257 research outputs found
Requirement of JNK1 for endothelial cell injury in atherogenesis
AbstractObjectiveThe c-Jun N-terminal kinase (JNK) family regulates fundamental physiological processes including apoptosis and metabolism. Although JNK2 is known to promote foam cell formation during atherosclerosis, the potential role of JNK1 is uncertain. We examined the potential influence of JNK1 and its negative regulator, MAP kinase phosphatase-1 (MKP-1), on endothelial cell (EC) injury and early lesion formation using hypercholesterolemic LDLRā/ā mice.Methods and resultsTo assess the function of JNK1 in early atherogenesis, we measured EC apoptosis and lesion formation in LDLRā/ā or LDLRā/ā/JNK1ā/ā mice exposed to a high fat diet for 6 weeks. En face staining using antibodies that recognise active, cleaved caspase-3 (apoptosis) or using Sudan IV (lipid deposition) revealed that genetic deletion of JNK1 reduced EC apoptosis and lesion formation in hypercholesterolemic mice. By contrast, although EC apoptosis was enhanced in LDLRā/ā/MKP-1ā/ā mice compared to LDLRā/ā mice, lesion formation was unaltered.ConclusionWe conclude that JNK1 is required for EC apoptosis and lipid deposition during early atherogenesis. Thus pharmacological inhibitors of JNK may reduce atherosclerosis by preventing EC injury as well as by influencing foam cell formation
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X-ray nanodiffraction on a single SiGe quantum dot inside a functioning field-effect transistor
For advanced electronic, optoelectronic, or mechanical nanoscale devices a detailed understanding of their structural properties and in particular the strain state within their active region is of utmost importance. We demonstrate that X-ray nanodiffraction represents an excellent tool to investigate the internal structure of such devices in a nondestructive way by using a focused synchotron X-ray beam with a diameter of 400 nm. We show results on the strain fields in and around a single SiGe island, which serves as stressor for the Si-channel in a fully functioning Si-metal-oxide semiconductor field-effect transistor
Signaling in Secret: Pay-for-Performance and the Incentive and Sorting Effects of Pay Secrecy
Key Findings: Pay secrecy adversely impacts individual task performance because it weakens the perception that an increase in performance will be accompanied by increase in pay; Pay secrecy is associated with a decrease in employee performance and retention in pay-for-performance systems, which measure performance using relative (i.e., peer-ranked) criteria rather than an absolute scale (see Figure 2 on page 5); High performing employees tend to be most sensitive to negative pay-for- performance perceptions; There are many signals embedded within HR policies and practices, which can influence employeesā perception of workplace uncertainty/inequity and impact their performance and turnover intentions; and When pay transparency is impractical, organizations may benefit from introducing partial pay openness to mitigate these effects on employee performance and retention
Formation of contact in massive close binaries
We present evolutionary calculations for 74 close binaries systems with
initial primary masses in the range 12...25 M_sun, and initial secondary masses
between 6 and 24 M_sun. The initial periods were chosen such that mass overflow
starts during the core hydrogen burning phase of the primary (Case A), or
shortly thereafter (Case B). We assume conservative evolution for contact-free
systems, i.e., no mass or angular momentum loss from those system except due to
stellar winds. We investigate the borderline between contact-free evolution and
contact, as a function of the initial system parameters. We also investigate
the effect of the treatment of convection, and found it relevant for contact
and supernova order in Case A systems, particularly for the highest considered
masses. For Case B systems we find contact for initial periods above
approximate 10 days and below. However, in that case (and for not too large
periods) contact occurs only after the mass ratio has been reversed, due to the
increased fraction of the donor's convective envelope. As most In all Cases we
find contact for mass ratios below approximate 0.65. We derive the observable
properties of our systems after the major mass transfer event, where the mass
gainer is a main sequence or supergiant O or early B type star, and the mass
loser is a helium star. We point out that the assumption of conservative
evolution for contact-free systems could be tested by finding helium star
companions to O stars.Comment: 19 pages, 14 figures, accepted by A&
āNot a country at allā: landscape and Wuthering Heights
This article explores the issue of womenās representational genealogies through an analysis of Andrea Arnoldās 2011 Wuthering Heights. Beginning with 1970s feminist arguments for a specifically female literary tradition, it argues that running through both these early attempts to construct an alternative female literary tradition and later work in feminist philosophy, cultural geography and film history is a concern with questions of āalternative landscapesā: of how to represent, and how to encounter, space differently. Adopting Mary Jacobusā notion of intertextual ācorrespondenceā between womenās texts, and taking Arnoldās film as its case study, it seeks to trace some of the intertextual movements ā the reframings, deframings and spatial reorderings ā that link Andrea Arnoldās film to Emily BrontĆ«ās original novel. Focusing on two elements of her treatment of landscape ā her use of āunframedā landscape and her focus on visceral textural detail ā it points to correspondences in other womenās writing, photography and film-making. It argues that these intensely tactile close-up sequences which puncture an apparently realist narrative constitute an insistent presence beneath, or within, the ordered framing which is our more usual mode of viewing landscape. As the novel Wuthering Heights is unmade in Arnoldās adaptation and its framings ruptured, it is through this disturbance of hierarchies of time, space and landscape that we can trace the correspondences of an alternative genealogy
Regionalized Pathology Correlates with Augmentation of mtDNA Copy Numbers in a Patient with Myoclonic Epilepsy with Ragged-Red Fibers (MERRF-Syndrome)
Human patients with myoclonic epilepsy with ragged-red fibers (MERRF) suffer from regionalized pathology caused by a mutation in the mitochondrial DNA (m.8344AāG). In MERRF-syndrome brain and skeletal muscles are predominantly affected, despite mtDNA being present in any tissue. In the past such tissue-specificity could not be explained by varying mtDNA mutation loads. In search for a region-specific pathology in human individuals we determined the mtDNA/nDNA ratios along with the mutation loads in 43 different post mortem tissue samples of a 16-year-old female MERRF patient and in four previously healthy victims of motor vehicle accidents. In brain and muscle we further determined the quantity of mitochondrial proteins (COX subunits II and IV), transcription factors (NRF1 and TFAM), and VDAC1 (Porin) as a marker for the mitochondrial mass. In the patient the mutation loads varied merely between 89ā100%. However, mtDNA copy numbers were increased 3ā7 fold in predominantly affected brain areas (e.g. hippocampus, cortex and putamen) and in skeletal muscle. Similar increases were absent in unaffected tissues (e.g. heart, lung, kidney, liver, and gastrointestinal organs). Such mtDNA copy number increase was not paralleled by an augmentation of mitochondrial mass in some investigated tissues, predominantly in the most affected tissue regions of the brain. We thus conclude that āfutileā stimulation of mtDNA replication per se or a secondary failure to increase the mitochondrial mass may contribute to the regionalized pathology seen in MERRF-syndrome
X-ray Nanodiffraction on a Single SiGe Quantum Dot inside a Functioning Field-Effect Transistor
For advanced electronic, optoelectronic, or mechanical nanoscale devices a detailed understanding of their structural properties and in particular the strain state within their active region is of utmost importance. We demonstrate that X-ray nanodiffraction represents an excellent tool to investigate the internal structure of such devices in a nondestructive way by using a focused synchotron X-ray beam with a diameter of 400 nm. We show results on the strain fields in and around a single SiGe island, which serves as stressor for the Si-channel in a fully functioning Si-metal-oxide semiconductor field-effect transistor
Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis
FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1ā5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2āCD44āSRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state
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