the obligate biotrophic barley powdery mildew pathogen, Blumeria graminis f. sp. hordei (Bgh). BEC1-BEC5 are expressed at different time points during barley infection. BEC1, BEC2 and BEC4 have orthologs in the Arabidopsis thaliana-infecting powdery mildew fungus Golovinomyces orontii. Arabidopsis lines stably expressing the G. orontii BEC2 ortholog, GoEC2, are more susceptible to infection with the non-adapted fungus Erysiphe pisi, suggesting that GoEC2 contributes to powdery mildew virulence. For BEC3 and BEC4, we identified thiopurine methyltransferase, an ubiquitin-conjugating enzyme and an ADP-ribosylation factor-GTPase activating factor (ARF-GAP) as potential host targets. Arabidopsis knock-out lines of the respective HvARF-GAP ortholog (AtAGD5) allowed higher entry levels of E. pisi but exhibited elevated resistance to the oomycete Hyaloperonospora arabidopsidis. We hypothesize that ARF-GAP proteins are conserved targets of powdery and downy mildew effectors and we speculate that BEC4 might interfere with defence-associated host vesicle trafficking.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.