514 research outputs found
Biomarkers and in vitro strategies for nephrotoxicity and renal disease assessment
Acute kidney injury (AKI) is a global public health concern, impacting nearly 13.3 million patients and resulting in three million deaths per year. Chronic kidney disease has increased by 135% since 1990, representing the pathology with the fastest growth rate worldwide. The annual costs of dialysis and kidney transplants range between US100,000 per patient. Despite its great impact, kidney disease has remained mostly asymptomatic for many years. AKI continues to be a major, unmet medical condition for which there are no pharmacological treatments available, while animal models are limited to provide direction for therapeutic translation into humans. Currently, serum creatinine is the standard biomarker to identify nephrotoxicity; however, it is a late stage biomarker. Hence, there is a pressing need to study in vitro biomarkers for the assessment of nephrotoxicity in order to develop new and safer drugs. Understanding of the mechanisms by which molecules produce nephrotoxicity is vital in order to both prevent adversity and treat kidney injury. In this review, we address new technologies and models that may be used to identify earlier biomarkers and pathways involved in nephrotoxicity, such as cell culture, omics, bioinformatics platform, CRISPR/Cas9 genome-editing, in silico, organoids and 3D bioprinting, considering AOP
Twisted mass chiral perturbation theory for 2+1+1 quark flavours
We present results for the masses of pseudoscalar mesons in twisted mass
lattice QCD with a degenerate doublet of u and d quarks and a non-degenerate
doublet of s and c quarks in the framework of next-to-leading order chiral
perturbation theory, including lattice effects up to O(a^2). The masses depend
on the two twist angles for the light and heavy sectors. For maximal twist in
both sectors, O(a)-improvement is explicitly exhibited. The mixing of
flavour-neutral mesons is also discussed, and results in the literature for the
case of degenerate s and c quarks are corrected.Comment: LaTeX2e, 12 pages, corrected typo
Direct entropy determination and application to artificial spin ice
From thermodynamic origins, the concept of entropy has expanded to a range of
statistical measures of uncertainty, which may still be thermodynamically
significant. However, laboratory measurements of entropy continue to rely on
direct measurements of heat. New technologies that can map out myriads of
microscopic degrees of freedom suggest direct determination of configurational
entropy by counting in systems where it is thermodynamically inaccessible, such
as granular and colloidal materials, proteins and lithographically fabricated
nanometre-scale arrays. Here, we demonstrate a conditional-probability
technique to calculate entropy densities of translation-invariant states on
lattices using limited configuration data on small clusters, and apply it to
arrays of interacting nanometre-scale magnetic islands (artificial spin ice).
Models for statistically disordered systems can be assessed by applying the
method to relative entropy densities. For artificial spin ice, this analysis
shows that nearest-neighbour correlations drive longer-range ones.Comment: 10 page
Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis
Common fragile sites (cfs) are specific regions in the human genome that are
particularly prone to genomic instability under conditions of replicative
stress. Several investigations support the view that common fragile sites play
a role in carcinogenesis. We discuss a genome-wide approach based on graph
theory and Gene Ontology vocabulary for the functional characterization of
common fragile sites and for the identification of genes that contribute to
tumour cell biology. CFS were assembled in a network based on a simple measure
of correlation among common fragile site patterns of expression. By applying
robust measurements to capture in quantitative terms the non triviality of the
network, we identified several topological features clearly indicating
departure from the Erdos-Renyi random graph model. The most important outcome
was the presence of an unexpected large connected component far below the
percolation threshold. Most of the best characterized common fragile sites
belonged to this connected component. By filtering this connected component
with Gene Ontology, statistically significant shared functional features were
detected. Common fragile sites were found to be enriched for genes associated
to the immune response and to mechanisms involved in tumour progression such as
extracellular space remodeling and angiogenesis. Our results support the
hypothesis that fragile sites serve a function; we propose that fragility is
linked to a coordinated regulation of fragile genes expression.Comment: 18 pages, accepted for publication in BMC Bioinformatic
Singular values of the Dirac operator in dense QCD-like theories
We study the singular values of the Dirac operator in dense QCD-like theories
at zero temperature. The Dirac singular values are real and nonnegative at any
nonzero quark density. The scale of their spectrum is set by the diquark
condensate, in contrast to the complex Dirac eigenvalues whose scale is set by
the chiral condensate at low density and by the BCS gap at high density. We
identify three different low-energy effective theories with diquark sources
applicable at low, intermediate, and high density, together with their
overlapping domains of validity. We derive a number of exact formulas for the
Dirac singular values, including Banks-Casher-type relations for the diquark
condensate, Smilga-Stern-type relations for the slope of the singular value
density, and Leutwyler-Smilga-type sum rules for the inverse singular values.
We construct random matrix theories and determine the form of the microscopic
spectral correlation functions of the singular values for all nonzero quark
densities. We also derive a rigorous index theorem for non-Hermitian Dirac
operators. Our results can in principle be tested in lattice simulations.Comment: 3 references added, version published in JHE
Nodular Worm Infection in Wild Chimpanzees in Western Uganda: A Risk for Human Health?
This study focused on Oeosophagostomum sp., and more especially on O. bifurcum, as a parasite that can be lethal to humans and is widespread among humans and monkeys in endemic regions, but has not yet been documented in apes. Its epidemiology and the role played by non-human primates in its transmission are still poorly understood. O. stephanostomum was the only species diagnosed so far in chimpanzees. Until recently, O. bifurcum was assumed to have a high zoonotic potential, but recent findings tend to demonstrate that O. bifurcum of non-human primates and humans might be genetically distinct. As the closest relative to human beings, and a species living in spatial proximity to humans in the field site studied, Pan troglodytes is thus an interesting host to investigate. Recently, a role for chimpanzees in the emergence of HIV and malaria in humans has been documented. In the framework of our long-term health monitoring of wild chimpanzees from Kibale National Park in Western Uganda, we analysed 311 samples of faeces. Coproscopy revealed that high-ranking males are more infected than other individuals. These chimpanzees are also the more frequent crop-raiders. Results from PCR assays conducted on larvae and dried faeces also revealed that O. stephanostomum as well as O. bifurcum are infecting chimpanzees, both species co-existing in the same individuals. Because contacts between humans and great apes are increasing with ecotourism and forest fragmentation in areas of high population density, this paper emphasizes that the presence of potential zoonotic parasites should be viewed as a major concern for public health. Investigations of the parasite status of people living around the park or working inside as well as sympatric non-human primates should be planned, and further research might reveal this as a promising aspect of efforts to reinforce measures against crop-raiding
The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state
We introduce and analyze a minimal model of epigenetic silencing in budding
yeast, built upon known biomolecular interactions in the system. Doing so, we
identify the epigenetic marks essential for the bistability of epigenetic
states. The model explicitly incorporates two key chromatin marks, namely H4K16
acetylation and H3K79 methylation, and explores whether the presence of
multiple marks lead to a qualitatively different systems behavior. We find that
having both modifications is important for the robustness of epigenetic
silencing. Besides the silenced and transcriptionally active fate of chromatin,
our model leads to a novel state with bivalent (i.e., both active and
silencing) marks under certain perturbations (knock-out mutations, inhibition
or enhancement of enzymatic activity). The bivalent state appears under several
perturbations and is shown to result in patchy silencing. We also show that the
titration effect, owing to a limited supply of silencing proteins, can result
in counter-intuitive responses. The design principles of the silencing system
is systematically investigated and disparate experimental observations are
assessed within a single theoretical framework. Specifically, we discuss the
behavior of Sir protein recruitment, spreading and stability of silenced
regions in commonly-studied mutants (e.g., sas2, dot1) illuminating the
controversial role of Dot1 in the systems biology of yeast silencing.Comment: Supplementary Material, 14 page
Acute febrile illness is associated with Rickettsia spp infection in dogs
BACKGROUND: Rickettsia conorii is transmitted by Rhipicephalus sanguineus ticks and causes Mediterranean Spotted Fever (MSF) in humans. Although dogs are considered the natural host of the vector, the clinical and epidemiological significance of R. conorii infection in dogs remains unclear. The aim of this prospective study was to investigate whether Rickettsia infection causes febrile illness in dogs living in areas endemic for human MSF. METHODS: Dogs from southern Italy with acute fever (n = 99) were compared with case–control dogs with normal body temperatures (n = 72). Serology and real-time PCR were performed for Rickettsia spp., Ehrlichia canis, Anaplasma phagocytophilum/A. platys and Leishmania infantum. Conventional PCR was performed for Babesia spp. and Hepatozoon spp. Acute and convalescent antibodies to R. conorii, E. canis and A. phagocytophilum were determined. RESULTS: The seroprevalence rates at first visit for R. conorii, E. canis, A. phagocytophilum and L. infantum were 44.8%, 48.5%, 37.8% and 17.6%, respectively. The seroconversion rates for R. conorii, E. canis and A. phagocytophilum were 20.7%, 14.3% and 8.8%, respectively. The molecular positive rates at first visit for Rickettsia spp., E. canis, A. phagocytophilum, A. platys, L. infantum, Babesia spp. and Hepatozoon spp. were 1.8%, 4.1%, 0%, 2.3%, 11.1%, 2.3% and 0.6%, respectively. Positive PCR for E. canis (7%), Rickettsia spp. (3%), Babesia spp. (4.0%) and Hepatozoon spp. (1.0%) were found only in febrile dogs. The DNA sequences obtained from Rickettsia and Babesia PCRs positive samples were 100% identical to the R. conorii and Babesia vogeli sequences in GenBank®, respectively. Febrile illness was statistically associated with acute and convalescent positive R. conorii antibodies, seroconversion to R. conorii, E. canis positive PCR, and positivity to any tick pathogen PCRs. Fourteen febrile dogs (31.8%) were diagnosed with Rickettsia spp. infection based on seroconversion and/or PCR while only six afebrile dogs (12.5%) seroconverted (P = 0.0248). The most common clinical findings of dogs with Rickettsia infection diagnosed by seroconversion and/or PCR were fever, myalgia, lameness, elevation of C-reactive protein, thrombocytopenia and hypoalbuminemia. CONCLUSIONS: This study demonstrates acute febrile illness associated with Rickettsia infection in dogs living in endemic areas of human MSF based on seroconversion alone or in combination with PCR
Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease
A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis
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