198 research outputs found
Involvement of Hepatic Innate Immunity in Alcoholic Liver Disease
Excessive alcohol consumption is one of the critical causative factors leading to alcoholic liver disease (ALD). ALD is characterized by a wide spectrum of liver damage, ranging from simple uncomplicated liver steatosis (fatty liver) to steatohepatitis and liver fibrosis/cirrhosis. It has been believed that the obvious underlying cause for ALD is due to hepatocyte death induced by alcohol itself. However, recent sparkling studies have shown that diverse immune responses contribute to ALD because liver is enriched with numerous immune cells. Especially, a line of evidence has suggested that innate immune cells such as Kupffer cells and natural killer (NK)/NKT cells are significantly involved in the pathogenesis of ALD via production of pro-inflammatory cytokines and other mediators. Indeed, more interestingly, hepatic stellate cells (HSCs), known as a major cell inducing liver steatosis and fibrosis, can be killed by liver NK cells, which could be suppressed by chronic alcohol consumption. In this review, with the view of liver as predominant innate immune organ, we describe the pathogenesis of ALD in which what roles of innate immune cells are and how they are interacting with HSCs
The interaction of PP1 with BRCA1 and analysis of their expression in breast tumors
<p>Abstract</p> <p>Background</p> <p>The breast cancer susceptibility gene, <it>BRCA1</it>, is implicated in multiple cellular processes including DNA repair, the transactivation of genes, and the ubiquitination of proteins; however its precise functions remain to be fully understood. Identification and characterization of BRCA1 protein interactions may help to further elucidate the function and regulation of BRCA1. Additionally, detection of changes in the expression levels of <it>BRCA1 </it>and its interacting proteins in primary human breast tumors may further illuminate their role in the development of breast cancer.</p> <p>Methods</p> <p>We performed a yeast two-hybrid study to identify proteins that interact with exon11 of BRCA1 and identified Protein Phosphatase 1β (PP1β), an isoform of the serine threonine phosphatase, PP1. GST-pull down and co-immunoprecipitation assays were performed to further characterize this interaction. Additionally, Real-Time PCR was utilized to determine the expression of <it>BRCA1</it>, <it>PP1</it>α, β and γ in primary human breast tumors and normal breast tissue to identify alterations in the expression of these genes in breast cancer.</p> <p>Results</p> <p>PP1 and BRCA1 co-immunoprecipitate and the region within BRCA1 as well as the specific PP1 interacting domain mediating this interaction were identified. Following mRNA expression analysis, we identified low levels of <it>BRCA1 </it>and variable levels of <it>PP1</it>α and β in primary sporadic human breast tumors. Furthermore, BRCA1, <it>PP1</it>β and PP1γ were significantly higher in normal tissue specimens (BRCA1 p = 0.01, <it>PP1</it>β: p = 0.03, <it>PP1</it>γ, p = 1.9 × 10<sup>-6</sup>) compared to sporadic breast tumor samples. Interestingly, we also identified that ER negative tumors are associated with low levels of <it>PP1</it>α expression.</p> <p>Conclusion</p> <p>The identification and characterization of the interaction of BRCA1 with PP1 and detection of changes in the expression of <it>PP1 </it>and genes encoding other BRCA1 associated proteins identifies important genetic pathways that may be significant to breast tumorigenesis. Alterations in the expression of genes, particularly phosphatases that operate in association with BRCA1, could negatively affect the function of BRCA1 or BRCA1 associated proteins, contributing to the development of breast cancer.</p
Reprogramming of Embryonic Human Fibroblasts into Fetal Hematopoietic Progenitors by Fusion with Human Fetal Liver CD34+ Cells
Experiments with somatic cell nuclear transfer, inter-cellular hybrid formation_ENREF_3, and ectopic expression of transcription factors have clearly demonstrated that cell fate can be dramatically altered by changing the epigenetic state of cell nuclei. Here we demonstrate, using chemical fusion, direct reprogramming of the genome of human embryonic fibroblasts (HEF) into the state of human fetal liver hFL CD34+ (hFL) hematopoietic progenitors capable of proliferating and differentiating into multiple hematopoietic lineages. We show that hybrid cells retain their ploidy and can differentiate into several hematopoietic lineages. Hybrid cells follow transcription program of differentiating hFL cells as shown by genome-wide transcription profiling. Using whole-genome single nucleotide polymorphism (SNP) profiling of both donor genomes we demonstrate reprogramming of HEF genome into the state of hFL hematopoietic progenitors. Our results prove that it is possible to convert the fetal somatic cell genome into the state of fetal hematopoietic progenitors by fusion. This suggests a possibility of direct reprogramming of human somatic cells into tissue specific progenitors/stem cells without going all the way back to the embryonic state. Direct reprogramming of terminally differentiated cells into the tissue specific progenitors will likely prove useful for the development of novel cell therapies
Superfluid transport of information in turning flocks of starlings
Collective decision-making in biological systems requires all individuals in
the group to go through a behavioural change of state. During this transition,
the efficiency of information transport is a key factor to prevent cohesion
loss and preserve robustness. The precise mechanism by which natural groups
achieve such efficiency, though, is currently not fully understood. Here, we
present an experimental study of starling flocks performing collective turns in
the field. We find that the information to change direction propagates across
the flock linearly in time with negligible attenuation, hence keeping group
decoherence to a minimum. This result contrasts with current theories of
collective motion, which predict a slower and dissipative transport of
directional information. We propose a novel theory whose cornerstone is the
existence of a conserved spin current generated by the gauge symmetry of the
system. The theory turns out to be mathematically identical to that of
superfluid transport in liquid helium and it explains the dissipationless
propagating mode observed in turning flocks. Superfluidity also provides a
quantitative expression for the speed of propagation of the information,
according to which transport must be swifter the stronger the group's
orientational order. This prediction is verified by the data. We argue that the
link between strong order and efficient decision-making required by
superfluidity may be the adaptive drive for the high degree of behavioural
polarization observed in many living groups. The mathematical equivalence
between superfluid liquids and turning flocks is a compelling demonstration of
the far-reaching consequences of symmetry and conservation laws across
different natural systems
Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?
Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women
Background: Most or mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both and are rare, and the consequences of transheterozygosity are poorly understood.
Methods: From 32,295 female mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at (SH1) or (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.
Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 ( = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 ( = 0.231), but was on average 4.5 years younger in TH than in SH2 ( < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive ( = 0.010) or progesterone receptor (PR) positive ( = 0.013) than in SH1, but less likely to be ER positive ( < 0.001) or PR positive ( = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for or in either BC or OC.
Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.ACA and the CIMBA data management are funded by Cancer Research UK (C12292/A20861 and C12292/A11174). TRR was supported by R01-CA083855, R01-CA102776, and P50-CA083638. KLN, TMF, and SMD are supported by the Basser Research Center at the University of Pennsylvania. BP is supported by R01-CA112520. Cancer Research UK provided financial support for this work. ACA is a Senior Cancer Research UK Cancer Research Fellow. DFE is Cancer Research UK Principal Research Fellow. Tumor analysis was funded by STOP CANCER (to SJR). Study-specific acknowledgements are as provided in the manuscript
Physical activity restriction in age-related eye disease: a cross-sectional study exploring fear of falling as a potential mediator
A single active catalytic site is sufficient to promote transport in P-glycoprotein
P-glycoprotein (Pgp) is an ABC transporter responsible for
the ATP-dependent efflux of chemotherapeutic compounds from
multidrug resistant cancer cells. Better understanding of the
molecular mechanism of Pgp-mediated transport could promote
rational drug design to circumvent multidrug resistance. By
measuring drug binding affinity and reactivity to a
conformation-sensitive antibody we show here that nucleotide
binding drives Pgp from a high to a low substrate-affinity
state and this switch coincides with the flip from the
inward- to the outward-facing conformation. Furthermore, the
outward-facing conformation survives ATP hydrolysis: the
post-hydrolytic complex is stabilized by vanadate, and the
slow recovery from this state requires two functional
catalytic sites. The catalytically inactive double Walker A
mutant is stabilized in a high substrate affinity inward-open
conformation, but mutants with one intact catalytic center
preserve their ability to hydrolyze ATP and to promote drug
transport, suggesting that the two catalytic sites are
randomly recruited for ATP hydrolysis
Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.
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