julilili42/papers huggingface dataset:
Serum Levels of Progranulin Do Not Reflect Cerebrospinal Fluid Levels in Neurodegenerative Disease.
2016-01-01

Altered progranulin levels play a major role in neurodegenerative diseases, like Alzheimer's dementia (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), even in the absence of GRN mutations. Increasing progranulin levels could hereby provide a novel treatment strategy. However, knowledge on progranulin regulation in neurodegenerative diseases remains limited. We here demonstrate that cerebrospinal fluid progranulin levels do not correlate with its serum levels in AD, FTD and ALS, indicating a differential regulation of its central and peripheral levels in neurodegeneration. Blood progranulin levels thus do not reliably predict central nervous progranulin levels and their response to future progranulin-increasing therapeutics.
The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels
2016-01-01

Background/Aims: Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K+ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. Methods: Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.1 channels. Results: We show that currents carried by Kv7.1 (EC50 = 1.48 μM), Kv7.1/KCNE1 (EC50 = 4.9 μM), and Kv7.4 (EC50 = 0.148 μM) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1.Conclusion: Rottlerin or an optimized derivative holds a potential as QT interval correcting drug.
Incidence and Impact of Lymph Node Metastases in Advanced Ovarian Cancer: Implications for Surgical Treatment
2016-01-01

<b>Background:</b> This study aimed to clarify the impact of node involvement (affected to resected nodes) in optimally cytoreduced (residual tumour ≤1cm) stage IIIC/IV ovarian cancer. <b>Methods:</b> 108 consecutive patients with primary stage IIIC/IV ovarian cancer underwent stage-related surgery and got adjuvant platinum-based chemotherapy. Median follow-up: 53.5 months. All patients got systematic para-aortic and pelvic lymphadenectomy. Clinical parameters were retrospectively evaluated. Patients were stratified into 3 groups to evaluate node affection: 1) no (0%), 2) minor (>0%, ≤50%) >0 and 3) major (>50% of affected nodes). Kaplan-Meier survival curve was used to evaluate the prognostic value. <b>Results:</b> On average, 21.3 pelvic and para-aortic nodes were removed per patient (range 1-60 nodes). Minor nodal involvement (node ratio >0-≤0.5: (59%) was most often detected. Increasing node ratio leads to significant decreased overall survival (p<0.001)<i>.</i> Significant best overall survival was associated with minor node involvement (node ratio >0 to ≤0.5). Complete cytoreduction correlated with node affection shows significant best prognostic impact in minor node affection compared to incomplete resection (R>0-≤1cm) independent to nodal status (OS p<0.001). <b>Conclusion:</b> Radical surgery is the main factor of improved overall and tumor free survival. Paraaortal and iliacal lymphadenectomy seems to play an important role for prognostic and therapeutic reasons: Prognostic in accurate staging and therapeutic in case of achieved optimal cytoreduction including lymph nodes with histology proven minor node involvement.
Injections of Local Anesthetics into the Pharyngeal Region Reduce Trapezius Muscle Tenderness
2016-01-01

Pharyngeal irritation may induce and maintain therapy-resistant cervical pain in patients with chronic pharyngeal disease. These patients could benefit from remote TLA/NT injections in the pharyngeal region.
Optimised synthesis of monoanionic bis(NHC)-pincer ligand precursors and their Li-complexes
2016-01-01

A straightforward preparation of bis(imidazol)carbazole <bold>4</bold> from carbazole, its transformation to various bis(imidazolium) salts and their deprotonation to Li carbene complexes is presented.
Gene expression profiling of the dorsolateral and medial orbitofrontal cortex in schizophrenia
2016-01-01

Abstract Schizophrenia is a complex polygenic disorder of unknown etiology. Over 3,000 candidate genes associated with schizophrenia have been reported, most of which being mentioned only once. Alterations in cognitive processing - working memory, metacognition and mentalization - represent a core feature of schizophrenia, which indicates the involvement of the prefrontal cortex in the pathophysiology of this disorder. Hence we compared the gene expression in postmortem tissue from the left and right dorsolateral prefrontal cortex (DLPFC, Brodmann's area 46), and the medial part of the orbitofrontal cortex (MOFC, Brodmann's area 11/12), in six patients with schizophrenia and six control brains. Although in the past decade several studies performed transcriptome profiling in schizophrenia, this is the first study to investigate both hemispheres, providing new knowledge about possible brain asymmetry at the level of gene expression and its relation to schizophrenia. We found that in the left hemisphere, twelve genes from the DLPFC and eight genes from the MOFC were differentially expressed in patients with schizophrenia compared to controls. In the right hemisphere there was only one gene differentially expressed in the MOFC. We reproduce the involvement of previously reported genes TARDBP and HNRNPC in the pathogenesis of schizophrenia, and report seven novel genes: SART1, KAT7, C1D, NPM1, EVI2A, XGY2 , and TTTY15 . As the differentially expressed genes only partially overlap with previous studies that analyzed other brain regions, our findings indicate the importance of considering prefrontal cortical regions, especially those in the left hemisphere, for obtaining disease-relevant insights.
Novel Therapeutic Approaches in Diabetes
2016-01-01

This chapter deals with novel therapeutic approaches, predominantly for type 2 diabetes. Incretin-based therapies utilize the effects of glucagon-like peptide-1 (GLP-1), which stimulates insulin and inhibits glucagon secretion in a glucose-dependent manner. Incretin-based therapies comprise injectable GLP-1 receptor agonists and orally active dipeptidyl peptidase-IV inhibitors. Both have a low hypoglycaemia risk. GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, dulaglutide, albiglutide) reduce glycated haemoglobin levels more effectively than oral antidiabetic agents do and lead to weight loss as well as a slight decrease in systolic blood pressure. The most common side effects are nausea and fullness, especially during the start of therapy. Dipeptidyl peptidase-IV inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) are not inferior to sulfonylureas, causing significantly less hypoglycaemia and not inducing weight gain. Specific adverse effects have not been discovered yet, and cardiovascular safety has been demonstrated in respective studies. Sodium-glucose transporter-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin) were introduced recently. They block the tubular reabsorption of glucose in the kidney and represent an insulin-independent mode of action, with low hypoglycaemia risk and allowing weight loss. The most common side effects are genital and urinary tract infections. Other novel drugs in development (G-protein-coupled receptor agonists, interleukin-1 antagonists) are also described.
Multicenter Clinical Trial of Vibroplasty Couplers to Treat Mixed/Conductive Hearing Loss: First Results
2016-01-01

&lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; To evaluate the safety and effectiveness of round window (RW), oval window (OW), CliP and Bell couplers for use with an active middle ear implant. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; This is a multicenter, long-term, prospective trial with consecutive enrollment, involving 6 university hospitals in Germany. Bone conduction, air conduction, implant-aided warble-tone thresholds and Freiburger monosyllable word recognition scores were compared with unaided preimplantation results in 28 moderate-to-profound hearing-impaired patients after 12 months of follow-up. All patients had previously undergone failed reconstruction surgeries (up to 5 or more). In a subset of patients, additional speech tests at 12 months postoperatively were used to compare the aided with the unaided condition after implantation with the processor switched off. An established quality-of-life questionnaire for hearing aids was used to determine patient satisfaction. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Postoperative bone conduction remained stable. Mean functional gain for all couplers was 37 dB HL (RW = 42 dB, OW = 35 dB, Bell = 38 dB, CliP = 27 dB). The mean postoperative Freiburger monosyllable score was 71% at 65 dB SPL. The postimplantation mean SRT&lt;sub&gt;50&lt;/sub&gt; (speech reception in quiet for 50% understanding of words in sentences) improved on average by 23 dB over unaided testing and signal-to-noise ratios also improved in all patients. The International Outcome Inventory for Hearing Aids (IOI-HA)quality-of-life questionnaire was scored very positively by all patients. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; A significant improvement was seen with all couplers, and patients were satisfied with the device at 12 months postoperatively. These results demonstrate that an active implant is an advantage in achieving good hearing benefit in patients with prior failed reconstruction surgery.
Simulation of Falling Rain for Robustness Testing of Video-Based Surround Sensing Systems
2016-01-01

Recently, optical sensors have become a standard item in modern cars, raising questions with respect to the necessary testing under various ambient effects. In order to achieve a high test coverage of vision-based surround sensing systems, a lot of different environmental conditions need to be tested. Unfortunately, it is by far too time-consuming to build test sets of all relevant environmental conditions by recording real video data. This paper presents a novel approach for ambient-aware virtual prototyping and robustness testing. We propose a method to significantly reduce the needed on-road recordings being used for design and validation of vision-based Advanced Driver Assistance Systems (ADAS) and fully automated driving. Our approach facilitates the generation of comparable test sets by using largely reduced amounts of real on-road recordings and applying computer-generated variations of falling rain to it in a comprehensive virtual prototyping environment. In combination with the simulation of camera properties, which influence the visual effects of falling rain to a great extent, we are able to generate different rain scenarios under a wide variety of parameters. Our approach has been applied to an automotive lane detection system using a series of multiple rain scenarios. We have explored, how falling rain can influence such a system and how such behavior can be detected using simulated rain scenarios.
Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H271
2016-01-01

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H271 clone 1 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line will provide the ideal control to model SCA2 by iPSC technology.
Comparative analysis of Edge Detection techniques for SAR images
2016-01-01

Paleo-shorelines and ancient lake terraces east of Lake Manyara in Tanzania were identified from the backscatter intensity of Terra SAR-X StripMap images. Because of their linear alignment, edge detector algorithms were applied to delineate these morphological structures from those Synthetic Aperture Radar scenes. Due to the physical properties of microwave signals, this application has proven to be a challenging task for edge detectors. This study compares the performance of different combinations of speckle reduction techniques and edge operator in detecting linear paleo-shorelines. The Roberts, Sobel, Laplacian of Gaussian and the Canny edge detector algorithms were applied to extract and revise those linear structures. The comparison shows that the Canny edge detector is especially suitable for images with strong speckle noise. Canny achieves relatively high accuracies compared to the other operators. The stronger the filtering and speckle noise reduction, the better the performance of the other edge detection operators, compared to the Canny edge detector. The application of a wavelet transformation reduces the presence of artifacts resulting from speckle noise and emphasizes the detection of the target features.
A CD2AP Mutation Associated with Focal Segmental Glomerulosclerosis in Young Adulthood
2016-01-01

Mutations in CD2-associated protein (CD2AP) have been identified in patients with focal segmental glomerulosclerosis (FSGS); however, reports of CD2AP mutations remain scarce. We performed Sanger sequencing in a patient with steroid-resistant FSGS and identified a heterozygous CD2AP mutation (p.T374A, c.1120 A &gt; G). Our patient displayed mild cognitive decline, a phenotypic characteristic not previously associated with CD2AP-associated FSGS. His proteinuria was remarkably reduced by treatment with cyclosporine A. Our findings expand the genetic spectrum of CD2AP-associated disorders and broaden the associated phenotype with the co-occurrence of cognitive decline. Our case shows that cyclosporin A is a treatment option for CD2AP-associated nephropathy.
Expression of JAK3 Sensitive Na+ Coupled Glucose Carrier SGLT1 in Activated Cytotoxic T Lymphocytes
2016-01-01

Background: Similar to tumor cells, activated T-lymphocytes generate ATP mainly by glycolytic degradation of glucose. Lymphocyte glucose uptake involves non-concentrative glucose carriers of the GLUT family. In contrast to GLUT isoforms, Na+-coupled glucose-carrier SGLT1 accumulates glucose against glucose gradients and is effective at low extracellular glucose concentrations. The present study explored expression and regulation of SGLT1 in activated murine splenic cytotoxic T cells (CTLs) and human Jurkat T cells. Methods: FACS analysis, immunofluorescence, confocal microscopy, chemiluminescence and Western blotting were employed to estimate SGLT1 expression, function and regulation in lymphocytes, as well as dual electrode voltage clamp in SGLT1 ± JAK3 expressing Xenopus oocytes to quantify the effect of janus kinase3 (JAK3) on SGLT1 function. Results: SGLT1 is expressed in murine CTLs and also in human Jurkat T cells. 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose uptake was significantly decreased by SGLT1-blocker phloridzin (0.2 mM) and by pharmacological inhibition of JAK3 with WHI-P131 (156 μM), WHI-P154 (11.2 μM) and JAK3 inhibitor VI (0.5 μM). Electrogenic glucose transport (Iglucose) in Xenopus oocytes expressing human SGLT1 was increased by additional expression of human wild type JAK3, active A568VJAK3 but not inactive K851AJAK3. Coexpression of JAK3 enhanced the maximal transport rate without significantly modifying affinity of the carrier. Iglucose in SGLT1+JAK3 expressing oocytes was significantly decreased by WHI-P154 (11.2 μM). JAK3 increased the SGLT1 protein abundance in the cell membrane. Inhibition of carrier insertion by brefeldin A (5 μM) in SGLT1+JAK3 expressing oocytes resulted in a decline of Iglucose, which was similar in presence and absence of JAK3. Conclusions: SGLT1 is expressed in murine cytotoxic T cells and human Jurkat T cells and significantly contributes to glucose uptake in those cells post activation. JAK3 up-regulates SGLT1 activity by increasing the carrier protein abundance in the cell membrane, an effect enforcing cellular glucose uptake into activated lymphocytes and thus contributing to the immune response.
Online Information Retrieval for Language Learning
2016-01-01

The reading material used in a language learning classroom should ideally be rich in terms of the grammatical constructions and vocabulary to be taught and in line with the learner's interests.We developed an online Information Retrieval system that helps teachers search for texts appropriate in form, content, and reading level.It identifies the 87 grammatical constructions spelled out in the official English language curriculum of schools in Baden-Württemberg, Germany.The tool incorporates a classical efficient algorithm for reranking the results by assigning weights to selected constructions and prioritizing the documents containing them.Supplemented by an interactive visualization module, it allows for a multifaceted presentation and analysis of the retrieved documents.
Cytomegalovirus Infection Minimally Affects the Frequencies of B-Cell Phenotypes in Peripheral Blood of Younger and Older Adults
2016-01-01

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; An accumulation of late-differentiated CD8+ T-cells together with fewer B-cells and seropositivity for cytomegalovirus (CMV) characterises an ‘immune risk profile' associated with mortality in elderly people and represents one of the hallmarks of ‘immunosenescence'. &lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; While differences in memory T-cell phenotypes between young and old people have been intensively studied, and the role of CMV is well-accepted as a driving force in this regard, the impact of CMV on B-cells, if any, has been relatively neglected thus far. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Here, we avail ourselves of blood samples from participants of the Berlin Aging Study II (BASE-II) to compare peripheral blood B-cell differentiation phenotypes of 140 age- and gender-matched CMV-seronegative or -seropositive adults aged between 24 and 85 years using multicolour flow cytometry analysis. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; We found that the frequencies of naïve B-cells within the CD19+ population were not significantly different in younger and older CMV-seronegative people. This was also true in CMV-seropositive subjects. The frequencies of late-differentiated B-cells were also not different in CMV-negative elderly and young. However, in marked contrast to the T-cell compartment, this was also true for late differentiated B-cells. Within age groups, the most marked differences in the distribution of B-cell phenotypes were between CMV-seronegative and -seropositive subjects, for both genders. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; These results emphasize the importance of including CMV serostatus in the analysis of immune signatures. Because the proportion of the population infected with CMV increases with age, the effect of CMV rather than age could confound analyses seeking age-associated changes to human immunity.
The calpain-suppressing effects of olesoxime in Huntington's disease
2016-01-01

Olesoxime, a small molecule drug candidate, has recently attracted attention due to its significant beneficial effects in models of several neurodegenerative disorders including Huntington's disease. Olesoxime's neuroprotective effects have been assumed to be conveyed through a direct, positive influence on mitochondrial function. In a long-term treatment study in BACHD rats, the latest rat model of Huntington's disease, olesoxime revealed a positive influence on mitochondrial function and improved specific behavioral and neuropathological phenotypes. Moreover, a novel target of the compound was discovered, as olesoxime was found to suppress the activation of the calpain proteolytic system, a major contributor to the cleavage of the disease-causing mutant huntingtin protein into toxic fragments, and key player in degenerative processes in general. Results from a second model of Huntington's disease, the Hdh (Q111) knock-in mouse, confirm olesoxime's calpain-suppressing effects and support the therapeutic value of olesoxime for Huntington's disease and other disorders involving calpain overactivation.
Induction of Myeloid-Derived Suppressor Cells in Cryopyrin-Associated Periodic Syndromes
2016-01-01

Cryopyrin-associated periodic syndromes (CAPS) are caused by mutations in the &lt;i&gt;NLRP3&lt;/i&gt; gene leading to overproduction of IL-1β and other NLRP3 inflammasome products. Myeloid-derived suppressor cells (MDSCs) represent a novel innate immune cell subset capable of suppressing T-cell responses. As inflammasome products were previously found to induce MDSCs, we hypothesized that NLRP3 inflammasome-dependent factors induce the generation of MDSCs in CAPS. We studied neutrophilic MDSCs, their clinical relevance, and MDSC-inducing factors in a unique cohort of CAPS patients under anti-IL-1 therapy. Despite anti-IL-1 therapy and low clinical disease activity, CAPS patients showed significantly elevated MDSCs compared to healthy controls. MDSCs were functionally competent, as they suppressed polyclonal T-cell proliferation, as well as Th1 and Th17 responses. In addition, MDSCs decreased monocytic IL-1β secretion. Multiplex assays revealed a distinct pattern of MDSC-inducing cytokines, chemokines, and growth factors. Experimental analyses demonstrated that IL-1 cytokine family members and autoinflammation-associated alarmins differentially induced human MDSCs. Increased MDSCs might represent a novel autologous anti-inflammatory mechanism in autoinflammatory conditions and may serve as a future therapeutic target.
Ex vivo Skin Permeation of Betulin from Water-in-Oil Foams
2016-01-01

Triterpenes of the outer bark of birch are known to improve wound healing. An oleogel with these triterpenes as active principle is approved by the European Medicines Agency. As foams can be applied without touching the skin, they might be an advantageous application form. A comparable wound-healing effect can be expected when the permeation flux of the triterpenes from different types of formulations, namely oleogels, water-in-oil emulsions and water-in-oil foams, is similar. The tested formulations were based on three lipids (medium-chain trigylcerides, sunflower oil and paraffin) which differ in their polarity and solvent power for the triterpenes. Infinite dose permeation experiments were performed using porcine skin which was injured by either tape stripping or skin grafting. The results showed that steady-state permeation flux and lag time depend clearly on the depth of the skin lesion. Moreover, it was substantially affected by the lipid used as basis for the different formulations. In contrast, the different formulation types showed a comparable permeation behaviour leading to the conclusion that all formulation types can be used alike for the treatment of wounds, and the results that have already been obtained with oleogels can be directly translated to the foam with its superior use properties.