Filling the void - enriching the feature space of successful stopping

The ability to inhibit behavior is crucial for adaptation in a fast changing environment and is commonly studied with the stop signal task. Current EEG research mainly focuses on the N200 and P300 ERPs and corresponding activity in the theta and delta frequency range, thereby leaving us with a limited understanding of the mechanisms of response inhibition. Here, 15 functional networks were estimated from time-frequency transformed EEG recorded during processing of a visual stop signal task. Cortical sources underlying these functional networks were reconstructed, and a total of 45 features, each representing spectrally and temporally coherent activity, were extracted to train a classifier to differentiate between go and stop trials. A classification accuracy of 85.55% for go and 83.85% for stop trials was achieved. Features capturing fronto-central delta- and theta activity, parieto-occipital alpha, fronto-central as well as right frontal beta activity were highly discriminating between trial-types. However, only a single network, comprising a feature defined by oscillatory activity below 12 Hz, was associated with a generator in the opercular region of the right inferior frontal cortex and showed the expected associations with behavioral inhibition performance. This study pioneers by providing a detailed ranking of neural features regarding their information content for stop and go differentiation at the single-trial level, and may further be the first to identify a scalp EEG marker of the inhibitory control network. This analysis allows for the characterization of the temporal dynamics of response inhibition by matching electrophysiological phenomena to cortical generators and behavioral inhibition performanc

Version 4.0 of PaxDb: Protein abundance data, integrated across model organisms, tissues, and cell-lines

Protein quantification at proteome-wide scale is an important aim, enabling insights into fundamental cellular biology and serving to constrain experiments and theoretical models. While proteome-wide quantification is not yet fully routine, many datasets approaching proteome-wide coverage are becoming available through biophysical and MS techniques. Data of this type can be accessed via a variety of sources, including publication supplements and online data repositories. However, access to the data is still fragmentary, and comparisons across experiments and organisms are not straightforward. Here, we describe recent updates to our database resource "PaxDb" (Protein Abundances Across Organisms). PaxDb focuses on protein abundance information at proteome-wide scope, irrespective of the underlying measurement technique. Quantification data is reprocessed, unified, and quality-scored, and then integrated to build a meta-resource. PaxDb also allows evolutionary comparisons through precomputed gene orthology relations. Recently, we have expanded the scope of the database to include cell-line samples, and more systematically scan the literature for suitable datasets. We report that a significant fraction of published experiments cannot readily be accessed and/or parsed for quantitative information, requiring additional steps and efforts. The current update brings PaxDb to 414 datasets in 53 organisms, with (semi-) quantitative abundance information covering more than 300,000 proteins

CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis

The mammalian cleavage factor I (CFIm) has been implicated in alternative polyadenylation (APA) in a broad range of contexts, from cancers to learning deficits and parasite infections. To determine how the CFIm expression levels are translated into these diverse phenotypes, we carried out a multi-omics analysis of cell lines in which the CFIm25 (NUDT21) or CFIm68 (CPSF6) subunits were either repressed by siRNA-mediated knockdown or over-expressed from stably integrated constructs. We established that >800 genes undergo coherent APA in response to changes in CFIm levels, and they cluster in distinct functional classes related to protein metabolism. The activity of the ERK pathway traces the CFIm concentration, and explains some of the fluctuations in cell growth and metabolism that are observed upon CFIm perturbations. Furthermore, multiple transcripts encoding proteins from the miRNA pathway are targets of CFIm-dependent APA. This leads to an increased biogenesis and repressive activity of miRNAs at the same time as some 3' UTRs become shorter and presumably less sensitive to miRNA-mediated repression. Our study provides a first systematic assessment of a core set of APA targets that respond coherently to changes in CFIm protein subunit levels (CFIm25/CFIm68). We describe the elicited signaling pathways downstream of CFIm, which improve our understanding of the key role of CFIm in integrating RNA processing with other cellular activities

Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine

Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, as an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients

Sickle cell trait (HbAS) and stunting in children below two years of age in an area of high malaria transmission

<p>Abstract</p> <p>Background</p> <p>While the protective effects of sickle cell trait (HbAS) against severe malaria and the resulting survival advantage are well known, the impact on the physical development in young children remains unclear. This study was aimed to investigate the relationship between HbS carriage and stunting in children below two years of age in a cohort from the Ashanti Region, Ghana.</p> <p>Methods</p> <p>1,070 children were recruited at three months of age and followed-up for 21 months with anthropometric measurements performed every three months. Incidence rate ratios with 95% confidence intervals were calculated by Poisson regression to estimate the association of β-globin genotypes with the number of malaria episodes. Odds ratios (OR) were calculated for the association between the occurrence of β-globin genotypes and/or malaria episodes and stunting. The age-dependent between-group and within-group effects for the β-globin genotypes were assessed by population-averaged models estimated by generalized estimation equation with autoregressive correlation structure.</p> <p>Results</p> <p>Analyses showed a significantly lower age-dependent risk of stunting (OR 0.56; 95% CI 0.33–0.96) in carriers of the HbAS genotype (n = 102) in comparison to those with HbAA (n = 692). This effect was restricted to children who experienced malaria episodes during the observation period suggesting that the beneficial effect of the β-globin HbS variant on the incidence of stunting is closely linked to its protection from mild malaria episodes.</p> <p>Conclusion</p> <p>The lower risk of chronic malnutrition in early childhood, mediated by protection against mild malaria episodes, may contribute to the survival advantage of HbAS carriers in areas of high malaria transmission.</p

A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity.

Keratin intermediate filaments (KIFs) protect the epidermis against mechanical force, support strong adhesion, help barrier formation, and regulate growth. The mechanisms by which type I and II keratins contribute to these functions remain incompletely understood. Here, we report that mice lacking all type I or type II keratins display severe barrier defects and fragile skin, leading to perinatal mortality with full penetrance. Comparative proteomics of cornified envelopes (CEs) from prenatal KtyI(-/-) and KtyII(-/-)(K8) mice demonstrates that absence of KIF causes dysregulation of many CE constituents, including downregulation of desmoglein 1. Despite persistence of loricrin expression and upregulation of many Nrf2 targets, including CE components Sprr2d and Sprr2h, extensive barrier defects persist, identifying keratins as essential CE scaffolds. Furthermore, we show that KIFs control mitochondrial lipid composition and activity in a cell-intrinsic manner. Therefore, our study explains the complexity of keratinopathies accompanied by barrier disorders by linking keratin scaffolds to mitochondria, adhesion, and CE formation

Acute effects of intracranial hypertension and ARDS on pulmonary and neuronal damage: a randomized experimental study in pigs

Abstract PURPOSE: To determine reciprocal and synergistic effects of acute intracranial hypertension and ARDS on neuronal and pulmonary damage and to define possible mechanisms. METHODS: Twenty-eight mechanically ventilated pigs were randomized to four groups of seven each: control; acute intracranial hypertension (AICH); acute respiratory distress syndrome (ARDS); acute respiratory distress syndrome in combination with acute intracranial hypertension (ARDS + AICH). AICH was induced with an intracranial balloon catheter and the inflation volume was adjusted to keep intracranial pressure (ICP) at 30-40 cmH2O. ARDS was induced by oleic acid infusion. Respiratory function, hemodynamics, extravascular lung water index (ELWI), lung and brain computed tomography (CT) scans, as well as inflammatory mediators, S100B, and neuronal serum enolase (NSE) were measured over a 4-h period. Lung and brain tissue were collected and examined at the end of the experiment. RESULTS: In both healthy and injured lungs, AICH caused increases in NSE and TNF-alpha plasma concentrations, extravascular lung water, and lung density in CT, the extent of poorly aerated (dystelectatic) and atelectatic lung regions, and an increase in the brain tissue water content. ARDS and AICH in combination induced damage in the hippocampus and decreased density in brain CT. CONCLUSIONS: AICH induces lung injury and also exacerbates pre-existing damage. Increased extravascular lung water is an early marker. ARDS has a detrimental effect on the brain and acts synergistically with intracranial hypertension to cause histological hippocampal damage

Structure and Functional Analysis of the RNA- and Viral Phosphoprotein-Binding Domain of Respiratory Syncytial Virus M2-1 Protein

Respiratory syncytial virus (RSV) protein M2-1 functions as an essential transcriptional cofactor of the viral RNA-dependent RNA polymerase (RdRp) complex by increasing polymerase processivity. M2-1 is a modular RNA binding protein that also interacts with the viral phosphoprotein P, another component of the RdRp complex. These binding properties are related to the core region of M2-1 encompassing residues S58 to K177. Here we report the NMR structure of the RSV M2-158–177 core domain, which is structurally homologous to the C-terminal domain of Ebola virus VP30, a transcription co-factor sharing functional similarity with M2-1. The partial overlap of RNA and P interaction surfaces on M2-158–177, as determined by NMR, rationalizes the previously observed competitive behavior of RNA versus P. Using site-directed mutagenesis, we identified eight residues located on these surfaces that are critical for an efficient transcription activity of the RdRp complex. Single mutations of these residues disrupted specifically either P or RNA binding to M2-1 in vitro. M2-1 recruitment to cytoplasmic inclusion bodies, which are regarded as sites of viral RNA synthesis, was impaired by mutations affecting only binding to P, but not to RNA, suggesting that M2-1 is associated to the holonucleocapsid by interacting with P. These results reveal that RNA and P binding to M2-1 can be uncoupled and that both are critical for the transcriptional antitermination function of M2-1

Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science

Optics and Quantum Electronics

Contains table of contents on Section 3 and reports on nineteen research projects.Defense Advanced Research Projects Agency Grant F49620-96-0126Joint Services Electronics Program Grant DAAH04-95-1-0038National Science Foundation Grant ECS 94-23737U.S. Air Force - Office of Scientific Research Contract F49620-95-1-0221U.S. Navy - Office of Naval Research Grant N00014-95-1-0715Defense Advanced Research Projects Agency/National Center for Integrated Photonics TechnologyMultidisciplinary Research InitiativeU.S. Air Force - Office of Scientific ResearchNational Science Foundation/MRSECU.S. Navy - Office of Naval Research (MFEL) Contract N00014-91-J-1956National Institutes of Health Grant R01-EY11289U.S. Navy - Office of Naval Research (MFEL) Contract N00014-94-0717Defense Advanced Research Projects Agency Contract N66001-96-C-863