While grammatical aspects of language are preserved, executive deficits are prominent in Lewy body spectrum disorder (LBSD), including Parkinson's disease (PD), Parkinson's dementia (PDD) and dementia with Lewy bodies (DLB). We examined executive control during sentence processing in LBSD by assessing temporary structural ambiguities. Using an on-line word detection procedure, patients heard sentences with a syntactic structure that has high-compatibility or low-compatibility with the main verb's statistically preferred syntactic structure, and half of the sentences were lengthened strategically between the onset of the ambiguity and its resolution. We found selectively slowed processing of lengthened ambiguous sentences in the PDD/DLB subgroup. This correlated with impairments on measures of executive control. Regression analyses related the working memory deficit during ambiguous sentence processing to significant cortical thinning in frontal and parietal regions. These findings emphasize the role of prefrontal disease in the executive limitations that interfere with processing ambiguous sentences in LBSD.

Cellular responses following low-dose irradiation have been widely debated. Several studies have revealed detrimental effects of low-dose irradiation; however, some studies have shown contrasting results. Moreover, the effects of periapical irradiation on osteoblastic cells have not yet been revealed. Therefore, in this study, we tested the hypothesis that low-dose dental irradiation of osteoblastic cells reduces reactive oxygen species (ROS) production and leads to increased cellular proliferation and high-dose dental irradiation of osteoblastic cells increases ROS production and leads to cellular apoptosis.

Expression of viral proteins causes important epigenetic changes leading to abnormal cell growth. Whether viral proteins directly target histone methyltransferases (HMTs), a key family enzyme for epigenetic regulation, and modulate their enzymatic activities remains elusive. Here we show that the E6 proteins of both low-risk and high-risk human papillomavirus (HPV) interact with three coactivator HMTs, CARM1, PRMT1 and SET7, and downregulate their enzymatic activities in vitro and in HPV-transformed HeLa cells. Furthermore, these three HMTs are required for E6 to attenuate p53 transactivation function. Mechanistically, E6 hampers CARM1- and PRMT1-catalyzed histone methylation at p53-responsive promoters, and suppresses the binding of p53 to chromatinized DNA independently of E6-mediated p53 degradation. p53 pre-methylated at lysine-372 (p53K372 mono-methylation) by SET7 protects p53 from E6-induced degradation. Consistently, E6 downregulates p53K372 mono-methylation and thus reduces p53 protein stability. As a result of the E6-mediated inhibition of HMT activity, expression of p53 downstream genes is suppressed. Together, our results not only reveal a clever approach for the virus to interfere with p53 function, but also demonstrate the modulation of HMT activity as a novel mechanism of epigenetic regulation by a viral oncoprotein.

Electro- and magnetoencephalography (EEG/MEG) are the means to investigate the dynamics of neuronal activity non-invasively in the human brain. However, both EEG and MEG are also sensitive to non-neural sources, which can severely complicate the interpretation. The saccadic spike potential (SP) at saccade onset has been identified as a particularly problematic artifact in EEG because it closely resembles synchronous neuronal gamma band activity. While the SP and its confounding effects on EEG have been thoroughly characterized, the corresponding artifact in MEG, the saccadic spike field (SF), has not been investigated. Here we provide a detailed characterization of the SF. We simultaneously recorded MEG, EEG, gaze position and electrooculogram (EOG). We compared the SF in MEG for different saccade sizes and directions and contrasted it with the well-known SP in EEG. Our results reveal a saccade amplitude and direction dependent, lateralized saccadic spike artifact, which was most prominent in the gamma frequency range. The SF was strongest at frontal and temporal sensors but unlike the SP in EEG did not contaminate parietal sensors. Furthermore, we observed that the source configurations of the SF were comparable for regular and miniature saccades. Using distributed source analysis we identified the sources of the SF in the extraocular muscles. In summary, our results show that the SF in MEG closely resembles neuronal activity in frontal and temporal sensors. Our detailed characterization of the SF constitutes a solid basis for assessing possible saccadic spike related contamination in MEG experiments.

We previously identified FOXF1 as a potential tumor suppressor gene with an essential role in preventing DNA rereplication to maintain genomic stability, which is frequently inactivated in breast cancer through the epigenetic mechanism. Here we further addressed the role of the p53-p21(WAF1) checkpoint pathway in DNA rereplication induced by silencing of FOXF1. Knockdown of FOXF1 by small interference RNA (siRNA) rendered colorectal p53-null and p21(WAF1)-null HCT116 cancer cells more susceptible to rereplication and apoptosis than the wild-type parental cells. In parental HCT116 cells with a functional p53 checkpoint, the p53-p21(WAF1) checkpoint pathway was activated upon FOXF1 knockdown, which was concurrent with suppression of the CDK2-Rb cascade and induction of G(1) arrest. In contrast, these events were not observed in FOXF1-depleted HCT116-p53-/- and HCT116-p21-/- cells, indicating that the p53-dependent checkpoint function is vital for inhibiting CDK2 to induce G(1) arrest and protect cells from rereplication. The pharmacologic inhibitor (caffeine) of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) protein kinases abolished activation of the p53-p21(WAF1) pathway upon FOXF1 knockdown, suggesting that suppression of FOXF1 function triggered the ATM/ATR-mediated DNA damage response. Cosilencing of p53 by siRNA synergistically enhanced the effect of FOXF1 depletion on the stimulation of DNA rereplication and apoptosis in wild-type HCT116. Finally, we show that FOXF1 expression is predominantly silenced in breast and colorectal cancer cell lines with inactive p53. Our study demonstrated that the p53-p21(WAF1) checkpoint pathway is an intrinsically protective mechanism to prevent DNA rereplication induced by silencing of FOXF1.

Over the past 50 years, the ovary development has been subject of fewer studies as compare to the male pathway. Nevertheless due to the advancement of genetics, mouse ES cells and the development of genetic models, studies of ovarian differentiation was boosted. This review emphasizes some of new progresses in the research field of the mammalian ovary differentiation that have occurred in recent years with focuses of the period around prophase I of meiosis and of recent roles of small non-RNAs in the ovarian gene expression.

The production of recombinant transmembrane proteins is due to their biochemical properties often troublesome and time consuming. Here the prokaryotic expression and purification of the transmembrane envelope proteins of the feline and primate foamy viruses using a screening assay for optimisation of expression in 96 deep well plates is described. Testing simultaneously various bacterial strains, media, temperatures, inducer concentrations and different transformants, conditions for an about twentyfold increased production were quickly determined. These small scale test conditions could be easily scaled up, allowing purification of milligram amounts of recombinant protein. Proteins with a purity of about 95% were produced using a new purification protocol, they were characterised by gel filtration and circular dichroism and successfully applied in immunological assays screening for foamy virus infection and in immunisation studies. Compared to the previously described protocol (M. Mühle, A. Bleiholder, S. Kolb, J. Hübner, M. Löchelt, J. Denner, Immunological properties of the transmembrane envelope protein of the feline foamy virus and its use for serological screening, Virology 412 (2011) 333-340), proteins with similar characteristics but about thirtyfold increased yields were obtained. The screening and production method presented here can also be applied for the production of transmembrane envelope proteins of other retroviruses, including HIV-1.

The Poisson process is an often employed model for the activity of neuronal populations. It is known, though, that superpositions of realistic, non- Poisson spike trains are not in general Poisson processes, not even for large numbers of superimposed processes. Here we construct superimposed spike trains from intracellular in vivo recordings from rat neocortex neurons and compare their statistics to specific point process models. The constructed superimposed spike trains reveal strong deviations from the Poisson model. We find that superpositions of model spike trains that take the effective refractoriness of the neurons into account yield a much better description. A minimal model of this kind is the Poisson process with dead-time (PPD). For this process, and for superpositions thereof, we obtain analytical expressions for some second-order statistical quantities-like the count variability, inter-spike interval (ISI) variability and ISI correlations-and demonstrate the match with the in vivo data. We conclude that effective refractoriness is the key property that shapes the statistical properties of the superposition spike trains. We present new, efficient algorithms to generate superpositions of PPDs and of gamma processes that can be used to provide more realistic background input in simulations of networks of spiking neurons. Using these generators, we show in simulations that neurons which receive superimposed spike trains as input are highly sensitive for the statistical effects induced by neuronal refractoriness.

Toll-like receptor (TLR) signaling is linked to autophagy that facilitates elimination of intracellular pathogens. However, it is largely unknown whether autophagy controls TLR signaling. Here, we report that poly(I:C) stimulation induces selective autophagic degradation of the TLR adaptor molecule TRIF and the signaling molecule TRAF6, which is revealed by gene silencing of the ubiquitin-editing enzyme A20. This type of autophagy induced formation of autophagosomes and could be suppressed by an autophagy inhibitor and lysosomal inhibitors. However, this autophagy was not associated with canonical autophagic processes, including involvement of Beclin-1 and conversion of LC3-I to LC3-II. Through screening of TRIF-interacting 'autophagy receptors' in human cells, we identified that NDP52 mediated the selective autophagic degradation of TRIF and TRAF6 but not TRAF3. NDP52 was polyubiquitinated by TRAF6 and was involved in aggregation of TRAF6, which may result in the selective degradation. Intriguingly, only under the condition of A20 silencing, NDP52 could effectively suppress poly(I:C)-induced proinflammatory gene expression. Thus, this study clarifies a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF-TRAF6. Furthermore, although A20 is known as a signaling fine-tuner to prevent excess TLR signaling, it paradoxically downregulates the fine-tuning effect of NDP52 on TLR signaling.

TFIIH is a multisubunit factor essential for transcription initiation and promoter escape of RNA polymerase II and for the opening of damaged DNA double strands in nucleotide excision repair (NER). In this study, we have analyzed at which step of the transcription cycle TFIIH is essential for transcription by RNA polymerase I. We demonstrate that TFIIH associates with the rDNA promoter and gene-internal sequences and leaves the rDNA promoter in a complex with RNA polymerase I after start of transcription. Moreover, mutations in the TFIIH subunits XPB and XPD found in Cockayne syndrome impair the interaction of TFIIH with the rDNA, but do not influence initiation complex formation or promoter escape of RNA polymerase I, but preclude the productivity of the enzyme by reducing transcription elongation in vivo and in vitro. Our results implicate that reduced RNA polymerase I transcription elongation and ribosomal stress could be one factor contributing to the Cockayne syndrome phenotype.

Propolis is a resinous product collected by honey bees. It was also reported that propolis has a wide variety of biological actions, including antimicrobial activity and antioxidant, anti-inflammatory, and suppressive effects of dioxin toxicity activities. The aim of this study was to compare the in vitro cytotoxic activities of green propolis (G12) and red propolis (G13) in human leukemia cells. These cells were incubated with different concentrations of propolis and 48 hours after the IC(50) was calculated for each cell. The results showed that the red propolis has cytotoxic effect in vitro higher than green propolis. Red propolis was showed to be cytostatic in K562 cells and caused the same amount of apoptosis as its control Gleevec. In conclusion, these results showed that red propolis is more cytotoxic than the green propolis in a variety of human cell lines of leukemia. Red propolis may contain drugs capable of inhibiting cancer cell growth. Therefore, further isolation of respective chemical ingredients from the red propolis (G13) for identification of the activities is necessary.

Studies in the 1990s have found that periconceptional dietary folate, supplementation of folic acid or supplemental multivitamins containing folic acid, help prevent neural tube defect (NTDs) if taken at the right time. This literature review assesses the extant folic acid public health campaigns literature and identifies some common variables used in folic acid consumption campaign evaluations.

We report the quantitative genetic analysis of seed oil quality and quantity in six Arabidopsis thaliana recombinant inbred populations, in which the parent accessions were from diverse geographical origins, and were selected on the basis of variation for seed oil content and lipid composition. Although most of the biochemical steps involved in lipid biosynthesis are known and the key genes have been identified, the regulation of the processes that results in the final oil composition and total amount is not understood. By using physically anchored markers it was possible to compare results across populations. A total of 219 quantitative trait loci (QTLs) were identified, of which 81 were significant at P<0.001. Some of these colocalise with QTLs identified previously, but many novel QTLs were also identified. The results highlight the importance of studying traits in multiple populations, which will lead to a better understanding of the contribution that natural variation makes to the genetic architecture of a phenotype.

The aim of the present study was to compare the ability of the hypertriglyceridemic waist phenotype and the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) clinical criteria to predict coronary artery disease (CAD) risk in a sample of women. We studied 254 women among whom the presence/absence of CAD was assessed by angiography. The hypertriglyceridemic waist phenotype was defined as having both a high waist circumference (≥85 cm) and increased fasting triglyceride levels (≥1.5 mmol/L), whereas the presence of at least 3 of the 5 NCEP-ATP III criteria was used as the "reference" screening approach to identify women with the features of the metabolic syndrome. Women with hypertriglyceridemic waist were characterized by higher adiposity indices as well as by a more disturbed fasting metabolic risk profile compared with women without this phenotype. Similar differences were observed when comparing the metabolic profile of women with vs without at least 3 of the NCEP-ATP III clinical criteria. Moreover, differences in the Framingham risk score were essentially similar when women were considered at low or high risk by either hypertriglyceridemic waist or by NCEP-ATP III clinical criteria (P < .0001). Finally, both clinical phenotypes were predictive of CAD (hypertriglyceridemic waist: relative odds ratio, 2.1; 95% confidence interval, 1.1-3.8; P = .02; NCEP-ATP III clinical criteria: relative odds ratio, 2.5; 95% confidence interval, 1.4-4.6; P < .003). These results suggest that hypertriglyceridemic waist is a simple screening tool to identify women with clustering metabolic abnormalities and at increased CAD risk.

Opioids are recommended by the World Health Organization for moderate to severe cancer pain. Oxycodone is one of the most commonly used opioids and is metabolized in the liver by CYP3A4 and CYP2D6 enzymes. The aim of this cross-sectional study was to assess the relationship between oxycodone pharmacokinetics, pharmacodynamics and the CYP2D6 genotypes "poor metaboliser" (PM), "extensive metaboliser" (EM) and "ultra-rapid metaboliser" (URM) in a cohort of patients with cancer pain.

Contrasting results have been reported concerning the association of a splice-site polymorphism (rs10774671) in OAS1 with multiple sclerosis (MS). We analysed two OAS1 regions encompassing alternatively spliced exons. While the region carrying the splice-site variant is neutrally evolving, a signature of long-standing balancing selection was observed across an alternative exon 7. Analysis of variants in this exon identified an insertion/deletion polymorphism (rs11352835, A/-) that originates predicted products with distinct C termini. This variant is located along the major branch of the haplotype genealogy, suggesting that it may represent the selection target. A case/control study for MS indicated that rs11352835 is associated with disease susceptibility (for an allelic model with the deleted allele predisposing to MS, OR 1.27, 95% CI 1.072-1.513, p = 0.010). No association was found between rs10774671 and MS. As the two SNPs are in linkage disequilibrium in Europeans, the previously reported association between rs10774671 and MS susceptibility might be driven by rs11352835, possibly explaining the contrasting results previously observed for the splice-site polymorphism. Thus, we describe a novel susceptibility variant for MS in OAS1 and show that population genetic analyses can be instrumental to the identification of selection targets and, consequently, of functional polymorphisms with an effect on phenotypic traits.

Androgens and the androgen receptor (AR) play important roles in the development of male urogenital organs. We previously found that mice with total AR knockout (ARKO) and epithelial ARKO failed to develop normal prostate with loss of differentiation. We have recently knocked out AR gene in smooth muscle cells and found the reduced luminal infolding and IGF-1 production in the mouse prostate. However, AR roles of stromal fibroblasts in prostate development remain unclear.

In visually guided grasping, possible hand shapes are computed from the geometrical features of the object, while prior knowledge about the object and the goal of the action influence both the computation and the selection of the hand shape. We investigated the system dynamics of the human brain for the pantomiming of grasping with two aspects accentuated. One is object recognition, with the use of objects for daily use. The subjects mimed grasping movements appropriate for an object presented in a photograph either by precision or power grip. The other is the selection of grip hand shape. We manipulated the selection demands for the grip hand shape by having the subjects use the same or different grip type in the second presentation of the identical object. Effective connectivity analysis revealed that the increased selection demands enhance the interaction between the anterior intraparietal sulcus (AIP) and posterior inferior temporal gyrus (pITG), and drive the converging causal influences from the AIP, pITG, and dorsolateral prefrontal cortex to the ventral premotor area (PMv). These results suggest that the dorsal and ventral visual areas interact in the pantomiming of grasping, while the PMv integrates the neural information of different regions to select the hand posture. The present study proposes system dynamics in visually guided movement toward meaningful objects, but further research is needed to examine if the same dynamics is found also in real grasping.

Proper movement of the vertebrate eye requires the formation of precisely patterned axonal connections linking cranial somatic motoneurons, located at defined positions in the ventral midbrain and hindbrain, with extraocular muscles. The aim of this research was to assess the relative contributions of intrinsic, population-specific properties and extrinsic, outgrowth site-specific cues during the early stages of abducens and oculomotor nerve development in avian embryos. This was accomplished by surgically transposing midbrain and caudal hindbrain segments, which had been pre-labeled by electroporation with an EGFP construct. Graft-derived EGFP+ oculomotor axons entering a hindbrain microenvironment often mimicked an abducens initial pathway and coursed cranially. Similarly, some EGFP+ abducens axons entering a midbrain microenvironment mimicked an oculomotor initial pathway and coursed ventrally. Many but not all of these axons subsequently projected to extraocular muscles that they would not normally innervate. Strikingly, EGFP+ axons also took initial paths atypical for their new location. Upon exiting from a hindbrain position, most EGFP+ oculomotor axons actually coursed ventrally and joined host branchiomotor nerves, whose neurons share molecular features with oculomotor neurons. Similarly, upon exiting from a midbrain position, some EGFP+ abducens axons turned caudally, elongated parallel to the brainstem, and contacted the lateral rectus muscle, their originally correct target. These data reveal an interplay between intrinsic properties that are unique to oculomotor and abducens populations and shared ability to recognize and respond to extrinsic directional cues. The former play a prominent role in initial pathway choices, whereas the latter appear more instructive during subsequent directional choices.

Thioredoxin (TRx) is a small redox protein that plays significant roles in protection against oxidative stress and in cell homeostasis by maintaining oxidized proteins in a reduced state. Here, we describe the isolation and characterization of a full-length TRx cDNA sequence from manila clam, Ruditapes philippinarum and named it as RpTRx. The full length sequence consists of 1416 bp with an open reading frame of 318 bp encoding for 106 amino acids. RpTRx protein harbors evolutionarily-conserved TRx active site (32)WCGPC(36). Phylogenetic analysis revealed a close proximity of RpTRx with the orthologue in Japanese scallop, Chlamys farreri. RpTRx was found to be constitutively expressed in hemocyte, gill, mantle, foot and siphon indicating a general role in physiological processes in various tissues. With regard to a potential role in immune responses, the RpTRx mRNA was found to be up-regulated in hemocytes after bacterial (Vibrio tapetis) and lipopolysaccharide (LPS) challenge at 3h post-infection (p.i.); a wavering increase was observed up to 96 h p.i. for LPS challenge and 48 h p.i. for bacterial challenge. Thus, RpTRx may function as an intracellular antioxidant to protect the cells against ROS induced by LPS and bacterial challenges. Indeed, when recombinant RpTRx protein (rRpTRx) was over-expressed in Escherichiacoli Rosetta gami(TM) (DE3) cells, it was able to scavenge free radicals and protect super-coiled DNA from oxidative damage induced by a metal-ion catalyzed oxidation reaction. In summary, RpTRx plays an essential role in cellular defense and maintenance of homeostasis in the manila clam.