2,156 research outputs found
Inducible cytochrome P450 activities in renal glomerular mesangial cells: biochemical basis for antagonistic interactions among nephrocarcinogenic polycyclic aromatic hydrocarbons
BACKGROUND: Benzo(a)pyrene (BaP), anthracene (ANTH) and chrysene (CHRY) are polynuclear aromatic hydrocarbons (PAHs) implicated in renal toxicity and carcinogenesis. These PAHs elicit cell type-specific effects that help predict toxicity outcomes in vitro and in vivo. While BaP and ANTH selectively injure glomerular mesangial cells, and CHRY targets cortico-tubular epithelial cells, binary or ternary mixtures of these hydrocarbons markedly reduce the overall cytotoxic potential of individual hydrocarbons. METHODS: To study the biochemical basis of these antagonistic interactions, renal glomerular mesangial cells were challenged with BaP alone (0.03 – 30 μM) or in the presence of ANTH (3 μM) or CHRY (3 μM) for 24 hr. Total RNA and protein will be harvested for Northern analysis and measurements of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-O-deethylase (EROD) activity, respectively, to evaluate cytochrome P450 mRNA and protein inducibility. Cellular hydrocarbon uptake and metabolic profiles of PAHs were analyzed by high performance liquid chromatography (HPLC). RESULTS: Combined hydrocarbon treatments did not influence the cellular uptake of individual hydrocarbons. ANTH or CHRY strongly repressed BaP-inducible cytochrome P450 mRNA and protein expression, and markedly inhibited oxidative BaP metabolism. CONCLUSION: These findings indicate that antagonistic interactions among nephrocarcinogenic PAHs involve altered expression of cytochrome P450s that modulate bioactivation profiles and nephrotoxic/ nephrocarcinogenic potential
Gauge symmetry and W-algebra in higher derivative systems
The problem of gauge symmetry in higher derivative Lagrangian systems is
discussed from a Hamiltonian point of view. The number of independent gauge
parameters is shown to be in general {\it{less}} than the number of independent
primary first class constraints, thereby distinguishing it from conventional
first order systems. Different models have been considered as illustrative
examples. In particular we show a direct connection between the gauge symmetry
and the W-algebra for the rigid relativistic particle.Comment: 1+22 pages, 1 figure, LaTeX, v2; title changed, considerably expanded
version with new results, to appear in JHE
Spinor-Vector Duality in Heterotic String Orbifolds
The three generation heterotic-string models in the free fermionic
formulation are among the most realistic string vacua constructed to date,
which motivated their detailed investigation. The classification of free
fermion heterotic string vacua has revealed a duality under the exchange of
spinor and vector representations of the SO(10) GUT symmetry over the space of
models. We demonstrate the existence of the spinor-vector duality using
orbifold techniques, and elaborate on the relation of these vacua to free
fermionic models.Comment: 20 pages. v2 minor corrections. Version to appear on JHEP. v3
misprints correcte
Non-supersymmetric heterotic model building
We investigate orbifold and smooth Calabi-Yau compactifications of the
non-supersymmetric heterotic SO(16)xSO(16) string. We focus on such Calabi-Yau
backgrounds in order to recycle commonly employed techniques, like index
theorems and cohomology theory, to determine both the fermionic and bosonic 4D
spectra. We argue that the N=0 theory never leads to tachyons on smooth
Calabi-Yaus in the large volume approximation. As twisted tachyons may arise on
certain singular orbifolds, we conjecture that such tachyonic states are lifted
in the full blow-up. We perform model searches on selected orbifold geometries.
In particular, we construct an explicit example of a Standard Model-like theory
with three generations and a single Higgs field.Comment: 1+30 pages latex, 11 tables; v2: references and minor revisions
added, matches version published in JHE
Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells
Peer reviewedPublisher PD
Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.
Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention
Processamento auditivo central: implicações para o processo tradutório do Português para a Língua Brasileira de Sinais
Routes for breaching and protecting genetic privacy
We are entering the era of ubiquitous genetic information for research,
clinical care, and personal curiosity. Sharing these datasets is vital for
rapid progress in understanding the genetic basis of human diseases. However,
one growing concern is the ability to protect the genetic privacy of the data
originators. Here, we technically map threats to genetic privacy and discuss
potential mitigation strategies for privacy-preserving dissemination of genetic
data.Comment: Draft for comment
Ageing and dementia in low and middle income countries - Using research to engage with public and policy makers
Abstract While two thirds of the 24 million people with dementia worldwide live in low and middle income countries, very little research has been conducted to support policy making in these regions. Among the non-communicable diseases, dementia (in common with other chronic NCDs linked more to long-term disability than to mortality) has been relatively under-prioritized. International agreements, plans and policy guidelines have called for an end to ageist discrimination and a focus upon reducing disadvantage arising from poverty and the consequences of ill health. Social protection, access to good quality age-appropriate healthcare and addressing the problem of disability are all key issues. However, as yet, little progress has been made in addressing these concerns. In this review we outline the current international policy agenda for older individuals, and its specific relevance to those with dementia and other disabling non-communicable diseases. We consider the potential for epidemiological research to raise awareness, refine the policy agenda, and promote action, using the example of the dissemination strategy developed by the 10/66 Dementia Research Group
- …