julilili42/papers huggingface dataset:
Pharmacokinetics and PET imaging properties of two recombinant anti-PSMA antibody fragments in comparison to their parental antibody
2014-03-09

Stable tumor uptake and fast serum clearance of the tested radiolabeled fragments was observed in this preclinical study compared to the full length mAb. Since the fragments show rapid and specific tumor uptake, the tested fragments might serve as tools for theranostic imaging with suitable isotopes for radioimmunotherapy.
Selectivity and Potency of Microcystin Congeners against OATP1B1 and OATP1B3 Expressing Cancer Cells
2014-03-10

Microcystins are potent phosphatase inhibitors and cellular toxins. They require active transport by OATP1B1 and OATP1B3 transporters for uptake into human cells, and the high expression of these transporters in the liver accounts for their selective hepatic toxicity. Several human tumors have been shown to have high levels of expression of OATP1B3 but not OATP1B1, the main transporter in liver cells. We hypothesized that microcystin variants could be isolated that are transported preferentially by OATP1B3 relative to OATP1B1 to advance as anticancer agents with clinically tolerable hepatic toxicity. Microcystin variants have been isolated and tested for cytotoxicity in cancer cells stably transfected with OATP1B1 and OATP1B3 transporters. Microcystin variants with cytotoxic OATP1B1/OATP1B3 IC50 ratios that ranged between 0.2 and 32 were found, representing a 150-fold range in transporter selectivity. As microcystin structure has a significant impact on transporter selectivity, it is potentially possible to develop analogs with even more pronounced OATP1B3 selectivity and thus enable their development as anticancer drugs.
p38 MAPK inhibitors: a patent review (2012 – 2013)
2014-03-10

The most promising approach is the development of linear binders, which induce a glycine flip at Gly110 of the kinase hinge region by a carbonyl oxygen atom of the respective ligand. The major focus of the patent works was the application of molecules in new indications. Previous applications were in the treatment of rheumatoid arthritis; currently, there are several new applications, including pulmonary diseases, cancer and Alzheimer's disease. Targeting p38 upstream kinases and downstream effectors has also proved to be a very promising step in the development of more effective inhibitors. A further trend is drug combination, applied to a wide range of indications, such as chronic obstructive pulmonary disease and cancer.
The Delineation of Paleo-Shorelines in the Lake Manyara Basin Using TerraSAR-X Data
2014-03-10

The purpose of this paper is to describe the delineation of paleo-shorelines using high resolution microwave images and digital image processing tools, and with that to contribute to the understanding of the complex landscape evolution of the Lake Manyara Basin. The surroundings of Lake Manyara are the focus of several paleo-archeological investigations, since the location is close to Olduvai Gorge, where paleo-anthropological findings can be traced back to homo habilis. In the catchment of Lake Manyara two hominin-bearing sites (0.78 to 0.63 Ma), lots of vertebrate fossils and hand axes from different periods were found. Understanding the development and extent of the lake is crucial for understanding the regional paleo-environment of the Quaternary. Morphological structures of shorelines and terraces east of Lake Manyara were identified from TerraSAR-X StripMap images. By applying a Canny edge detector, linear features were extracted and revised for different image acquisitions using a contextual approach. Those features match literature and field references. A digital elevation model of the region was used to map the most distinct paleo-shorelines according to their elevation.
The effect of brain lesions on sound localization in complex acoustic environments
2014-03-10

Localizing sound sources of interest in cluttered acoustic environments--as in the 'cocktail-party' situation--is one of the most demanding challenges to the human auditory system in everyday life. In this study, stroke patients' ability to localize acoustic targets in a single-source and in a multi-source setup in the free sound field were directly compared. Subsequent voxel-based lesion-behaviour mapping analyses were computed to uncover the brain areas associated with a deficit in localization in the presence of multiple distracter sound sources rather than localization of individually presented sound sources. Analyses revealed a fundamental role of the right planum temporale in this task. The results from the left hemisphere were less straightforward, but suggested an involvement of inferior frontal and pre- and postcentral areas. These areas appear to be particularly involved in the spectrotemporal analyses crucial for effective segregation of multiple sound streams from various locations, beyond the currently known network for localization of isolated sound sources in otherwise silent surroundings.
Neuron-Specific Alterations in Signal Transduction Pathways associated with Alzheimer's Disease
2014-03-10

The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways. We performed single-cell analyses of neurons with different vulnerabilities to AD-related changes. Using quantitative PCR (qPCR), we measured the levels of MAPK1 and PRKCB transcript in CA1 (high vulnerability), CA2 pyramidal cells from the hippocampus, granule cells from the cerebellum (low vulnerability), and neurons from the brain stem (nucleus tractus spinalis nervi trigemini, characterized by early neurophysiological deficits) at progressive Braak stages compared to age-matched controls. The highly vulnerable CA1 pyramidal neurons were characterized by age- and disease-unrelated increases in PRCKB levels and by age- and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region-specific manner. In addition, multiple signal transduction pathways need to be affected to result in AD instead of physiological aging.
Unraveling the Equine Lymphocyte Proteome: Differential Septin 7 Expression Associates with Immune Cells in Equine Recurrent Uveitis
2014-03-10

Equine recurrent uveitis is a spontaneous, lymphocyte-driven autoimmune disease. It affects horses worldwide and presents with painful remitting-relapsing inflammatory attacks of inner eye structures eventually leading to blindness. Since lymphocytes are the key players in equine recurrent uveitis, we were interested in potential changes of their protein repertoire which may be involved in disease pathogenesis. To create a reference for differential proteome analysis, we first unraveled the equine lymphocyte proteome by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and subsequently identified 352 protein spots. Next, we compared lymphocytes from ERU cases and healthy horses with a two-dimensional fluorescence difference in gel electrophoresis approach. With this technique, we identified seven differentially expressed proteins between conditions. One of the significantly lower expressed candidates, septin 7, plays a role in regulation of cell shape, motility and migration. Further analyses revealed T cells as the main cell type with decreased septin 7 abundance in equine recurrent uveitis. These findings point to a possible pathogenetic role of septin 7 in this sight-threatening disease.
Optical knife-edge displacement sensor for high-speed atomic force microscopy
2014-03-10

Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter Facebook Reddit LinkedIn Tools Icon Tools Reprints and Permissions Cite Icon Cite Search Site Citation Christoph Braunsmann, Veronika Prucker, Tilman E. Schäffer; Optical knife-edge displacement sensor for high-speed atomic force microscopy. Appl. Phys. Lett. 10 March 2014; 104 (10): 103101. https://doi.org/10.1063/1.4868043 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAIP Publishing PortfolioApplied Physics Letters Search Advanced Search |Citation Search
Tumour necrosis factor receptor superfamily member 9 (TNFRSF9) is up‐regulated in reactive astrocytes in human gliomas
2014-03-10

Aims The prognosis of patients with malignant gliomas is still dismal despite maximum treatment. Novel therapeutic alternatives targeting tumorigenic pathways are, therefore, demanded. In murine glioma models, targeting of tumour necrosis factor receptor superfamily ( TNFRSF ) 9 led to complete tumour eradication. Thus, TNFRSF 9 might also constitute a promising target in human diffuse gliomas. As there is a lack of data, we aimed to define the expression pattern and cellular source of TNFRSF 9 in human gliomas. Methods We investigated TNFRSF 9 expression in normal human central nervous system ( CNS ) tissue and glioma specimens using immunohistochemistry, immunofluorescence and W estern blotting techniques. Results Our results show that TNFRSF 9 is considerably up‐regulated in human gliomas when compared with normal brain tissue. In addition, our data provides evidence for an immune cell‐independent de novo expression pattern of TNFRSF 9 in mainly non‐neoplastic reactive astrocytes and excludes classic immunological cell types, namely lymphocytes and microglia as the source of TNFRSF 9. Moreover, TNFRSF 9 is predominantly expressed in a perivascular and peritumoural distribution with significantly higher expression in IDH ‐1 mutant gliomas. Conclusions Our findings provide a novel, TNFRSF 9‐positive, reactive astrocytic phenotype and challenge the therapeutic suitability of TNFRSF 9 as a promising target for human gliomas.
Genome-wide association study reveals two new risk loci for bipolar disorder
2014-03-11

Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.
Metaplasticity in Human Cortex
2014-03-11

Metaplasticity refers to the modification of plasticity induction (direction, magnitude, duration) by previous activity of the same postsynaptic neuron or neuronal network. In recent years evidence from animal studies has been accumulated that metaplasticity significantly contributes to network function and behavior. Here, we review the evidence for metaplasticity at the system level of the human cortex as investigated by non-invasive brain stimulation. These studies support the notion that metaplasticity is also operative in the human brain and is mostly homeostatic in nature, that is, keeping network activity within a physiological range. However, non-homeostatic metaplasticity has also been described, which can increase non-invasive brain stimulation–induced aftereffects on cortical excitability, or learning. Current evidence further suggests that aberrant metaplasticity may underlie some neurological and psychiatric diseases. Finally, first proof-of-principle studies show that the concept of metaplasticity can be harnessed for treatment of patients suffering from brain diseases.
Overexpression of the calpain-specific inhibitor calpastatin reduces human alpha-Synuclein processing, aggregation and synaptic impairment in [A30P]αSyn transgenic mice
2014-03-11

Lewy bodies, a pathological hallmark of Parkinson's disease (PD), contain aggregated alpha-synuclein (αSyn), which is found in several modified forms and can be discovered phosphorylated, ubiquitinated and truncated. Aggregation-prone truncated species of αSyn caused by aberrant cleavage of this fibrillogenic protein are hypothesized to participate in its sequestration into inclusions subsequently leading to synaptic dysfunction and neuronal death. Here, we investigated the role of calpain cleavage of αSyn in vivo by generating two opposing mouse models. We crossed into human [A30P]αSyn transgenic (i) mice deficient for calpastatin, a calpain-specific inhibitor, thus enhancing calpain activity (SynCAST(-)) and (ii) mice overexpressing human calpastatin leading to reduced calpain activity (SynCAST(+)). As anticipated, a reduced calpain activity led to a decreased number of αSyn-positive aggregates, whereas loss of calpastatin led to increased truncation of αSyn in SynCAST(-). Furthermore, overexpression of calpastatin decreased astrogliosis and the calpain-dependent degradation of synaptic proteins, potentially ameliorating the observed neuropathology in [A30P]αSyn and SynCAST(+) mice. Overall, our data further support a crucial role of calpains, particularly of calpain 1, in the pathogenesis of PD and in disease-associated aggregation of αSyn, indicating a therapeutic potential of calpain inhibition in PD.
Cyclical Appearance of African Trypanosomes in the Cerebrospinal Fluid: New Insights in How Trypanosomes Enter the CNS
2014-03-11

It is textbook knowledge that human infective forms of Trypanosoma brucei, the causative agent of sleeping sickness, enter the brain across the blood-brain barrier after an initial phase of weeks (rhodesiense) or months (gambiense) in blood. Based on our results using an animal model, both statements seem questionable. As we and others have shown, the first infection relevant crossing of the blood brain border occurs via the choroid plexus, i.e. via the blood-CSF barrier. In addition, counting trypanosomes in blood-free CSF obtained by an atlanto-occipital access revealed a cyclical infection in CSF that was directly correlated to the trypanosome density in blood infection. We also obtained conclusive evidence of organ infiltration, since parasites were detected in tissues outside the blood vessels in heart, spleen, liver, eye, testis, epididymis, and especially between the cell layers of the pia mater including the Virchow-Robin space. Interestingly, in all organs except pia mater, heart and testis, trypanosomes showed either a more or less degraded appearance of cell integrity by loss of the surface coat (VSG), loss of the microtubular cytoskeleton and loss of the intracellular content, or where taken up by phagocytes and degraded intracellularly within lysosomes. This is also true for trypanosomes placed intrathecally into the brain parenchyma using a stereotactic device. We propose a different model of brain infection that is in accordance with our observations and with well-established facts about the development of sleeping sickness.
The actin cytoskeleton in rapid steroid hormone actions
2014-03-11

Early actin cytoskeleton reorganization is an important regulatory step of membrane‐initiated, non‐genomic steroid hormone actions. Specific intracellular signaling cascades control the rapid alterations of actin polymerization in a variety of cell models. Moreover, actin remodeling is a decisive component in the signaling of hormone‐induced early and late cellular responses. This article briefly summarizes the current knowledge on the steroid hormone‐induced early actin cytoskeleton rearrangements. It focuses on the current progress to characterize the glucocorticoid‐ and androgen‐initiated, tissue‐specific actin signaling pathways and discusses the plethora of cellular responses that are regulated by the early actin redistribution. It also provides insights into the potential clinical significance of actin dynamics and actin‐specific molecular signaling for nongenomic steroid hormone actions on tumor cells. © 2014 Wiley Periodicals, Inc.
Inhibition by Cellular Vacuolar ATPase Impairs Human Papillomavirus Uncoating and Infection
2014-03-11

ABSTRACT Several viruses, including human papillomaviruses, depend on endosomal acidification for successful infection. Hence, the multisubunit enzyme vacuolar ATPase (V-ATPase), which is mainly responsible for endosome acidification in the cell, represents an attractive target for antiviral strategies. In the present study, we show that V-ATPase is required for human papillomavirus (HPV) infection and that uncoating/disassembly but not endocytosis is affected by V-ATPase inhibition. The infection inhibitory potencies of saliphenylhalamide, a proven V-ATPase inhibitor, and its derivatives, as well as those of other V-ATPase inhibitors, were analyzed on different HPV types in relevant cell lines. Variation in the selectivity indices among V-ATPase inhibitors was high, while variation for the same inhibitor against different HPV subtypes was low, indicating that broad-spectrum anti-HPV activity can be provided.
The Relationship between Mindfulness and the Mental Self-Boundary: Validation of the Boundary Protection Scale-14 (BPS-14) and Its Correlation with the Freiburg Mindfulness Inventory (FMI)
2014-03-11

The Boundary Protection Scale - 14 (BPS-14) represents a new instrument to capture the degree of protection of the mental self-boundary for use in mindfulness training, therapeutic work and scientific research. We assumed a relation between the ability to protect the self-boundary and mindfulness skills. For more efficient use the original version consisting 20 items was abridged and studied with regard to its validity and reliability. Also first reference values were calculated in a sample of 1,089 subjects, consisting predominantly of students. The total score of the abridged version with 14 items shows an acceptable reliability (Cronbach's ? = 0.79) and a medium correlation (r = -0.48) with mindfulness, measured by means of the Freiburg Mindfulness Inventory (FMI), regarding the convergent validity. Further studies are encouraged, as well as use of the BPS in mindfulness research, social neuroscience or everyday life.
To Repress or Not to Repress—Regime Survival Strategies in the Arab Spring
2014-03-12

Authoritarian regimes use repression as an essential strategy to attain regime stability and survival. During the Arab Spring, different forms of repression have been employed. We argue that to explain this variation, three bundles of characteristics have to be taken into account: the setup of the regime, the state, and the challenge. As we assume that elites have a wider repertoire of strategies besides repression at their disposal, the analysis of repression has to be embedded in a broader framework of strategies of rule. Including specific forms and target groups of repression, we develop an explanatory model addressing the question of which repressive measures rulers utilize under which circumstances. The postulated relationship between repression and characteristics of the state, regime, and challenge are then tested in a comparative analysis of the reactions to the challenges arising with the 2011 uprisings in two very different Arab countries, Bahrain and Egypt. On the basis of these empirical findings, we propose a readjusted model explaining repression.
Shaping Memory Accuracy by Left Prefrontal Transcranial Direct Current Stimulation
2014-03-12

Human memory is dynamic and flexible but is also susceptible to distortions arising from adaptive as well as pathological processes. Both accurate and false memory formation require executive control that is critically mediated by the left prefrontal cortex (PFC). Transcranial direct current stimulation (tDCS) enables noninvasive modulation of cortical activity and associated behavior. The present study reports that tDCS applied to the left dorsolateral PFC (dlPFC) shaped accuracy of episodic memory via polaritiy-specific modulation of false recognition. When applied during encoding of pictures, anodal tDCS increased whereas cathodal stimulation reduced the number of false alarms to lure pictures in subsequent recognition memory testing. These data suggest that the enhancement of excitability in the dlPFC by anodal tDCS can be associated with blurred detail memory. In contrast, activity-reducing cathodal tDCS apparently acted as a noise filter inhibiting the development of imprecise memory traces and reducing the false memory rate. Consistently, the largest effect was found in the most active condition (i.e., for stimuli cued to be remembered). This first evidence for a polarity-specific, activity-dependent effect of tDCS on false memory opens new vistas for the understanding and potential treatment of disturbed memory control.
Operational Momentum Affects Eye Fixation Behaviour
2014-03-12

The operational momentum effect (OM) indicates an association of mental addition with a rightward spatial bias, whereas subtraction is associated with a leftward bias. To evaluate the assumed attentional origin of the OM effect, we evaluated not only participants’ relative estimation error in a task requiring them to locate addition and subtraction results on a given number line but also their eye-fixation behaviour. Furthermore, to investigate the situatedness of spatial–numerical associations, the orientation of the number line (left-to-right vs. right-to left) was manipulated. OM biases in participants’ explicit number line estimations and more implicit eye-fixation behaviour are integrated into a two-process hypothesis of the OM effect suggesting a first rough spatial anticipation followed by an evaluation/correction process. This account not only is capable of accounting for the results observed for participants’ relative estimation error but is also corroborated by the eye-fixation results. Importantly, the fact that all effects were found independent of the orientation of the number line indicates that spatial–numerical associations such as the OM effect may not be hard-wired associations of spatial and numerical representations but rather reflect influences of situatedness on numerical cognition.