1,230 research outputs found
Control of epithelial morphogenesis by cell signaling and integrin molecules in the Drosophila foregut
Expression and function of the insulin receptor substrate proteins in cancer
The Insulin Receptor Substrate (IRS) proteins are cytoplasmic adaptor proteins that function as essential signaling intermediates downstream of activated cell surface receptors, many of which have been implicated in cancer. The IRS proteins do not contain any intrinsic kinase activity, but rather serve as scaffolds to organize signaling complexes and initiate intracellular signaling pathways. As common intermediates of multiple receptors that can influence tumor progression, the IRS proteins are positioned to play a pivotal role in regulating the response of tumor cells to many different microenvironmental stimuli. Limited studies on IRS expression in human tumors and studies on IRS function in human tumor cell lines and in mouse models have provided clues to the potential function of these adaptor proteins in human cancer. A general theme arises from these studies; IRS-1 and IRS-4 are most often associated with tumor growth and proliferation and IRS-2 is most often associated with tumor motility and invasion. In this review, we discuss the mechanisms by which IRS expression and function are regulated and how the IRS proteins contribute to tumor initiation and progression
Spin-wave spectrum of copper metaborate in the commensurate phase 10K<T<21K
We have investigated the spin-wave spectrum of copper metaborate,
CuBO, by means of inelastic neutron scattering in the commensurate
magnetic phase. We have found two branches of spin-wave excitations associated
with the two magnetic sublattices Cu(A) and Cu(B), respectively. In the
temperature regime , where only the Cu(A) magnetic moments
are ordered, the interaction between the two sublattices is found to be
negligible. With this approximation we have determined the `easy plane'
exchange parameters of the Cu(A) subsystem within standard spin-wave theory.Comment: 4 figure
Identical transacting factor requirement for knirps and knirps-related Gene expression in the anterior but not in the posterior region of the Drosophila embryo.
LOW SERUM SODIUM LEVELS AT HOSPITAL ADMISSION: OUTCOMES AMONG 2.3 MILLION HOSPITALIZED PATIENTS
Background: Hyponatremia is the most common electrolyte disorder among hospitalized patients. Controversies still exist over the relationship between hyponatremia and outcomes of hospitalized patients. Methods: To analyze the association of low serum sodium levels at hospital admission with in-hospital mortality and patient disposition and to compare the distribution of the risk of death associated with hyponatremia across the lifespan of hospitalized patients, we conducted an observational study of 2.3 million patients using data extracted from the Cerner Health Facts database between 2000 and 2014. Logistic regression models were used in the analyses. Results: 14.4% of hospitalized patients had serum sodium levels [Na]/L. In adjusted multinomial logistic regression analysis, we found that the risk of in-hospital mortality significantly increases for [Na] levels \u3c 135 or ≥143 to ≤145 mEq/L compared to the reference interval of 140 toConclusions:Hyponatremia is common among hospitalized patients and is independently associated with in-hospital mortality, discharge to hospice or to a nursing facility. The risk of death and other outcomes was more evident for [Na]/L. The mortality associated with low [Na] was significantly higher in younger versus older patients
Dislocation loops in overheated free-standing smectic films
Static and dynamic phenomena in overheated free-standing smectic-A films are
studied using a generalization of de Gennes' theory for a confined presmectic
liquid. A static application is to determine the profile of the film meniscus
and the meniscus contact angle, the results being compared with those of a
recent study employing de Gennes' original theory. The dynamical generalization
of the theory is based on on a time-dependent Ginzburg-Landau approach. This is
used to compare two modes for layer-thinning transitions in overheated films,
namely "uniform thinning" vs. nucleation of dislocation loops. Properties such
as the line tension and velocity of a moving dislocation line are evaluated
self-consistently by the theory.Comment: 16 pages, 8 figure
Copy Number Variation in Familial Parkinson Disease
Copy number variants (CNVs) are known to cause Mendelian forms of Parkinson disease (PD), most notably in SNCA and PARK2. PARK2 has a recessive mode of inheritance; however, recent evidence demonstrates that a single CNV in PARK2 (but not a single missense mutation) may increase risk for PD. We recently performed a genome-wide association study for PD that excluded individuals known to have either a LRRK2 mutation or two PARK2 mutations. Data from the Illumina370Duo arrays were re-clustered using only white individuals with high quality intensity data, and CNV calls were made using two algorithms, PennCNV and QuantiSNP. After quality assessment, the final sample included 816 cases and 856 controls. Results varied between the two CNV calling algorithms for many regions, including the PARK2 locus (genome-wide p = 0.04 for PennCNV and p = 0.13 for QuantiSNP). However, there was consistent evidence with both algorithms for two novel genes, USP32 and DOCK5 (empirical, genome-wide p-values<0.001). PARK2 CNVs tended to be larger, and all instances that were molecularly tested were validated. In contrast, the CNVs in both novel loci were smaller and failed to replicate using real-time PCR, MLPA, and gel electrophoresis. The DOCK5 variation is more akin to a VNTR than a typical CNV and the association is likely caused by artifact due to DNA source. DNA for all the cases was derived from whole blood, while the DNA for all controls was derived from lymphoblast cell lines. The USP32 locus contains many SNPs with low minor allele frequency leading to a loss of heterozygosity that may have been spuriously interpreted by the CNV calling algorithms as support for a deletion. Thus, only the CNVs within the PARK2 locus could be molecularly validated and associated with PD susceptibility
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Corticotropinoma as a Component of Carney Complex.
Known germline gene abnormalities cause one-fifth of the pituitary adenomas in children and adolescents, but, in contrast with other pituitary tumor types, the genetic causes of corticotropinomas are largely unknown. In this study, we report a case of Cushing disease (CD) due to a loss-of-function mutation in PRKAR1A, providing evidence for association of this gene with a corticotropinoma. A 15-year-old male presenting with hypercortisolemia was diagnosed with CD. Remission was achieved after surgical resection of a corticotropin (ACTH)-producing pituitary microadenoma, but recurrence 3 years later prompted reoperation and radiotherapy. Five years after the original diagnosis, the patient developed ACTH-independent Cushing syndrome, and a diagnosis of primary pigmented nodular adrenocortical disease was confirmed. A PRKAR1A mutation (c.671delG, p.G225Afs*16) was detected in a germline DNA sample from the patient, which displayed loss of heterozygosity in the corticotropinoma. No other germline or somatic mutations of interest were found. As corticotropinomas are not a known component of Carney complex (CNC), we performed loss of heterozygosity and messenger RNA stability studies in the patient's tissues, and analyzed the effect of Prkar1a silencing on AtT-20/D16v-F2 mouse corticotropinoma cells. No PRKAR1A defects were found among 97 other pediatric CD patients studied. Our clinical case and experimental data support a role for PRKAR1A in the pathogenesis of a corticotroph cell tumor. This is a molecularly confirmed report of a corticotropinoma presenting in association with CNC. We conclude that germline PRKAR1A mutations are a novel, albeit apparently infrequent, cause of CD
Genome-wide association of familial late-onset alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10-81), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10-8). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies. © 2011 Wijsman et al
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