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ObjectiveIndividuals with temporal lobe epilepsy (TLE) often experience diminished quality of life (QoL). Although comorbid depression is one of the most recognized predictors of poor QoL in TLE, impairments in verbal memory (VM) and executive functioning (EF), have also been identified as risk factors, independent of other biological and psychosocial factors. In this study, we examine the contribution of depression, VM, and EF to QoL in 52 well-characterized medically-refractory TLE patients.MethodsQuality of life was assessed with the Quality of Life in Epilepsy (QOLIE-31) questionnaire and depression symptomatology was evaluated with the Beck Depression Inventory-II (BDI-II). Tests of VM included the California Verbal Learning Test-Second Edition and the Wechsler Memory Scale-Third Edition, Logical Memory and Verbal Paired Associates subtests. Tests of EF included the D-KEFS Category Switching and Color Word Interference Tests, and the Trail Making Test. Using these measures, a principal component (PC) was derived for VM and for EF. Hierarchical multiple linear regression analysis was used to evaluate the unique contributions of BDI-II Score, VM PC, and EF PC to the QOLIE-31 Total Score, while controlling for important clinical and demographic variables. Post-hoc analyses were also performed to examine the contribution of each variable to specific QOLIE subscales.ResultsOf the clinical variables, only number of antiepileptic drugs contributed to QOLIE scores. As expected, severity of depressive symptoms was the most significant predictor of QOLIE Total Score, explaining 43.4% of the variance in total QoL. The VM PC did not contribute to the QOLIE Total Score. Rather, our EF PC emerged as an important predictor of QoL, explaining an additional 5% of the variance, after controlling for clinical variables, depression severity, and VM performance.SignificanceThese findings suggest that a combination of clinical, affective, and cognitive factors influence QoL in patients with TLE. Designing interventions with careful attention to depression and EF may be needed to optimize QoL in patients with refractory TLE and potentially other epilepsy syndromes.

BackgroundMolecular markers of WHO grade II/III glioma are known to have important prognostic and predictive implications and may be associated with unique imaging phenotypes. The purpose of this study is to determine whether three clinically relevant molecular markers identified in gliomas-IDH, 1p/19q, and MGMT status-show distinct quantitative MRI characteristics on FLAIR imaging.MethodsSixty-one patients with grade II/III gliomas who had molecular data and MRI available prior to radiation were included. Quantitative MRI features were extracted that measured tissue heterogeneity (homogeneity and pixel correlation) and FLAIR border distinctiveness (edge contrast; EC). T-tests were conducted to determine whether patients with different genotypes differ across the features. Logistic regression with LASSO regularization was used to determine the optimal combination of MRI and clinical features for predicting molecular subtypes.ResultsPatients with IDH wildtype tumors showed greater signal heterogeneity (p = 0.001) and lower EC (p = 0.008) within the FLAIR region compared to IDH mutant tumors. Among patients with IDH mutant tumors, 1p/19q co-deleted tumors had greater signal heterogeneity (p = 0.002) and lower EC (p = 0.005) compared to 1p/19q intact tumors. MGMT methylated tumors showed lower EC (p = 0.03) compared to the unmethylated group. The combination of FLAIR border distinctness, heterogeneity, and pixel correlation optimally classified tumors by IDH status.ConclusionQuantitative imaging characteristics of FLAIR heterogeneity and border pattern in grade II/III gliomas may provide unique information for determining molecular status at time of initial diagnostic imaging, which may then guide subsequent surgical and medical management.

We investigated the role of Bruton's tyrosine kinase (Btk) in FcepsilonRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcepsilonRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcepsilonRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcepsilonRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcepsilonRI signal transduction in mast cells.

Author(s): The ENCODE Project Consortium; Analysis Coordination; Ewan Birney (corresponding author) [1]; John A. Stamatoyannopoulos (corresponding author) [2]; Anindya Dutta (corresponding author) [3]; Roderic Guigó (corresponding author) [4, 5]; Thomas [...]

The regions of human chromosome 22 bound by Single Transducers and Activators of Transcription (STAT)1 and STAT2 in interferon-treated cells are identified using chromatin immunoprecipitation and DNA microarray analysis. Results demonstrate that the DNA-binding behavior of STAT1 homodimers is not conserved between the different interferon treatment conditions.

We have mapped the chromosomal binding site distribution of a transcription factor in human cells. The NF-[kappa]B family of transcription factors plays an essential role in regulating the induction of genes involved in several physiological processes, including apoptosis, immunity, and inflammation. The binding sites of the NF-[kappa]B family member p65 were determined by using chromatin immunoprecipitation and a genomic microarray of human chromosome 22 DNA. Sites of binding were observed along the entire chromosome in both coding and noncoding regions, with an enrichment at the 5' end of genes. Strikingly, a significant proportion of binding was seen in intronic regions, demonstrating that transcription factor binding is not restricted to promoter regions. NF-[kappa]B binding was also found at genes whose expression was regulated by tumor necrosis factor [alpha], a known inducer of NF-[kappa]B-dependent gene expression, as well as adjacent to genes whose expression is not affected by tumor necrosis factor [alpha]. Many of these latter genes are either known to be activated by NF-[kappa]B under other conditions or are consistent with NF-[kappa]B's role in the immune and apoptotic responses. Our results suggest that binding is not restricted to promoter regions and that NF-KB binding occurs at a significant number of genes whose expression is not altered, thereby suggesting that binding alone is not sufficient for gene activation.

Mast cells derived from Bruton's tyrosine kinase (Btk)-defective xid or btk null mice showed greater expansion in culture containing interleukin-3 (IL-3) than those from wild-type (wt) mice. Although the proliferative response to IL-3 was not significantly different between the wt and xid mast cells, xid and btk null mast cells died by apoptosis more slowly than their wt counterparts upon IL-3 deprivation. Consistent with these findings, the apoptosis-linked c-Jun N-terminal kinase/stress-activated protein kinase (JNK) activity was compromised in these btk-mutated cells upon Fc[Epsilon]RI crosslinking or upon stimulation with IL-3 or with stem cell factor. p38 activity was less severely, but significantly, affected by btk mutation, whereas extracellular signal-regulated kinases were not affected by the same mutation. Btk-mediated regulation of apoptosis and JNK activity was confirmed by reconstitution of btk null mutant mast cells with the wt btk cDNA. Furthermore, growth factor withdrawal induced the activation and sustained activity of JNK in wt mast cells, while JNK activity was consistently lower in btk-mutated mast cells. These results support the notion that Btk regulates apoptosis through the JNK activation.

Research has been conducted on human cromosome 22. The authors report the construction of DNA microarray which represents the unique sequences of this chromosome, and the use of the microarray for measuring global-transcriptional activity in placental poly(A) (super)+ RNA.

Two protein-tyrosine kinases, Bruton's tyrosine kinase (Btk) and Syk, and members of the protein kinase C (PKC) subfamily of serine/threonine kinases play crucial roles in signal transduction through antigen receptors in B lymphocytes and high-affinity IgE receptors (Fc[Epsilon]RI) in mast cells. The present study provides genetic, biochemical, and pharmacological evidence that, on Fc[Epsilon]RI stimulation, Syk regulates Btk, and Btk selectively regulates the membrane translocation and enzymatic activity of PKC[Beta]I among the conventional PKC isoforms ([Alpha], [Beta]I, and [Beta]II) expressed in mast cells. Syk/Btk-mediated PKC[Beta]I regulation is involved in transcriptional activation of the IL-2 and tumor necrosis factor [Alpha] genes through the JNK pathway induced by Fc[Epsilon]RI stimulation. Accordingly, Fc[Epsilon]RI-induced production of these cytokines is inhibited by specific inhibitors of Btk and Syk, as well as broad-specificity inhibitors of PKC and a selective inhibitor of PKC[Beta]. Specific regulation of PKC[Beta]I by Btk is consistent with the selective association of Btk with PKC[Beta]I. Components of this signaling pathway may represent all attractive set of potential targets of pharmaceutical interference for the treatment of allergic and other immunologic diseases.

In marked contrast to the single, narrow 29Si MAS NMR resonance for pure forsterite (Mg2SiO4), the spectra for synthetic forsterite containing 0.05 to 5% of the Mg2+ replaced with Ni2+, Co2+, or Fe2+ display between 4 and 26 additional, small, paramagnetically shifted peaks that are caused by interactions of the unpaired electron spins on the transition metal cations and the nuclear spins. Analyses of these relative peak areas, their numbers, and comparison of their positions to those in spectra of synthetic monticellites (CaMgSiO4) containing similar levels of transition metals, allows at least partial assignment to the effects of cations in either the M1 octahedral site only or to both M1 and M2 sites. More detailed analyses indicate that in forsterite, Ni2+ occupies only M1, Fe2+ occupies M1 and M2 roughly equally, and Co2+ occupies both M1 and M2 in an approximately 3:1 ratio. These findings for low concentrations agree with expectations from previous studies by other methods (e.g., XRD) of olivines with much higher transition metal cation contents. However, even low concentrations of Mn2+ (e.g., 0.1%), as well as higher Fe2+ contents (e.g., in natural San Carlos olivine) can broaden NMR peaks sufficiently to greatly reduce this kind of information content in spectra. [ABSTRACT FROM AUTHOR]

We have mapped the chromosomal binding site distribution of a transcription factor in human cells. The NF-KB family of transcription factors plays an essential role in regulating the induction of genes involved in several physiological processes, including apoptosis, immunity, and inflammation. The binding sites of the NF-&key;B family member p65 were determined by using chromatin immunoprecipiration and a genomic microarray of human chromosome 22 DNA. Sites of binding were observed along the entire chromosome in both ceding and noncoding regions, with an enrichment at the 5' end of genes. Strikingly, a significant proportion of binding was seen in intronic regions, demonstrating that transcription factor binding is not restricted to promoter regions. NF-&key;B binding was also found at genes whose expression was regulated by tumor necrosis factor a, a known inducer of NF-&key;B-dependent gene expression, as well as adjacent to genes whose expression is not affected by tumor necrosis factor α. Many of these latter genes are either known to be activated by NF-&key;B under other conditions or are consistent with NF-&key;B's role in the immune and apoptotic responses. Our results suggest that binding is not restricted to promoter regions and that NF-&key;B binding occurs at a significant number of genes whose expression is not altered, thereby suggesting that binding alone is not sufficient for gene activation. [ABSTRACT FROM AUTHOR]

This article is intended to posit the hypothesis that defense spending has had and continues to have a very heavy impact, with widely varying outcomes, on our domestic economic position. The importance that defense spending has had since World War II is shown in the Economic Report of the President. Under the national defense category the total estimated amount this nation has spent from 1946 to 1972 has been one trillion, two hundred and sixty-four billion uncorrected dollars. It should be pointed out, however, that this expenditure category corresponds closely to the national defense classification in the "Budget of the United States Government for the Fiscal Year Ending June 30, 1973." It does not include veterans expenditures and interest payments on the war-related debt which rightfully should be considered as defense-related expenditures. Total estimated veterans expenditures from appropriated funds from 1946 to 1972 were approximately $169 billion, while total estimated interest payments on the war-related debt from 1946 to 1972 were approximately $254 billion. This comprises the grand total of $423 billion which, when added to the national defense category, brings total estimated defense-related expenditures from 1946 to 1972 to one trillion, six hundred and eighty-seven billion uncorrected dollars. This 13-place number does not include: (1) inflationary price rises due to war spending and the cost to this nation in terms of reduced GNP; (2) the opportunity costs incurred by spending the nation's resources on an essentially destructive rather than constructive enterprise; (3) defense-related expenditures of the CIA, since these are secret and not published in the U.S. budget totals, and (4) international balance of trade and payment dislocations.

Age-related macular degeneration (AMD), the most common cause of irreversible vision loss in individuals aged older than 50 years, is classified as either wet (neovascular) or dry (nonneovascular). Inherited variation in the complement factor H gene is a major risk factor for drusen in dry AMD. Here we report that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD. A whole-genome association mapping strategy was applied to a Chinese population, yielding a P value of <10-11. Individuals with the risk-associated genotype were estimated to have a likelihood of developing wet AMD 10 times that of individuals with the wild-type genotype. [ABSTRACT FROM AUTHOR]

Glypican-3 (GPC3) is a cell-surface glycoprotein that is frequently overexpressed in hepatocellular carcinoma (HCC). GPC3 undergoes extensive posttranslational modification (PTM) including cleavage and glycosylation. This review focuses on the structure and function of GPC3 in liver cancer, highlighting the PTM of the tertiary and quaternary structures of GPC3 as a potential oncogenic regulatory mechanism. We propose that the function of GPC3 in normal development can vary with extensive PTM and that dysregulation of these processes leads to disease. Defining the regulatory impact of these modifications can provide a deeper understanding of the role of GPC3 in oncogenesis, epithelial-mesenchymal transition, and drug development. Through review of current literature, this article provides a unique perspective on the role of GPC3 in liver cancer, focusing on potential regulatory mechanisms of PTM on GPC3 function at the molecular, cellular, and disease level., (©2023 The Authors; Published by the American Association for Cancer Research.)