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This article explores the distribution and composition of the ferritin complex in the adult brain and its connection to neuroferritinopathy (NF), a type of neurodegeneration with brain iron accumulation (NBIA). NF is characterized by symptoms like movement disturbances and tremors. The study identifies a novel variant in the ferritin heavy chain gene (FTH1) that is associated with NF and provides insights into the role of ferritin in both healthy and diseased brains. The authors, a diverse group of researchers, present their findings in a respectful and culturally sensitive manner, making this report a valuable resource for library patrons researching this topic. [Extracted from the article]

Influenza A viruses (IAVs) quickly adapt to new environments and are well known to cross species barriers. To reveal a molecular basis for these phenomena, we compared the Ser/Thr and Tyr phosphoproteomes of murine lung epithelial cells early and late after infection with mouse-adapted SC35M virus or its non-adapted SC35 counterpart. With this analysis we identified a large set of upregulated Ser/Thr phosphorylations common to both viral genotypes, while Tyr phosphorylations showed little overlap. Most of the proteins undergoing massive changes of phosphorylation in response to both viruses regulate chromatin structure, RNA metabolism and cell adhesion, including a focal adhesion kinase (FAK)-regulated network mediating the regulation of actin dynamics. IAV also affected phosphorylation of activation loops of 37 protein kinases including FAK and several phosphatases, many of which were not previously implicated in influenza virus infection. Inhibition of FAK proved its contribution to IAV infection. Novel phosphorylation sites were found on IAV-encoded proteins, and the functional analysis of selected phosphorylation sites showed that they either support (NA Ser178) or inhibit (PB1 Thr223) virus propagation. Together, this data allow novel insights into IAV-triggered regulatory phosphorylation circuits and signaling networks. [ABSTRACT FROM AUTHOR]

We describe a technically very simple analytical approach to the deep infrared regime of Yang-Mills theory in the Landau gauge via Callan-Symanzik renormalization group equations in an epsilon expansion. This approach recovers all the solutions for the infrared gluon and ghost propagators previously found by solving the Dyson-Schwinger equations of the theory and singles out the solution with decoupling behavior, confirmed by lattice calculations, as the only one corresponding to an infrared attractive fixed point (for space-time dimensions above two). For the case of four dimensions, we describe the crossover of the system from the ultraviolet to the infrared fixed point and determine the complete momentum dependence of the propagators. The results for different renormalization schemes are compared to the lattice data. [ABSTRACT FROM AUTHOR]

Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl+ K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells, Stat5 is predominantly present in the cytoplasm and the survival of the Jak2(V617F)+ HEL cells is impeded through the inhibition of the cytoplasmic functions of Stat5. [ABSTRACT FROM AUTHOR]

Background: A 3.68 Mbp duplication of 8p23.1 defines the 8p23.1 duplication syndrome. The main features of this syndrome are developmental delay and/or learning problems. Results: Here we present a patient with a 1.80 Mbp duplication in 8p23.1 and characteristic signs and symptoms of the syndrome, including delay of motor and speech development and intellectual disability. Discussion: The case indicates that genes within this interval, in particular dosage sensitive genes SOX7 and TNKS1, and possibly MIR124-1 and MIR598 as well suffice to cause the pathognomonic features of the 8p23.1 duplication syndrome. [ABSTRACT FROM AUTHOR]

Within the refined Gribov–Zwanziger scenario for four-dimensional Yang–Mills theory in the Landau gauge, a gluon mass term is generated from the restriction of the gauge field configurations to the first Gribov region. Tissier and Wschebor have pointed out that adding a gluon mass term to the usual Faddeev–Popov action yields one-loop renormalization group improved gluon and ghost propagators which are in reasonable agreement with the lattice data even in the infrared regime. In this work, we extend their analysis to several alternative renormalization schemes and show how the renormalization scheme dependence can be used to achieve an almost perfect matching to the lattice data for the gluon and ghost propagators. • The conditions for a renormalization scheme to be infrared safe are scrutinized. • The propagators results are compared with the lattice data for different schemes. • The analytic behavior, both for low and high momenta, of the propagators is derived. [ABSTRACT FROM AUTHOR]

Objective: This study was investigated the prognostic role of the number of involved extraspinal organs in the survival of patients with metastatic spinal cord compression (MSCC). Methods: Data of 552 patients treated with 30 Gy in 10 fractions of radiotherapy (RT) alone for MSCC were retrospectively analyzed. In addition to the number of involved extraspinal organs, eight potential prognostic factors were investigated including age, gender, Eastern Cooperative Oncology Group performance score (ECOG-PS), primary tumor type, number of involved vertebrae, interval from cancer diagnosis to RT, pre-RT ambulatory status, and time developing motor deficits. Results: The 6-month survival rates for the involvement of 0, 1, 2, 3, and ≥4 extraspinal organs were 88%, 55%, 30%, 13%, and 12%, respectively (P < 0.001). In the multivariate analysis, number of involved extraspinal organs maintained significance (risk ratio 1.61 ; 95%-confidence interval 1.47-1.77; P < 0.001). On multivariate analysis, gender (P = 0.017), ECOG-PS (P < 0.001), primary tumor type (P < 0.001), interval from cancer diagnosis to RT (P < 0.001), pre-RT ambulatory status (P < 0.001 ), and time developing motor deficits (P < 0.001) were also independent predictors for survival. Conclusions: The number of involved extraspinal organs is a new and independent prognostic factor in patients with MSCC and should be considered in future clinical trials. [ABSTRACT FROM AUTHOR]

Equal-time correlation functions play a central role in the recent noncovariant approaches to infrared QCD in the Coulomb gauge. In this article, we explore the possibilities to derive equal-time correlation functions from a generating functional, represent them diagrammatically, and formulate nonperturbative relations similar to Dyson-Schwinger equations among them, in analogy to the covariant n-point functions. For simplicity, we set up the formalism for λϕ4 theory and derive explicit expressions for the equal-time 2- and 4-point functions. [ABSTRACT FROM AUTHOR]

Background. Cancer in childhood is rare, but nevertheless one of the most frequent causes of disease related death. Initial symptoms are often unspecific, frequently leading to a delay of cancer diagnosis. As a timely diagnosis can be crucial for the clinical outcome, our aim is to point out when unspecific symptoms should be considered suspect of being associated with specific cancer entities. Data sources. A systematic literature research in PubMed and current biliographies, as well as an evaluation of published epidemiologic data was performed. Results. This article reviews the typical presenting features and epidemiologic characteristics of the more common childhood malignancies, elucidates when specific and virtually unspecific symptoms require further evaluation, and gives advice how to start a rational diagnostic workup. Furthermore, genetic syndromes requiring increased watchfulness for cancer in childhood are demonstrated. Conclusion. Patients showing suspect symptoms should early be referred to specialized centres to assure optimal diagnostic and therapeutic capabilities. [ABSTRACT FROM AUTHOR]

The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract: A generalization of the Gell-Mann–Low theorem is applied to lowest nontrivial order to determine an effective Hamiltonian for two-fermion states in relativistic Yukawa theory. The consistency of the corresponding effective Schrödinger equation is thoroughly investigated in various aspects, among others the nonrelativistic and one-body limits, and the small-distance or large-momentum regime of the bound state solutions is discussed in detail. [Copyright &y& Elsevier]

Cytotoxic agents, alone or in combination, are being used in the treatment of colorectal cancer. Despite progress in the therapeutic regimes, this common malignancy is still the cause of considerable morbidity and mortality, and further improvements are required. Cancer cells often exhibit intrinsic resistance against chemotherapeutic agents or they develop resistance over the time of treatment. Several mechanisms have been made responsible, e.g., drugs may fail to reach tumor cells or drugs may fail to elicit cytotoxicity. The molecular characterization of drug resistance in cancer cells may lead to strategies to overcome it and enhance the sensitivity to chemotherapy. Irinotecan is one of the main treatments of colorectal cancer; it is converted into its active metabolite SN38 and acts as a topoisomerase I inhibitor. Inhibition of this enzyme prevents DNA relegation following uncoiling. Irinotecan has been used as a chemotherapeutic agent either as a single agent or in combination with 5-fluorouracil and targeted therapies directed against the epidermal growth factor receptor, such as cetuximab. The transcription factor signal transducer and activator of transcription 3 (Stat3) is a member of the signal transducer and activator of transcription protein family. Its persistent activation is found in tumor cells and has been associated with drug and radiation resistance. The treatment of colorectal cancer cells with irinotecan leads to senescence or apoptosis following DNA double-strand break induction. This process is impaired by the activation of Stat3. We have derived a Stat3 specific peptide aptamer [recombinant Stat3 inhibitory peptide aptamer (rS3-PA)] that recognizes the dimerization domain of Stat3 and effectively inhibits its function. The delivery of rS3-PA into colon cancer cells and the resulting inhibition of Stat3 strongly enhanced the cytotoxic action of SN38. These data show that the targeted inhibition of Stat3 decreases drug resistance and enhances SN38-mediated cell death. The combination of these agents has a potent antitumor effect and could become beneficial for the treatment of patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Abstract: Infection or cell damage triggers the release of pro-inflammatory cytokines such as interleukin(IL)-1α or β and tumor necrosis factor (TNF)α which are key mediators of the host immune response. Following their identification and the elucidation of central signaling pathways, recent results show a highly complex crosstalk between various cytokines and their signaling effectors. The molecular mechanisms controlling signaling thresholds, signal integration and the function of feed-forward and feedback loops are currently revealed by combining methods from biochemistry, genetics and in silico analysis. Increasing evidence is mounted that defects in information processing circuits or their components can be causative for chronic or overshooting inflammation. As progress in biosciences has always benefitted from the use of well-studied model systems, research on inflammatory cytokines may function as a paradigm to reveal general principles of signal integration, crosstalk mechanisms and signaling networks. [Copyright &y& Elsevier]

The article presents the author's insight regarding challenges for monetary policy that the European Monetary Union (EMU) faces. He states that EMU will find it difficult to ensure monetary policy stability if membership requirement will not be met in the union. He mentions that in order for the policy not continually be challenged by financial crisis, the central bankers should take into consideration the implication of monetary policy in the financial stability as well as the price stability.

Reliable diagnostic strategies for individuals with cancer demand practical methods for highly sensitive and specific detection of tumor cells. Amplification of genomic regions that include putative oncogenes is common in tumor cells of various types. Genomic array platforms offer the opportunity to identify and precisely map amplified genomic regions (ampGRs). The stable existence of these tumor cell–specific genomic aberrations during and after therapy, in theory, make ampGRs optimal targets for cancer diagnostics. In this study, we mapped ampGRs around the proto-oncogene MYCN of human neuroblastomas using a high-resolution tiling array (HR-TA). Based on the HR-TA data, we were able to precisely describe the telomeric and centromeric borders of the ampGRs and deduce virtual fusion sites of the joined ampGRs (amplicon fusion sites [AFSs]). These AFSs served as blueprints for the subsequent design of AFS bridging PCR assays (AFS-PCRs). Strikingly, these assays were absolutely tumor cell specific and capable of detecting 1 tumor cell in 1 × 10(6) to 8 × 10(6) control cells. We successfully proved the in vivo practicability of AFS-PCR by detecting and quantifying the specific AFS DNA of human MYCN-amplified neuroblastomas in the patients’ corresponding peripheral blood and bone marrow samples. Thus, we believe AFS-PCR could become a powerful and nevertheless feasible personalized diagnostic tool applicable to a large number of cancer patients, including children with MYCN-amplified neuroblastomas. [ABSTRACT FROM AUTHOR]

Background: Mutations in PRRT2 cause autosomal dominant paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC). Case presentation: A previously not recognized intronic PRRT2 mutation (c.880-35G > A; p.S294Lfs*29) was found in an 18 month old girl with IC and in her mother with classical presentation of PKD. The mutation results in a novel splice acceptor site in intron 2 of PRRT2. Due to frameshift and a subsequent premature stop-codon the resulting transcript appears to render the PRRT2 protein non/dysfunctional and is the likely cause of disease in this family. Conclusion: Our findings expand the mutational spectrum of this disease. [ABSTRACT FROM AUTHOR]

We consider the energies of the one-particle states of relativistic quantum field theories in old-fashioned perturbation theory, and treat their regularization and renormalization from a strictly Hamiltonian perspective. We show that the one-loop diagrams lead to the renormalization of the mass for bosons and fermions identically to covariant perturbation theory, provided an appropriate regularization scheme is used. In particular, we show that a naive spatial momentum cutoff breaks covariance (in the limit where the cutoff is removed) in the case of the one-fermion states. [ABSTRACT FROM AUTHOR]

A generalization of the Gell-Mann–Low Theorem is applied to lowest nontrivial order to bound state calculations in Yukawa theory. We present the solution of the corresponding effective Schrödinger equation for two-fermion bound states with the exchange of a massless boson. The complete low-lying bound state spectrum is obtained for fine structure constants below one and different ratios of the constituent masses. The consistency of the nonrelativistic and one-body limits is explicitly verified. [ABSTRACT FROM AUTHOR]

In response to stimuli that activate p53, cells can undergo either apoptosis or cell cycle arrest, depending on the precise pattern of p53 target genes that is activated. We show here that Zbtb4, a transcriptional repressor protein, associates with the Sin3/histone deacetylase co-repressor and represses expression of P21CIP1 as part of a heterodimeric complex with Miz1. In vivo, expression of ZBTB4 is downregulated in advanced stages of multiple human tumours. In cell culture, depletion of ZBTB4 promotes cell cycle arrest in response to activation of p53 and suppresses apoptosis through regulation of P21CIP1, thereby promoting long-term cell survival. Our data suggest that Zbtb4 is a critical determinant of the cellular response to p53 activation and reinforce the notion that p21Cip1 can provide an essential survival signal in cells with activated p53. [ABSTRACT FROM AUTHOR]

A pulsed electron double resonance (PELDOR) setup working at S-band frequencies is introduced and its performance compared with an X-band setup. Furthermore, to verify experimentally that it is possible to disentangle the dipolar coupling νDip from the exchange coupling J by PELDOR we synthesized and investigated four bisnitroxide radicals. They exhibit in pairs the same distances rAB between the nitroxide moieties but only one of each pair possesses a non-zero J. The experimental values for rAB match the ones from molecular modeling very well for the molecules without exchange coupling. For one bisnitroxide it was possible to separate νDip from J and to ascertain the magnitude and sign of J to +11 MHz (antiferromagnetic spin–spin coupling). [Copyright &y& Elsevier]

Patients with Gilles de la Tourette syndrome (TS) frequently show obsessions and compulsions. Pathophysiologically, TS has been linked to abnormalities of the basal ganglia and forebrain which are related to emotional processes. Because recordings of event-related potentials (ERPs) have shown that the emotional content of words interacts with the subjects' ability to recognise repeated words we hypothesised that patients who were diagnosed to have TS and obsessive compulsive disorder (OCD) utilised a changed cognitive process for the recognition of emotional words. ERPs were recorded while 12 patients and matched control subjects viewed a series of emotionally neutral, negative, and positive words. These were repeated after some intervening items with the task being to discriminate between new words and repeated words. In both groups, correctly detected repeated words showed a more positive ERP waveform than new words between 350msec and 550msec after stimulus presentation. Although we found no group difference of this old-new effect for emotionally neutral words, patients had a smaller effect than control subjects for negative and positive words. This finding is discussed with respect to the literature and is viewed as evidence for changed memory mechanisms for emotionally charged words in patients with TS and OCD. [ABSTRACT FROM AUTHOR]

Escherichia coli ribonucleotide reductase (RNR) catalyzes the conversion of nucleoside diphosphates (NDPs) to deoxynucleoside diphosphates. This RNR is composed of two homodimeric subunits: R1 and R2. RI binds the NDPs in an active site with three essential cysteines and houses the binding sites for the allosteric effectors that govern turnover and specificity. R2 harbors the essential di-iron tyrosyl radical (Y) cofactor. The mechanism of nucleotide reduction has been extensively studied, and structures of R1 and of R2 are available. Despite this wealth of information, a major unresolved issue is the mechanism of radical initiation: how the Y on R2 generates a transient thiyl radical on R1 over a 35Å distance based on a docking model of a 1:1 complex of RI and R2.

Investigates the use of pulsed electron double resonance (PELDOR) scheme for determining the intramolecular long-range distances on RNA. Measurement of spin-spin coupling; Degree of aggregation; Analysis of PELDOR spectrum of RNA.

In this study an evaluation of the performance of the Philips MOSAIC small animal PET scanner is presented, with special emphasis on the ability of the system to provide quantitatively accurate PET images. The performance evaluation was structured according to NEMA-like procedures. The transaxial spatial resolution of the system (radial component) ranged between 2.7 mm FWHM at the centre and 3.2 mm FWHM at a radial offset of 45 mm from the centre. The axial spatial resolution of the system ranged between 3.4 mm FWHM at the centre and 5.8 mm FWHM at a radial offset of 45 mm from the centre. The scatter fraction was determined for a mouse- as well as for a rat-sized phantom, and the values obtained were 9.6% and 16.8%, respectively. For the mouse phantom, the maximum count rate measured was 560 kcps at 93 MBq; the maximum NEC rate equalled 308 kcps at 1.7 MBq/ml. For the rat phantom, these values were 400 kcps at 100 MBq and 129 kcps at 0.24 MBq/ml, respectively. The sensitivity of the system was derived to be 0.65%. An energy window between 410 and 665 keV was used in all experiments. The MOSAIC system exhibits moderate spatial resolution and sensitivity values, but good NEC performance. In combination with its relatively large field of view, the system allows for high-throughput whole-body imaging of mice and rats. The accurate measurement of relative changes in radiotracer distributions is feasible. [ABSTRACT FROM AUTHOR]

Social protection is increasingly seen as an important tool for poverty reduction, but to date there have been few quantitative cross-country assessments of social protection provision. This article develops a social protection index that systematically and consistently quantifies activities at the national level. Four summary indicators representing the cost, coverage, poverty targeting and impact are scaled and weighted to produce an additive index of the overall level of social protection provision. The index is calculated for six very different Asian countries: Bangladesh, Indonesia, Mongolia, Nepal, Pakistan and Vietnam. Considerable contrasts are revealed between their levels of social protection provision. [ABSTRACT FROM AUTHOR]

We examine the relation between the damping rate of a chiral fermion mode propagating in a hot plasma and the rate at which the mode approaches equilibrium. We show how these two quantities, obtained from the imaginary part of the fermion self-energy, are equal when the reaction rate is defined using the appropriate wave function of the mode in the medium. As an application, we compute the production rate of hard axions by Compton-like scattering processes in a hot QED plasma starting from both, the axion self-energy and the electron self-energy. We show that the latter rate coincides with the former only when this is computed using the corresponding medium spinor modes. [ABSTRACT FROM AUTHOR]

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families. [ABSTRACT FROM AUTHOR]

In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, several advances have been made. First trimester screening, combining maternal age, maternal serum parameters and ultrasound findings, emerged in the 1990s with a detection rate (DR) of around 90–95% and a false positive rate (FPR) of around 5%, also looking for trisomy 13 and 18. With the development of high-resolution ultrasound, around 50% of fetal anomalies are now detected in the first trimester. Non-invasive prenatal testing (NIPT) for trisomy 21, 13 and 18 is a highly efficient screening method and has been applied as a first-line or a contingent screening approach all over the world since 2012, in some countries without a systematic screening program. Concomitant with the rise in technology, the possibility of screening for other genetic conditions by analysis of cfDNA, such as sex chromosome anomalies (SCAs), rare autosomal anomalies (RATs) and microdeletions and duplications, is offered by different providers to an often not preselected population of pregnant women. Most of the research in the field is done by commercial providers, and some of the tests are on the market without validated data on test performance. This raises difficulties in the counseling process and makes it nearly impossible to obtain informed consent. In parallel with the advent of new screening technologies, an expansion of diagnostic methods has begun to be applied after invasive procedures. The karyotype has been the gold standard for decades. Chromosomal microarrays (CMAs) able to detect deletions and duplications on a submicroscopic level have replaced the conventional karyotyping in many countries. Sequencing methods such as whole exome sequencing (WES) and whole genome sequencing (WGS) tremendously amplify the diagnostic yield in fetuses with ultrasound anomalies. [ABSTRACT FROM AUTHOR]

Homeostasis of solid tissue is characterized by a low proliferative activity of differentiated cells while special conditions like tissue damage induce regeneration and proliferation. For some cell types it has been shown that various tissue-specific functions are missing in the proliferating state, raising the possibility that their proliferation is not compatible with a fully differentiated state. While endothelial cells are important players in regenerating tissue as well as in the vascularization of tumors, the impact of proliferation on their features remains elusive. To examine cell features in dependence of proliferation, we established human endothelial cell lines in which proliferation is tightly controlled by a doxycycline-dependent, synthetic regulatory unit. We observed that uptake of macromolecules and establishment of cell-cell contacts was more pronounced in the growth-arrested state. Tube-like structures were formed in vitro in both proliferating and non-proliferating conditions. However, functional vessel formation upon transplantation into immune-compromised mice was restricted to the proliferative state. Kaposi's sarcoma-associated herpes virus (KSHV) infection resulted in reduced expression of endothelial markers. Upon transplantation of infected cells, drastic differences were observed: proliferation arrested cells acquired a high migratory activity while the proliferating counterparts established a tumor-like phenotype, similar to Kaposi Sarcoma lesions. The study gives evidence that proliferation governs endothelial functions. This suggests that several endothelial functions are differentially expressed during angiogenesis. Moreover, since proliferation defines the functional properties of cells upon infection with KSHV, this process crucially affects the fate of virus-infected cells. [ABSTRACT FROM AUTHOR]

Chudley-McCullough syndrome (CMS) is a rare autosomal recessive disorder characterized by sensorineural deafness, agenesis of the corpus callosum, frontal polymicrogyria, interhemispheric cyst, and ventricular enlargement. CMS is caused by mutations in the GPSM2 gene, but until now no more than eight different mutations are on record. We describe two dizygotic twins with a novel homozygous loss-of-function mutation (c.1093C > T; p.Arg365). While one child developed hydrocephalus-prompting shunt implantation immediately after birth, the other sibling did not. The combination of sensorineural hearing loss and partial agenesis of the corpus callosum is a highly recognizable clinico-radiological entity that should prompt mutational analysis of the GPSM2 gene. [ABSTRACT FROM AUTHOR]

Summary: Given the intimate link between inflammation and dysregulated cell proliferation in cancer, we investigated cytokine-triggered gene expression in different cell cycle stages. Transcriptome analysis revealed that G1 release through cyclin-dependent kinase 6 (CDK6) and CDK4 primes and cooperates with the cytokine-driven gene response. CDK6 physically and functionally interacts with the NF-κB subunit p65 in the nucleus and is found at promoters of many transcriptionally active NF-κB target genes. CDK6 recruitment to distinct chromatin regions of inflammatory genes was essential for proper loading of p65 to its cognate binding sites and for the function of p65 coactivators, such as TRIP6. Furthermore, cytokine-inducible nuclear translocation and chromatin association of CDK6 depends on the kinase activity of TAK1 and p38. These results have widespread biological implications, as aberrant CDK6 expression or activation that is frequently observed in human tumors modulates NF-κB to shape the cytokine and chemokine repertoires in chronic inflammation and cancer. [ABSTRACT FROM AUTHOR]

Interleukin-1 (IL-1)-induced mRNA expression of ccl2 (also called MCP-1), a prototypic highly regulated inflammatory gene, is severely suppressed in cells lacking c-Jun or Jun N-terminal protein kinase 1 (JNK1)/JNK2 genes and is only partially restored in cells expressing a c-Jun(SS63/73AA) mutant protein. We used chromatin immunoprecipitation to identify three c-Jun-binding sites located in the far 5' region close to the transcriptional start site and in the far 3' region of murine and human ccl2 genes. Mutational analysis revealed that the latter two sites contribute to ccl2 transcription in response to the presence of IL-1 or of ectopically expressed c-Jun-ATF-2 dimers. Further experiments comparing wild-type and c-Jun-deficient cells revealed that c-Jun regulates Ser10 phosphorylation of histone H3, acetylation of histones H3 and H4, and recruitment of histone deacetylase 3 (HDAC3), NF-B subunits, and RNA polymerase II across the ccl2 locus. c-Jun also coimmunoprecipitated with p65 NF-B and HDAC3. Based on DNA microarray analysis, c-Jun was required for full expression of 133 out of 162 IL-1-induced genes. For inflammatory genes, these data support the idea of an activator function of c-Jun that is executed by multiple mechanisms, including phosphorylation-dependent interaction with p65 NF-B and HDAC3 at the level of chromatin. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (Stat3) assumes central functions in the regulation of apoptosis, proliferation, angiogenesis, and immune responses in normal cells. It also plays crucial roles in inflammatory and malignant diseases and in the cellular communication in the tissue microenvironment. Signaling interactions among normal endothelial cells, immune cells, and tumor cells, mediated by the release of cytokines, chemokines, and growth factors, often result in the activation of Stat3 and promotion of cancer cell proliferation, invasion, angiogenesis, and immune evasion. Stat3 also causes the differentiation and activation of T helper 17 (Th17) cells, which is involved, e.g., in psoriasis, an inflammatory autoimmune disease of the skin. Here, we describe molecular characteristics of a mouse model triggered by the treatment of mouse skin with the immune modulator imiquimod. The application of this compound causes the local release of proinflammatory cytokines and symptoms that resemble human psoriasis. We show that this process is accompanied by strong Stat3 activation. We also investigated the effects of a membrane-permeable, peptide-based Stat3 inhibitor, recombinant Stat3-specific peptide aptamer (rS3-PA). This molecule specifically interacts with Stat3 and prevents its transactivation potential in cultured cells. rS3-PA is able to penetrate the skin, enter cells, and reduce the level of activated Stat3. The topical applications of rS3-PA to the skin could thus possibly become useful in the treatment of inflammatory skin diseases and skin cancer. [ABSTRACT FROM AUTHOR]

Abstract: This paper presents a fully automated method for atlas-based whole-body segmentation in non-contrast-enhanced Micro-CT data of mice. The position and posture of mice in such studies may vary to a large extent, complicating data comparison in cross-sectional and follow-up studies. Moreover, Micro-CT typically yields only poor soft-tissue contrast for abdominal organs. To overcome these challenges, we propose a method that divides the problem into an atlas constrained registration based on high-contrast organs in Micro-CT (skeleton, lungs and skin), and a soft tissue approximation step for low-contrast organs. We first present a modification of the MOBY mouse atlas (Segars et al., 2004) by partitioning the skeleton into individual bones, by adding anatomically realistic joint types and by defining a hierarchical atlas tree description. The individual bones as well as the lungs of this adapted MOBY atlas are then registered one by one traversing the model tree hierarchy. To this end, we employ the Iterative Closest Point method and constrain the Degrees of Freedom of the local registration, dependent on the joint type and motion range. This atlas-based strategy renders the method highly robust to exceptionally large postural differences among scans and to moderate pathological bone deformations. The skin of the torso is registered by employing a novel method for matching distributions of geodesic distances locally, constrained by the registered skeleton. Because of the absence of image contrast between abdominal organs, they are interpolated from the atlas to the subject domain using Thin-Plate-Spline approximation, defined by correspondences on the already established registration of high-contrast structures (bones, lungs and skin). We extensively evaluate the proposed registration method, using 26 non-contrast-enhanced Micro-CT datasets of mice, and the skin registration and organ interpolation, using contrast-enhanced Micro-CT datasets of 15 mice. The posture and shape varied significantly among the animals and the data was acquired in vivo. After registration, the mean Euclidean distance was less than two voxel dimensions for the skeleton and the lungs respectively and less than one voxel dimension for the skin. Dice coefficients of volume overlap between manually segmented and interpolated skeleton and organs vary between 0.47±0.08 for the kidneys and 0.73±0.04 for the brain. These experiments demonstrate the method’s effectiveness for overcoming exceptionally large variations in posture, yielding acceptable approximation accuracy even in the absence of soft-tissue contrast in in vivo Micro-CT data without requiring user initialization. [Copyright &y& Elsevier]

Purpose: [C]Choline has been established as a PET tracer for imaging prostate cancer. The aim of this study was to determine whether [C]choline can be used for monitoring the effects of therapy in a prostate cancer mouse xenograft model. Methods: The androgen-independent human prostate cancer cell line PC-3 was implanted subcutaneously into the flanks of 13 NMRI (nu/nu) mice. All mice were injected 4–6 weeks after xenograft implantation with 37 MBq [C]choline via a tail vein. Dynamic imaging was performed for 60 min with a small-animal PET/CT scanner (Siemens Medical Solutions). Six mice were subsequently injected intravenously with docetaxel twice (days 1 and 5) at a dose of 3 mg/kg body weight. Seven mice were treated with PBS as a control. [C]Choline imaging was performed prior to and 1, 2 and 3 weeks after treatment. To determine choline uptake the images were analysed in terms of tumour-to-muscle (T/M) ratios. Every week the size of the implanted tumour was determined with a sliding calliper. Results: The PC-3 tumours could be visualized by [C]choline PET. Before treatment the T/M ratio was 1.6±0.5 in the control group and 1.8±0.4 in the docetaxel-treated group ( p=0.65). There was a reduction in the mean [C]choline uptake after docetaxel treatment as early as 1 week after initiation of therapy (T/M ratio 1.8±0.4 before treatment, 0.9±0.3 after 1 week, 1.1±0.3 after 2 weeks and 0.8±0.2 after 3 weeks). There were no decrease in [C]choline uptake in the control group following treatment (T/M ratio 1.6±0.5 before treatment, 1.7±0.4 after 1 week, 1.8±0.7 after 2 weeks and 1.7±0.4 after 3 weeks). For analysis of the dynamic data, a generalized estimation equation model revealed a significant decrease in the T/M ratios 1 week after docetaxel treatment, and the ratio remained at that level through week 3 (mean change −0.93±0.24, p<0.001, after 1 week; −0.78±0.21, p<0.001, after 2 weeks; −1.08±0.26, p<0.001, after 3 weeks). In the control group there was no significant decrease in the T/M ratios (mean change 0.085±0.39, p=0.83, after 1 week; 0.31±0.48, p=0.52, after 2 weeks; 0.11±0.30, p=0.72, after 3 weeks). Metabolic changes occurred 1 week after therapy and preceded morphological changes of tumour size during therapy. Conclusion: Our results demonstrate that [C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a prostate cancer xenograft animal model. The results also indicate that PET with radioactively labelled choline derivatives might be a useful tool for monitoring responses to taxane-based chemotherapy in patients with advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: p21Waf1 (p21) was described as a cyclin-dependent kinase inhibitor, but other p21 activities have subsequently been described, including its ability to inhibit apoptosis in some models. Comparative work on the human colon cancer isogenic cell lines HCT116 and HCT116p21−/− led to the proposal that p21 protects colon cancer cells against apoptosis by genotoxic drugs. We asked whether p21 also protected from cell death induced by non-genotoxic drugs, such as tyrosine kinase inhibitors. We found that p21-deficient cells were dramatically more sensitive towards imatinib and gefitinib than parental cells. Interestingly, HCT116p21−/− also showed higher basal activity of protein kinases as c-Abl, c-Src, and Akt. We generated HCT116p21−/− sublines with inducible p21 expression and found that p21 did not rescue the hypersensitivity to imatinib. Moreover, down-regulation of p21 by enforced c-Myc expression or by p21 siRNA did not sensitize parental HCT116 cells. We found that, in HCT116p21−/− cells, p53 showed higher stability, higher transcriptional activity and phosphorylation in serines associated with p53 activity. Furthermore, silencing of p53 with siRNA and inactivation of p53 with a dominant negative mutant rescued the hypersensitive response to kinases inhibitors, 5-fluorouracil and adriamycin in HCT116p21−/− cells. Consistently, HCT116p53−/− cells are more resistant to imatinib than parental cells, suggesting that imatinib activity is partly dependent on p53 in colon cancer cells. We conclude that high p53 activity, rather than p21 deficiency, is the mechanism responsible for hypersensitivity to drugs of HCT116p21−/− cells. Therefore the role of p21 on apoptosis of HCT116 colon cancer cells should be re-evaluated. [Copyright &y& Elsevier]

This article reports on the continuous activities of Deutsche Telekom in setting up comprehensive ASON/GMPLS network demonstrators. The goal is to enable practical evaluations and early experiences with prototype implementations related to new standards and specifications from ITU-T, IETF, and OIF. Evolving from the GSN Demonstrator toward the current GSN+ Demonstrator configuration, this field testbed comprises ASON/GMPLS-based backbone network domains, as well as key client networks such as IP, Ethernet (metro and access networks), storage area networks, and broadband video applications to exemplify the wide range of network functions enabled by these new technologies. These ASON/GMPLS demonstrator activities were embedded in the OIF World Interoperability Tests and Demonstration in 2004, and are linked with the German national (VIOLA) and pan-European (MUPBED) project activities ensuring the highest level of interoperable implementations. [ABSTRACT FROM AUTHOR]

Objective: Fronto-striatal dysfunction has been discussed as underlying symptoms of Tourette syndrome (TS) with co-morbid Obsessive Compulsive Disorder (OCD). This suggests possible impairments of executive functions in this disorder, which were therefore targeted in the present study.Methods: A comprehensive series of neuropsychological tests examining attention, memory and executive functions was performed in a group of 14 TS/OCD in co-occurrence with OCD patients and a matched control group.Results: While attentional and memory mechanisms were not altered, TS/OCS patients showed deficits in executive functions predominately in the areas of response inhibition and action monitoring.Conclusions: These findings provide further evidence for a substantial impairment of the frontal-striatal-thalamic-frontal circuit. We propose that the deficits in monitoring, error detection and response inhibition constitute the major impairment of TS/OCD patients in the cognitive domain. [ABSTRACT FROM AUTHOR]

Simple Summary: Here, we reveal that basal turnover and autophagy-induced decay of the ubiquitin E3 ligase TRAF6 is antagonized by IKKε-mediated phosphorylation at five serines. Phosphoproteomic experiments show that TRAF6 and its phosphorylation contribute to the remodeling of LPS- and autophagyinduced signaling networks, revealing an intricate link between inflammatory and metabolic processes that are frequently dysregulated in cancer. The ubiquitin E3 ligase TNF Receptor Associated Factor 6 (TRAF6) participates in a large number of different biological processes including innate immunity, differentiation and cell survival, raising the need to specify and shape the signaling output. Here, we identify a lipopolysaccharide (LPS)-dependent increase in TRAF6 association with the kinase IKKε (inhibitor of NF-κB kinase subunit ε) and IKKε-mediated TRAF6 phosphorylation at five residues. The reconstitution of TRAF6-deficient cells, with TRAF6 mutants representing phosphorylation-defective or phospho-mimetic TRAF6 variants, showed that the phospho-mimetic TRAF6 variant was largely protected from basal ubiquitin/proteasome-mediated degradation, and also from autophagy-mediated decay in autolysosomes induced by metabolic perturbation. In addition, phosphorylation of TRAF6 and its E3 ligase function differentially shape basal and LPS-triggered signaling networks, as revealed by phosphoproteome analysis. Changes in LPS-triggered phosphorylation networks of cells that had experienced autophagy are partially dependent on TRAF6 and its phosphorylation status, suggesting an involvement of this E3 ligase in the interplay between metabolic and inflammatory circuits. [ABSTRACT FROM AUTHOR]