Structural and metabolic changes in language areas linked to formal thought disorder

BACKGROUND: The role of the language network in the pathophysiology of formal thought disorder has yet to be elucidated. AIMS: To investigate whether specific grey-matter deficits in schizophrenic formal thought disorder correlate with resting perfusion in the left-sided language network. METHOD: We investigated 13 right-handed patients with schizophrenia and formal thought disorder of varying severity and 13 matched healthy controls, using voxel-based morphometry and magnetic resonance imaging perfusion measurement (arterial spin labelling). RESULTS: We found positive correlations between perfusion and the severity of formal thought disorder in the left frontal and left temporoparietal language areas. We also observed bilateral deficits in grey-matter volume, positively correlated with the severity of thought disorder in temporoparietal areas and other brain regions. The results of the voxel-based morphometry and the arterial spin labelling measurements overlapped in the left posterior superior temporal gyrus and left angular gyrus. CONCLUSIONS: Specific grey-matter deficits may be a risk factor for state-related dysfunctions of the left-sided language system, leading to local hyperperfusion and formal thought disorder.

Democracy a Casualty of Voter-Suppression Politics

A Montana Public Radio Commentary by Evan Barrett. Published newspaper columns written by Evan Barrett on this topic, which vary somewhat in content from this commentary, appeared in the following publications: Missoulian, August 8, 2014 Independent Record, August 13, 2014 Billings Gazette, August 18, 2014 Montana Standard, August 19, 2014

Serum metabolomics reveals irreversible inhibition of fatty acid beta-oxidation through the suppression of PPARalpha activation as a contributing mechanism of acetaminophen-induced hepatotoxicity

Metabolic bioactivation, glutathione depletion, and covalent binding are the early hallmark events after acetaminophen (APAP) overdose. However, the subsequent metabolic consequences contributing to APAP-induced hepatic necrosis and apoptosis have not been fully elucidated. In this study, serum metabolomes of control and APAP-treated wild-type and Cyp2e1-null mice were examined by liquid chromatography-mass spectrometry (LC-MS) and multivariate data analysis. A dose-response study showed that the accumulation of long-chain acylcarnitines in serum contributes to the separation of wild-type mice undergoing APAP-induced hepatotoxicity from other mouse groups in a multivariate model. This observation, in conjunction with the increase of triglycerides and free fatty acids in the serum of APAP-treated wild-type mice, suggested that APAP treatment can disrupt fatty acid beta-oxidation. A time-course study further indicated that both wild-type and Cyp2e1-null mice had their serum acylcarnitine levels markedly elevated within the early hours of APAP treatment. While remaining high in wild-type mice, serum acylcarnitine levels gradually returned to normal in Cyp2e1-null mice at the end of the 24 h treatment. Distinct from serum aminotransferase activity and hepatic glutathione levels, the pattern of serum acylcarnitine accumulation suggested that acylcarnitines can function as complementary biomarkers for monitoring the APAP-induced hepatotoxicity. An essential role for peroxisome proliferator-activated receptor alpha (PPARalpha) in the regulation of serum acylcarnitine levels was established by comparing the metabolomic responses of wild-type and Ppara-null mice to a fasting challenge. The upregulation of PPARalpha activity following APAP treatment was transient in wild-type mice but was much more prolonged in Cyp2e1-null mice. Overall, serum metabolomics of APAP-induced hepatotoxicity revealed that the CYP2E1-mediated metabolic activation and oxidative stress following APAP treatment can cause irreversible inhibition of fatty acid oxidation, potentially through suppression of PPARalpha-regulated pathways.

BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma

The BCL6 proto-oncogene encodes a transcriptional repressor that is required for germinal center (GC) formation and whose deregulation by genomic lesions is implicated in the pathogenesis of GC-derived diffuse large B cell lymphoma (DLBCL) and, less frequently, follicular lymphoma (FL). The biological function of BCL6 is only partially understood because no more than a few genes have been functionally characterized as direct targets of BCL6 transrepression activity. Here we report that the anti-apoptotic proto-oncogene BCL2 is a direct target of BCL6 in GC B cells. BCL6 binds to the BCL2 promoter region by interacting with the transcriptional activator Miz1 and suppresses Miz1-induced activation of BCL2 expression. BCL6-mediated suppression of BCL2 is lost in FL and DLBCL, where the 2 proteins are pathologically coexpressed, because of BCL2 chromosomal translocations and other mechanisms, including Miz1 deregulation and somatic mutations in the BCL2 promoter region. These results identify an important function for BCL6 in facilitating apoptosis of GC B cells via suppression of BCL2, and suggest that blocking this pathway is critical for lymphomagenesis.

Systematic Functional Analysis of BicD Serine Phosphorylation and Intragenic Suppression of a Female Sterile Allele of BicD

Protein phosphorylation is involved in posttranslational control of essentially all biological processes. Using mass spectrometry, recent analyses of whole phosphoproteomes led to the identification of numerous new phosphorylation sites. However, the function of most of these sites remained unknown. We chose the Drosophila Bicaudal-D protein to estimate the importance of individual phosphorylation events. Being involved in different cellular processes, BicD is required for oocyte determination, for RNA transport during oogenesis and embryogenesis, and for photoreceptor nuclei migration in the developing eye. The numerous roles of BicD and the available evidence for functional importance of BicD phosphorylation led us to identify eight phosphorylation sites of BicD, and we tested a total of 14 identified and suspected phosphoserine residues for their functional importance in vivo in flies. Surprisingly, all these serines turned out to be dispensable for providing sufficient basal BicD activity for normal growth and development. However, in a genetically sensitized background where the BicD(A40V) protein variant provides only partial activity, serine 103 substitutions are not neutral anymore, but show surprising differences. The S103D substitution completely inactivates the protein, whereas S103A behaves neutral, and the S103F substitution, isolated in a genetic screen, restores BicD(A40V) function. Our results suggest that many BicD phosphorylation events may either be fortuitous or play a modulating function as shown for Ser(103). Remarkably, amongst the Drosophila serines we found phosphorylated, Ser(103) is the only one that is fully conserved in mammalian BicD.

Age-dependent suppression of SERCA2a mRNA in pediatric atrial myocardium

Differential expression of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban (PLB) has been shown in heart failure and atrial arrhythmias. We investigated the influence of volume overload and age on their expression in pediatric atrial myocardium. Right atrial specimens from 18 children with volume overloaded right atrium (VO) and 12 patients without overload were studied. Each group was further divided into patients less than and older than 12 months of age. Only in the younger patients SERCA2a was significantly reduced in the VO group. In younger patients PLB mRNA level tended to be lower in VO. The PLB:SERCA protein ratio was significantly reduced in the VO group. Age itself did not influence the SERCA2a and PLB expression, if the hemodynamic overload was not taken into account. This study is the first to show a combined influence of volume overload and age on atrial SERCA2a expression.

REVERSIBLE SUPPRESSION OF NITRIC OXIDE SYSTEM IN ESSENTIAL HYPERTENSION

Despite enormous research in the field of hypertension, its pathophysiology still remains largely unresolved and appears to be multifactorial. In the present communication, we have analyzed the status of nitric oxide (NO) in the patients with essential hypertension and age matched controls. We have found that the levels of NO are lowered in essential hypertension. The normalization of blood pressure by administration of antihypertensive therapy causes rise in the NO level indicating that perturbed NO status in essential hypertension is reversible. Addition of antioxidant to the antihypertensive drugs causes a further, though non significant, rise in the levels of NO, suggesting that antioxidants may be combined with antihypertensive drugs as adjunct in the management of essential hypertension.

Modeling and Vibration Suppression for Telescopic Systems of Structural Members with Clearance

Telescopic systems of structural members with clearance are found in many applications, e.g., mobile cranes, rack feeders, fork lifters, stacker cranes (see Figure 1). Operating these machines, undesirable vibrations may reduce the performance and increase safety problems. Therefore, this contribution has the aim to reduce these harmful vibrations. For a better understanding, the dynamic behaviour of these constructions is analysed. The main interest is the overlapping area of each two sections of the above described systems (see markings in Figure 1) which is investigated by measurements and by computations. A test rig is constructed to determine the dynamic behaviour by measuring fundamental vibrations and higher frequent oscillations, damping coefficients, special appearances and more. For an appropriate physical model, the governing boundary value problem is derived by applying Hamilton’s principle and a classical discretisation procedure is used to generate a coupled system of nonlinear ordinary differential equations as the corresponding truncated mathematical model. On the basis of this model, a controller concept for preventing harmful vibrations is developed.

Suppression of OCT4B enhances sensitivity of lung adenocarcinoma A549 cells to cisplatin via increased apoptosis

BACKGROUND Resistance to chemotherapy in lung adenocarcinoma remains a major obstacle. We examined the potential role of Octamer-binding transcription factor-4B (OCT4B) in enhancing sensitivity of lung adenocarcinoma cells to cisplatin. MATERIALS AND METHODS RNAi interference was used to examine the role of OCT4B in cisplatin-treated A549 cells. Cells were transfected with OCT4B siRNA prior to a 48-h cisplatin treatment. Propidium iodide (PI) and caspase-3 staining were used to determine cell viability and apoptosis. Cell-cycle analysis was performed to evaluate alterations in phase distribution. RESULTS OCT4B suppression in cells increased the number of non-viable, PI(+), and apoptotic, caspase-3(+) cells in the presence and absence of cisplatin treatment. Importantly, cisplatin treatment of OCT4B-suppressed cells resulted in a marked transition of cells from G0/G1 to G2/M phase. CONCLUSION Silencing of OCT4B confers sensitivity to cisplatin treatment in A549 cells via cell-cycle regulation, increased proliferation and enhancement of cisplatin-induced apoptosis. OCT4B clearly protects A549 cells from apoptosis.