4,796 research outputs found
HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes
HOXA10 is necessary for embryonic patterning of skeletal elements, but its function in bone formation beyond this early developmental stage is unknown. Here we show that HOXA10 contributes to osteogenic lineage determination through activation of Runx2 and directly regulates osteoblastic phenotypic genes. In response to bone morphogenic protein BMP2, Hoxa10 is rapidly induced and functions to activate the Runx2 transcription factor essential for bone formation. A functional element with the Hox core motif was characterized for the bone-related Runx2 P1 promoter. HOXA10 also activates other osteogenic genes, including the alkaline phosphatase, osteocalcin, and bone sialoprotein genes, and temporally associates with these target gene promoters during stages of osteoblast differentiation prior to the recruitment of RUNX2. Exogenous expression and small interfering RNA knockdown studies establish that HOXA10 mediates chromatin hyperacetylation and trimethyl histone K4 (H3K4) methylation of these genes, correlating to active transcription. HOXA10 therefore contributes to early expression of osteogenic genes through chromatin remodeling. Importantly, HOXA10 can induce osteoblast genes in Runx2 null cells, providing evidence for a direct role in mediating osteoblast differentiation independent of RUNX2. We propose that HOXA10 activates RUNX2 in mesenchymal cells, contributing to the onset of osteogenesis, and that HOXA10 subsequently supports bone formation by direct regulation of osteoblast phenotypic genes. <br/
Ideology and the telephone: the social reception of a technology, London 1876-1920.
This thesis explores the social reception of the telephone mainly in late-Victorian and
Edwardian London. My objective is to understand how urban populations are educated to
a new technology, and how technology is socially appraised and embedded. "The social
reception of technology" is defined as the development and promotion of a new
technology, the political reactions and social comment it stimulates, and the nature of its
social and geographic diffusion. This approach, I argue, reveals important connections
between technology, ideology and social power in the city.
The telephone was one of several new space-binding technologies introduced into
Britain between 1870 and 1920. The telephone contributed to the creation of a "networked
city", and to the extension of the "public sphere". Because of the telephone's basic
characteristics -- its speed and immediacy of communication -- commentators have
regarded it as essentially modern and democratic. This view is considered deterministic
and an exaggeration of the telephone's early significance.
The telephone system developed gradually. Initially an elite technology, the
telephone was first used and introduced in traditional ways. Developed in Britain largely
by private interests, the telephone was commoditised by its promoters and marketed as
a business machine. The long distance network was prioritised over local networks,
business over social uses, and the extension of the price system over other possible social
objectives. As the telephone system developed, this "entrepreneurialism" clashed with
other ideological agents in the city: the individualism of private land ownership,
professionalism of engineers and public servants, and with diverse state and non-state
institutions claiming to represent the public interest. If not modern in function or
consequence, the telephone I suggest was institutionally modern; in the attempts of its
promoters and their opponents to use the "public sphere" in their own interest, yet always
subject to it; to generate through the press and through material and symbolic practices
talk about the telephone, yet always subject to public scrutiny in the form of press
comment and criticism.
The thesis illustrates these arguments through a survey of how the telephone was
reported in the press; through a study of policy as revealed in the archives of the Post
Office and the National Telephone Company; and through a case study of the telephone's
diffusion in the middle class suburb of Hampstead
Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders.
Genes for autism spectrum disorders (ASDs) are also implicated in fragile X syndrome (FXS), intellectual disabilities (ID) or schizophrenia (SCZ), and converge on neuronal function and differentiation. The SH-SY5Y neuroblastoma cell line, the most widely used system to study neurodevelopment, is currently discussed for its applicability to model cortical development. We implemented an optimal neuronal differentiation protocol of this system and evaluated neurodevelopment at the transcriptomic level using the CoNTeXT framework, a machine-learning algorithm based on human post-mortem brain data estimating developmental stage and regional identity of transcriptomic signatures. Our improved model in contrast to currently used SH-SY5Y models does capture early neurodevelopmental processes with high fidelity. We applied regression modelling, dynamic time warping analysis, parallel independent component analysis and weighted gene co-expression network analysis to identify activated gene sets and networks. Finally, we tested and compared these sets for enrichment of risk genes for neuropsychiatric disorders. We confirm a significant overlap of genes implicated in ASD with FXS, ID and SCZ. However, counterintuitive to this observation, we report that risk genes affect pathways specific for each disorder during early neurodevelopment. Genes implicated in ASD, ID, FXS and SCZ were enriched among the positive regulators, but only ID-implicated genes were also negative regulators of neuronal differentiation. ASD and ID genes were involved in dendritic branching modules, but only ASD risk genes were implicated in histone modification or axonal guidance. Only ID genes were over-represented among cell cycle modules. We conclude that the underlying signatures are disorder-specific and that the shared genetic architecture results in overlaps across disorders such as ID in ASD. Thus, adding developmental network context to genetic analyses will aid differentiating the pathophysiology of neuropsychiatric disorders
Polynomial Carleson operators along monomial curves in the plane
We prove bounds for partial polynomial Carleson operators along
monomial curves in the plane with a phase polynomial
consisting of a single monomial. These operators are "partial" in the sense
that we consider linearizing stopping-time functions that depend on only one of
the two ambient variables. A motivation for studying these partial operators is
the curious feature that, despite their apparent limitations, for certain
combinations of curve and phase, bounds for partial operators along
curves imply the full strength of the bound for a one-dimensional
Carleson operator, and for a quadratic Carleson operator. Our methods, which
can at present only treat certain combinations of curves and phases, in some
cases adapt a method to treat phases involving fractional monomials, and
in other cases use a known vector-valued variant of the Carleson-Hunt theorem.Comment: 27 page
Measuring portfolio performance using a modified measure of risk
This paper reports the results of an investigation into the properties of a theoretical modification of beta proposed by Leland (1999) and based on earlier work of Rubinstein (1976). It is shown that when returns are elliptically symmetric, beta is the appropriate measure of risk and that there are other situations in which the modified beta will be similar to the traditional measure based on the capital asset pricing model. For the case where returns have a normal distribution, it is shown that the criterion either does not exist or reduces exactly to the conventional beta. It is therefore conjectured that the modified measure will only be useful for portfolios that have nonstandard return distributions which incorporate skewness. For such situations, it is shown how to estimate the measure using regression and how to compare the resulting statistic with a traditional estimated beta using Hotelling's test. An empirical study based on stocks from the FTSE350 does not find evidence to support the use of the new measure even in the presence of skewness.Journal of Asset Management (2007) 7, 388-403. doi:10.1057/palgrave.jam.225005
Functional characterization of a 28-Kilobase Catabolic Island from Pseudomonas sp. Strain M1 involved in biotransformation of β-Myrcene and related plant-derived volatiles
Pseudomonas
sp. strain M1 is able to mineralize highly hydrophobic and recalcitrant compounds, such as benzene, phenol, and their methylated/halogenated derivatives, as well as the backbone of several monoterpenes. The ability to use such a spectrum of compounds as the sole carbon source is, most probably, associated with a genetic background evolved under different environmental constraints. The outstanding performance of strain M1 regarding β-myrcene catabolism was elucidated in this work, with a focus on the biocatalytical potential of the β-myrcene-associated core code, comprised in a 28-kb genomic island (GI), predicted to be organized in 8 transcriptional units. Functional characterization of this locus with promoter probes and analytical approaches validated the genetic organization predictedin silicoand associated the β-myrcene-induced promoter activity to the production of β-myrcene derivatives. Notably, by using a whole-genome mutagenesis strategy, different genotypes of the 28-kb GI were generated, resulting in the identification of a novel putative β-myrcene hydroxylase, responsible for the initial oxidation of β-myrcene into myrcen-8-ol, and a sensor-like regulatory protein, whose inactivation abolished themyr
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trait of M1 cells. Moreover, it was demonstrated that the range of monoterpene substrates of the M1 enzymatic repertoire, besides β-myrcene, also includes other acyclic (e.g., β-linalool) and cyclic [e.g.,R-(+)-limonene and (-)-β-pinene] molecules. Our findings are the cornerstone for following metabolic engineering approaches and hint at a major role of the 28-kb GI in the biotransformation of a broad monoterpene backbone spectrum for its future biotechnological applications.IMPORTANCEInformation regarding microbial systems able to biotransform monoterpenes, especially β-myrcene, is limited and focused mainly on nonsystematic metabolite identification. Complete and detailed knowledge at the genetic, protein, metabolite, and regulatory levels is essential in order to set a model organism or a catabolic system as a biotechnology tool. Moreover, molecular characterization of reported systems is scarce, almost nonexistent, limiting advances in the development of optimized cell factories with strategies based on the new generation of metabolic engineering platforms. This study provides new insights into the intricate molecular functionalities associated with β-myrcene catabolism inPseudomonas, envisaging the production of a molecular knowledge base about the underlying catalytic and regulatory mechanisms of plant-derived volatile catabolic pathways.Vectors from the Standard European Vector Architecture (SEVA) library and pBAM1
used in this work were kindly provided by Victor de Lorenzo (CNB-CSIC, Madrid, Spain).
This work was supported by the strategic program UID/BIA/04050/2013 (POCI-01-
0145-FEDER-007569) funded by national funds through the FCT I.P. and by the ERDF
through the COMPETE2020-Programa Operacional Competitividade e Internacionalização
(POCI) and through a Ph.D. grant (grant SFRH/BD/76894/2011) to P.S.-C.info:eu-repo/semantics/publishedVersio
Economic and other barriers to adopting recommendations to prevent childhood obesity: results of a focus group study with parents
Abstract Background Parents are integral to the implementation of obesity prevention and management recommendations for children. Exploration of barriers to and facilitators of parental decisions to adopt obesity prevention recommendations will inform future efforts to reduce childhood obesity. Methods We conducted 4 focus groups (2 English, 2 Spanish) among a total of 19 parents of overweight (BMI ≥ 85th percentile) children aged 5-17 years. The main discussion focused on 7 common obesity prevention recommendations: reducing television (TV) watching, removing TV from child's bedroom, increasing physically active games, participating in community or school-based athletics, walking to school, walking more in general, and eating less fast food. Parents were asked to discuss what factors would make each recommendation more difficult (barriers) or easier (facilitators) to follow. Participants were also asked about the relative importance of economic (time and dollar costs/savings) barriers and facilitators if these were not brought into the discussion unprompted. Results Parents identified many barriers but few facilitators to adopting obesity prevention recommendations for their children. Members of all groups identified economic barriers (time and dollar costs) among a variety of pertinent barriers, although the discussion of dollar costs often required prompting. Parents cited other barriers including child preference, difficulty with changing habits, lack of information, lack of transportation, difficulty with monitoring child behavior, need for assistance from family members, parity with other family members, and neighborhood walking safety. Facilitators identified included access to physical activity programs, availability of alternatives to fast food and TV which are acceptable to the child, enlisting outside support, dietary information, involving the child, setting limits, making behavior changes gradually, and parental change in shopping behaviors and own eating behaviors. Conclusions Parents identify numerous barriers to adopting obesity prevention recommendations, most notably child and family preferences and resistance to change, but also economic barriers. Intervention programs should consider the context of family priorities and how to overcome barriers and make use of relevant facilitators during program development.http://deepblue.lib.umich.edu/bitstream/2027.42/78270/1/1471-2431-9-81.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78270/2/1471-2431-9-81.pdfPeer Reviewe
Abdominal venous thrombosis presenting in myeloproliferative neoplasm with JAK2 V617F mutation: a case report
<p>Abstract</p> <p>Introduction</p> <p>An unprovoked thombotic event in a patient is cause for further evaluation of an underlying hypercoaguable state. The investigation should include a thorough search, including checking for a variety of known inherited and acquired hypercoaguble states (protein C or S deficiency, anti-phospholipid antibodies, and anti-thrombin III deficiency) and gene mutations that predispose patients to an increased risk of clotting (for example, prothrombin gene 20210 mutation, factor V Leiden, and the <it>JAK2 V617F </it>mutation).</p> <p>Case presentation</p> <p>We report the case of a 38-year-old Caucasian woman with spontaneous, unprovoked abdominal venous thrombosis and demonstrate how testing for the <it>JAK2 V617F </it>mutation was useful in unmasking an underlying hypercoaguable state.</p> <p>Conclusions</p> <p><it>JAK2 V617F</it>-positive myeloproliferative neoplasm was diagnosed. This case illustrates the importance of testing for <it>JAK2 V617F </it>in patients presenting with Budd-Chiari syndrome, even in the absence of overt hematologic abnormalities, in order to establish a diagnosis of underlying myeloproliferative neoplasm.</p
Risk factors for high anti-HHV-8 antibody titers (≥1:51,200) in black, HIV-1 negative South African cancer patients: a case control study
Background: Infection with human herpesvirus 8 (HHV-8) is the necessary causal agent in the
development of Kaposi's sarcoma (KS). Infection with HIV-1, male gender and older age all increase
risk for KS. However, the geographic distribution of HHV-8 and KS both prior to the HIV/AIDS
epidemic and with HIV/AIDS suggest the presence of an additional co-factor in the development of
KS.
Methods: Between January 1994 and October 1997, we interviewed 2576 black in-patients with
cancer in Johannesburg and Soweto, South Africa. Blood was tested for antibodies against HIV-1
and HHV-8 and the study was restricted to 2191 HIV-1 negative patients. Antibodies against the
latent nuclear antigen of HHV-8 encoded by orf73 were detected with an indirect
immunofluorescence assay. We examined the relationship between high anti-HHV-8 antibody
titers (≥1:51,200) and sociodemographic and behavioral factors using unconditional logistic
regression models. Variables that were significant at p = 0.10 were included in multivariate analysis.
Results: Of the 2191 HIV-1 negative patients who did not have Kaposi's sarcoma, 854 (39.0%)
were positive for antibodies against HHV-8 according to the immunofluorescent assay. Among
those seropositive for HHV-8, 530 (62.1%) had low titers (1:200), 227 (26.6%) had medium titers
(1:51,200) and 97 (11.4%) had highest titers (1:204,800). Among the 2191 HIV-1 negative patients,
the prevalence of high anti-HHV-8 antibody titers (≥1:51,200) was independently associated with
increasing age (ptrend = 0.04), having a marital status of separated or divorced (p = 0.003), using
wood, coal or charcoal as fuel for cooking 20 years ago instead of electricity (p = 0.02) and
consuming traditional maize beer more than one time a week (p = 0.02; p-trend for increasing
consumption = 0.05) although this may be due to chance given the large number of predictors
considered in this analysis.
Conclusions: Among HIV-negative subjects, patients with high anti-HHV-8 antibody titers are
characterized by older age. Other associations that may be factors in the development of high anti-
HHV-8 titers include exposure to poverty or a low socioeconomic status environment and
consumption of traditional maize beer. The relationship between these variables and high anti-
HHV-8 titers requires further, prospective study
Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition
BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations
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