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The impact of naval sonar on beaked whales is of increasing concern. In recent years the presence of gas and fat embolism consistent with decompression sickness (DCS) has been reported through postmortem analyses on beaked whales that stranded in connection with naval sonar exercises. In the present study, we use basic principles of diving physiology to model nitrogen tension and bubble growth in several tissue compartments during normal div ng behavior and for several hypothetical dive profiles to assess the risk of DCS. Assuming that normal diving does not cause nitrogen tensions in excess of those shown to be safe for odontocetes, the modeling indicates that repetitive shallow dives, perhaps as a consequence of an extended avoidance reaction to sonar sound, can indeed pose a risk for DCS and that this risk should increase with the duration of the response. If the model is correct, then limiting the duration of sonar exposure to minimize the duration of any avoidance reaction therefore has the potential to reduce the risk of DCS.
Background We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) and updated this as Hereditary angioedema: a current state-of-the-art review: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Objective To update the International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema (circa 2010). Methods The Canadian Hereditary Angioedema Network (CHAEN)/Reseau Canadien d'angioedeme hereditaire (RCAH) (www.haecanada.com) and cosponsors University of Calgary and the Canadian Society of Allergy and Clinical Immunology (with an unrestricted educational grant from CSL Behring) held our third Conference May 15th to 16th, 2010 in Toronto Canada to update our consensus approach. The Consensus document was reviewed at the meeting and then circulated for review. Results This manuscript is the 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema that resulted from that conference. Conclusions Consensus approach is only an interim guide to a complex disorder such as HAE and should be replaced as soon as possible with large phase III and IV clinical trials, meta analyses, and using data base registry validation of approaches including quality of life and cost benefit analyses, followed by large head-to-head clinical trials and then evidence-based guidelines and standards for HAE disease management.
The resprouting response of plant species to fire is a key life history trait that has profound effects on post-fire population dynamics and community composition. This study documents the post-fire response (resprouting and maturation times) of woody species in six contrasting formations in the New England Tableland Bioregion of eastern Australia. Rainforest had the highest proportion of resprouting woody taxa and rocky outcrops had the lowest. Surprisingly, no significant difference in the median maturation length was found among habitats, but the communities varied in the range of maturation times. Within these communities, seedlings of species killed by fire, mature faster than seedlings of species that resprout. The slowest maturing species were those that have canopy held seed banks and were killed by fire, and these were used as indicator species to examine fire immaturity risk. Finally, we examine whether current fire management immaturity thresholds appear to be appropriate for these communities and find they need to be amended.
Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
Gastric cancer is one of the most common malignancies and a leading cause of cancer death worldwide. The prognosis of stomach cancer is generally poor as this cancer is not very sensitive to commonly used chemotherapies. Epigenetic modifications play a key role in gastric cancer and contribute to the development and progression of this malignancy. In order to explore new treatment options in this target area we have screened a library of epigenetic inhibitors against gastric cancer cell lines and identified inhibitors for the BET family of bromodomains as potent inhibitors of gastric cancer cell proliferations. Here we show that both the pan-BET inhibitor (+)-JQ1 as well as a newly developed specific isoxazole inhibitor, PNZ5, showed potent inhibition of gastric cancer cell growth. Intriguingly, we found differences in the antiproliferative response between gastric cancer cells tested derived from Brazilian patients as compared to those from Asian patients, the latter being largely resistant to BET inhibition. As BET inhibitors are entering clinical trials these findings provide the first starting point for future therapies targeting gastric cancer.
Background: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome.
Methods: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1–8 reference strains.
Results: A total of 14 653 patients with GT1–6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12.
Conclusions: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.
The population diversity of Doranthes excelsa Corrêa (Doryanthaceae) was measured from nine distinct geographic populations across eastern Australia, using random amplified polymorphic DNA (RAPD) markers. An UPGMA dendrogram of individuals was derived from squared Euclidian distances based on the Dice (1945) algorithm. Three clusters corresponding to populations at Somersby, Newfoundland and Kremnos Creek populations were found to be distinct from the remainder of the sampled individuals. A ΦST value of 0.443 indicated that a significant diversity between geographic populations existed; this appeared to be a product of geographical distance and isolation between some of the populations. (PCR = Polymerase Chain Reaction; RAPD = Random Amplified Polymorphic DNA) The results suggest that there is lesser gene flow between the‘northern’ populations (Kremnos Creek and Newfoundland) when compared to the ‘southern’ populations and that they have a significant level of genetic isolation. The two ‘northern’ populations should therefore be regarded as being of considerable value for conservation authorities and the commercial breeding sector and should be given priority for conservation. The plants there appear to exhibit a smaller phenotype but confirming this requires further quantification.
Lyme disease (LD), which is caused by genospecies of the Borrelia burgdorferi sensu lato complex, is the most common vector-borne disease in the Northern hemisphere. Spirochetes are transmitted by Ixodes ticks and maintained in diverse vertebrate animal hosts. Following tick bite, spirochetes initially establish a localized infection in the skin. However, they may also disseminate hematogenously to several distal sites, including heart, joints, or the CNS. Because they need to survive in diverse microenvironments, from tick vector to mammalian hosts, spirochetes have developed multiple strategies to combat the numerous host defense mechanisms. One of these strategies includes the production of a number of complement-regulator acquiring surface proteins (CRASPs) which encompass CspA, CspZ, and OspE paralogs to blunt the complement pathway. These proteins are capable of preventing complement activation on the spirochete surface by binding to complement regulator Factor H. The genes encoding these CRASPs differ in their expression patterns during the tick-to-host infection cycle, implying that these proteins may exhibit different functions during infection. This review summarizes the recent published reports which investigated the roles that each of these molecules plays in conferring tick-borne transmission and dissemination in vertebrate hosts. These findings offer novel mechanistic insights into LD pathobiology and may facilitate the identification of new targets for preventive strategies against Lyme borreliosis.
Cell-free expression represents an attractive method to produce large quantities of selectively labeled protein for NMR applications. Here, cell-free expression was used to label specific regions of the growth hormone secretagogue receptor (GHSR) with NMR-active isotopes. The GHSR is a member of the class A family of G protein-coupled receptors. A cell-free expression system was established to produce the GHSR in the precipitated form. The solubilized receptor was refolded in vitro and reconstituted into DMPC lipid membranes. Methionines, arginines, and histidines were chosen for 13C-labeling as they are representative for the transmembrane domains, the loops and flanking regions of the transmembrane α-helices, and the C-terminus of the receptor, respectively. The dynamics of the isotopically labeled residues was characterized by solid-state NMR measuring motionally averaged 1H-13C dipolar couplings, which were converted into molecular order parameters. Separated local field DIPSHIFT experiments under magic-angle spinning conditions using either varying cross polarization contact times or direct excitation provided order parameters for these residues showing that the C-terminus was the segment with the highest motional amplitude. The loop regions and helix ends as well as the transmembrane regions of the GHSR represent relatively rigid segments in the overall very flexible receptor molecule. Although no site resolution could be achieved in the experiments, the previously reported highly dynamic character of the receptor concluded from uniformly 13C labeled receptor samples could be further specified by this segmental labeling approach, leading to a more diversified understanding. of the receptor dynamics under equilibrium conditions
Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
The relation between the complexity of a time-switched dynamics and the complexity of its control sequence depends critically on the concept of a non-autonomous pullback attractor. For instance, the switched dynamics associated with scalar dissipative affine maps has a pullback attractor consisting of singleton component sets. This entails that the complexity of the control sequence and switched dynamics, as quantified by the topological entropy, coincide. In this paper we extend the previous framework to pullback attractors with nontrivial components sets in order to gain further insights in that relation. This calls, in particular, for distinguishing two distinct contributions to the complexity of the switched dynamics. One proceeds from trajectory segments connecting different component sets of the attractor; the other contribution proceeds from trajectory segments within the component sets. We call them “macroscopic” and “microscopic” complexity, respectively, because only the first one can be measured by our analytical tools. As a result of this picture, we obtain sufficient conditions for a switching system to be more complex than its unswitched subsystems, i.e., a complexity analogue of Parrondo’s paradox.
The Frullania taxa on Mount Albert Edward, Papua New Guinea, form many associations that suggest a high degree of niche similarity, but at different altitudes, different associations form. The species diversity of the genus is greatest at the middle altitudes and least in the dry lowlands. This altitudinal separation is apparent in the niche widths of the taxa. The members of the four sibling taxa pairs examined exhibit distinct altitudinal niches, suggesting that the sibling taxa are distinct, with different niche optima.
Neutron total cross sections are an important source of experimental data in the evaluation of neutron-induced cross sections. The sum of all neutron-induced reaction cross sections can be determined with a precision of a few per cent in a relative measurement. The neutron spectrum of the photoneutron source nELBE extends in the fast region from about 100 keV to 10 MeV and has favourable conditions for transmission measurements due to the low instantaneous flux of neutrons and low gamma-flash background. Several materials of interest (in part included in the CIELO evaluation or on the HPRL of OECD/NEA) have been investigated: 197Au [1, 2], natFe [2], natW [2], 238U, natPt, 4He, natO, natNe, natXe. For gaseous targets high pressure gas cells with flat end-caps have been built that hold up to 200 bar pressure. The experimental setup will be presented including results from several transmission experiments and the data analysis leading to the total cross sections will be discussed.
To understand what makes some species successful invaders, it is critical to quantify performance differences between native and introduced regions, and among populations occupying a broad range of environmental conditions within each region. However, these data are not available even for the world’s most notorious invasive species. Here we introduce the Global Garlic Mustard Field Survey, a coordinated distributed field survey to collect performance data and germplasm from a single invasive species: garlic mustard (Alliaria petiolata) across its entire distribution using minimal resources. We chose this species for its ecological impacts, prominence in ecological studies of invasion success, simple life history, and several genetic and life history attributes that make it amenable to experimental study. We developed a standardised field survey protocol to estimate population size (area) and density, age structure, plant size and fecundity, as well as damage by herbivores and pathogens in each population, and to collect representative seed samples. Across four years and with contributions from 164 academic and non-academic participants from 16 countries in North America and Europe thus far, we have collected 45,788 measurements and counts of 137,811 plants from 383 populations and seeds from over 5,000 plants. All field data and seed resources will be curated for release to the scientific community. Our goal is to establish A. petiolata as a model species for plant invasion biology and to encourage large collaborative studies of other invasive species.
Much is known about when children acquire an understanding of mental states, but few, if any, experiments identify social contexts in which children tend to use this capacity and dispositions that influence its usage. Social exclusion is a common situation that compels us to reconnect with new parties, which may crucially involve attending to those parties’ mental states. Across two studies, this line of inquiry was extended to typically developing preschoolers (Study 1) and young children with and without anxiety disorder (AD) (Study 2). Children played the virtual game of toss “Cyberball” ostensibly over the Internet with two peers who first played fair (inclusion), but eventually threw very few balls to the child (exclusion). Before and after Cyberball, children in both studies completed stories about peer-scenarios. For Study 1, 36 typically developing 5-year-olds were randomly assigned to regular exclusion (for no apparent reason) or accidental exclusion (due to an alleged computer malfunction). Compared to accidental exclusion, regular exclusion led children to portray story-characters more strongly as intentional agents (intentionality), with use of more mental state language (MSL), and more between-character affiliation in post-Cyberball stories. For Study 2, 20 clinically referred 4 to 8-year-olds with AD and 15 age- and gender-matched non-anxious controls completed stories before and after regular exclusion. While we replicated the post regular-exclusion increase of intentional and MSL portrayals of story-characters among non-anxious controls, anxious children exhibited a decline on both dimensions after regular exclusion. We conclude that exclusion typically induces young children to mentalize, enabling more effective reconnection with others. However, excessive anxiety may impair controlled mentalizing, which may, in turn, hamper effective reconnection with others after exclusion.
This paper addresses the open debate about the usefulness of high-frequency (HF) data in large-scale portfolio allocation. Daily covariances are estimated based on HF data of the S&P 500 universe employing a blocked realized kernel estimator. We propose forecasting covariance matrices using a multi-scale spectral decomposition where volatilities, correlation eigenvalues and eigenvectors evolve on different frequencies. In an extensive out-of-sample forecasting study, we show that the proposed approach yields less risky and more diversified portfolio allocations as prevailing methods employing daily data. These performance gains hold over longer horizons than previous studies have shown.
Background Polypharmacy interventions are resource-intensive and should be targeted to those at risk of negative health outcomes. Our aim was to develop and internally validate prognostic models to predict health-related quality of life (HRQoL) and the combined outcome of falls, hospitalisation, institutionalisation and nursing care needs, in older patients with multimorbidity and polypharmacy in general practices.
Methods Design: two independent data sets, one comprising health insurance claims data (n=592 456), the other data from the PRIoritising MUltimedication in Multimorbidity (PRIMUM) cluster randomised controlled trial (n=502). Population: ≥60 years, ≥5 drugs, ≥3 chronic diseases, excluding dementia. Outcomes: combined outcome of falls, hospitalisation, institutionalisation and nursing care needs (after 6, 9 and 24 months) (claims data); and HRQoL (after 6 and 9 months) (trial data). Predictor variables in both data sets: age, sex, morbidity-related variables (disease count), medication-related variables (European Union-Potentially Inappropriate Medication list (EU-PIM list)) and health service utilisation. Predictor variables exclusively in trial data: additional socio-demographics, morbidity-related variables (Cumulative Illness Rating Scale, depression), Medication Appropriateness Index (MAI), lifestyle, functional status and HRQoL (EuroQol EQ-5D-3L). Analysis: mixed regression models, combined with stepwise variable selection, 10-fold cross validation and sensitivity analyses.
Results Most important predictors of EQ-5D-3L at 6 months in best model (Nagelkerke’s R² 0.507) were depressive symptoms (−2.73 (95% CI: −3.56 to −1.91)), MAI (−0.39 (95% CI: −0.7 to −0.08)), baseline EQ-5D-3L (0.55 (95% CI: 0.47 to 0.64)). Models based on claims data and those predicting long-term outcomes based on both data sets produced low R² values. In claims data-based model with highest explanatory power (R²=0.16), previous falls/fall-related injuries, previous hospitalisations, age, number of involved physicians and disease count were most important predictor variables.
Conclusions Best trial data-based model predicted HRQoL after 6 months well and included parameters of well-being not found in claims. Performance of claims data-based models and models predicting long-term outcomes was relatively weak. For generalisability, future studies should refit models by considering parameters representing well-being and functional status.
Background: Amyloid precursor protein (APP) processing is central to Alzheimer’s disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη–α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo.
Methods: With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology.
Results: We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη–α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη–α in vivo.
Conclusions: These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.
In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axiorecombination, the "BCA processes." Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling gae and axion-photon interaction strength ga using the CAST phase-I data (vacuum phase). For ma <~ 10 meV/c2 we find ga gae < 8.1 × 10−23 GeV−1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission.
In local scalar quantum field theories at finite temperature correlation functions are known to satisfy certain nonperturbative constraints, which for two-point functions in particular implies the existence of a generalization of the standard Källén-Lehmann representation. In this work, we use these constraints in order to derive a spectral representation for the shear viscosity arising from the thermal asymptotic states, η0. As an example, we calculate η0 in ϕ4 theory, establishing its leading behavior in the small and large coupling regimes.
Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our “hub-spoke” model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.
In situ measurements of ice crystal size distributions in tropical upper troposphere/lower stratosphere (UT/LS) clouds were performed during the SCOUT-AMMA campaign over West Africa in August 2006. The cloud properties were measured with a Forward Scattering Spectrometer Probe (FSSP-100) and a Cloud Imaging Probe (CIP) operated aboard the Russian high altitude research aircraft M-55 Geophysica with the mission base in Ouagadougou, Burkina Faso. A total of 117 ice particle size distributions were obtained from the measurements in the vicinity of Mesoscale Convective Systems (MCS). Two to four modal lognormal size distributions were fitted to the average size distributions for different potential temperature bins. The measurements showed proportionately more large ice particles compared to former measurements above maritime regions. With the help of trace gas measurements of NO, NOy, CO2, CO, and O3 and satellite images, clouds in young and aged MCS outflow were identified. These events were observed at altitudes of 11.0 km to 14.2 km corresponding to potential temperature levels of 346 K to 356 K. In a young outflow from a developing MCS ice crystal number concentrations of up to (8.3 ± 1.6) cm−3 and rimed ice particles with maximum dimensions exceeding 1.5 mm were found. A maximum ice water content of 0.05 g m−3 was observed and an effective radius of about 90 μm. In contrast the aged outflow events were more diluted and showed a maximum number concentration of 0.03 cm−3, an ice water content of 2.3 × 10−4 g m−3, an effective radius of about 18 μm, while the largest particles had a maximum dimension of 61 μm.
Close to the tropopause subvisual cirrus were encountered four times at altitudes of 15 km to 16.4 km. The mean ice particle number concentration of these encounters was 0.01 cm−3 with maximum particle sizes of 130 μm, and the mean ice water content was about 1.4 × 10−4 g m−3. All known in situ measurements of subvisual tropopause cirrus are compared and an exponential fit on the size distributions is established for modelling purposes.
A comparison of aerosol to ice crystal number concentrations, in order to obtain an estimate on how many ice particles may result from activation of the present aerosol, yielded low ratios for the subvisual cirrus cases of roughly one cloud particle per 30 000 aerosol particles, while for the MCS outflow cases this resulted in a high ratio of one cloud particle per 300 aerosol particles.
In-situ measurements of ice crystal size distributions in tropical upper troposphere/lower stratosphere (UT/LS) clouds were performed during the SCOUT-AMMA campaign over West Africa in August 2006. The cloud properties were measured with a Forward Scattering Spectrometer Probe (FSSP-100) and a Cloud Imaging Probe (CIP) operated aboard the Russian high altitude research aircraft M-55 ''Geophysica'' with the mission base in Ouagadougou, Burkina Faso. A total of 117 ice particle size distributions were obtained from the measurements in the vicinity of Mesoscale Convective Systems (MCS). Two or three modal lognormal size distributions were fitted to the average size distributions for different potential temperature bins. The measurements showed proportionate more large ice particles compared to former measurements above maritime regions. With the help of trace gas measurements of NO, NOy, CO2, CO, and O3, and satellite images clouds in young and aged MCS outflow were identified. These events were observed at altitudes of 11.0 km to 14.2 km corresponding to potential temperature levels of 346 K to 356 K. In a young outflow (developing MCS) ice crystal number concentrations of up to 8.3 cm−3 and rimed ice particles with maximum dimensions exceeding 1.5 mm were found. A maximum ice water content of 0.05 g m−3 was observed and an effective radius of about 90 μm. In contrast the aged outflow events were more diluted and showed a maximum number concentration of 0.03 cm−3, an ice water content of 2.3 × 10−4 g m−3, an effective radius of about 18 μm, while the largest particles had a maximum dimension of 61 μm.
Close to the tropopause subvisual cirrus were encountered four times at altitudes of 15 km to 16.4 km. The mean ice particle number concentration of these encounters was 0.01 cm−3 with maximum particle sizes of 130 μm, and the mean ice water content was about 1.4 × 10−4 g m−3. All known in-situ measurements of subvisual tropopause cirrus are compared and an exponential fit on the size distributions is established in order to give a parameterisation for modelling.
A comparison of aerosol to ice crystal number concentrations, in order to obtain an estimate on how many ice particles result from activation of the present aerosol, yielded low activation ratios for the subvisual cirrus cases of roughly one cloud particle per 30 000 aerosol particles, while for the MCS outflow cases this resulted in a high ratio of one cloud particle per 300 aerosol particles.
Background: Common warts (verrucae vulgares) are human papilloma virus (HPV) infections with a high incidence and prevalence, most often affecting hands and feet, being able to impair quality of life. About 30 different therapeutic regimens described in literature reveal a lack of a single striking strategy. Recent publications showed positive results of photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) in the treatment of HPV-induced skin diseases, especially warts, using visible light (VIS) to stimulate an absorption band of endogenously formed protoporphyrin IX. Additional experiences adding waterfiltered infrared A (wIRA) during 5-ALA-PDT revealed positive effects. Aim of the study: First prospective randomised controlled blind study including PDT and wIRA in the treatment of recalcitrant common hand and foot warts. Comparison of "5-ALA cream (ALA) vs. placebo cream (PLC)" and "irradiation with visible light and wIRA (VIS+wIRA) vs. irradiation with visible light alone (VIS)". Methods: Pre-treatment with keratolysis (salicylic acid) and curettage. PDT treatment: topical application of 5-ALA (Medac) in "unguentum emulsificans aquosum" vs. placebo; irradiation: combination of VIS and a large amount of wIRA (Hydrosun® radiator type 501, 4 mm water cuvette, waterfiltered spectrum 590-1400 nm, contact-free, typically painless) vs. VIS alone. Post-treatment with retinoic acid ointment. One to three therapy cycles every 3 weeks. Main variable of interest: "Percent change of total wart area of each patient over the time" (18 weeks). Global judgement by patient and by physician and subjective rating of feeling/pain (visual analogue scales). 80 patients with therapy-resistant common hand and foot warts were assigned randomly into one of the four therapy groups with comparable numbers of warts at comparable sites in all groups. Results: The individual total wart area decreased during 18 weeks in group 1 (ALA+VIS+wIRA) and in group 2 (PLC+VIS+wIRA) significantly more than in both groups without wIRA (group 3 (ALA+VIS) and 4 (PLC+VIS)): medians and interquartile ranges: -94% (-100%/-84%) vs. -99% (-100%/-71%) vs. -47% (-75%/0%) vs. -73% (-92%/-27%). After 18 weeks the two groups with wIRA differed remarkably from the two groups without wIRA: 42% vs. 7% completely cured patients; 72% vs. 34% vanished warts. Global judgement by patient and by physician and subjective rating of feeling was much better in the two groups with wIRA than in the two groups without wIRA. Conclusions: The above described complete treatment scheme of hand and foot warts (keratolysis, curettage, PDT treatment, irradiation with VIS+wIRA, retinoic acid ointment; three therapy cycles every 3 weeks) proved to be effective. Within this treatment scheme wIRA as non-invasive and painless treatment modality revealed to be an important, effective factor, while photodynamic therapy with 5-ALA in the described form did not contribute recognisably - neither alone (without wIRA) nor in combination with wIRA - to a clinical improvement. For future treatment of warts an even improved scheme is proposed: one treatment cycle (keratolysis, curettage, wIRA, without PDT) once a week for six to nine weeks. © 2004 Fuchs et al; licensee German Medical Science. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL : http://www.egms.de/en/gms/volume2.shtml
Background: H5N1 influenza vaccines, including live intranasal, appear to be relatively less immunogenic compared to seasonal analogs. The main influenza virus surface glycoprotein hemagglutinin (HA) of highly pathogenic avian influenza viruses (HPAIV) was shown to be more susceptible to acidic pH treatment than that of human or low pathogenic avian influenza viruses. The acidification machinery of the human nasal passageway in response to different irritation factors starts to release protons acidifying the mucosal surface (down to pH of 5.2). We hypothesized that the sensitivity of H5 HA to the acidic environment might be the reason for the low infectivity and immunogenicity of intranasal H5N1 vaccines for mammals. Methodology/Principal Findings: We demonstrate that original human influenza viruses infect primary human nasal epithelial cells at acidic pH (down to 5.4), whereas H5N1 HPAIVs lose infectivity at pH <= 5.6. The HA of A/Vietnam/1203/04 was modified by introducing the single substitution HA2 58K -> I, decreasing the pH of the HA conformational change. The H5N1 reassortants containing the indicated mutation displayed an increased resistance to acidic pH and high temperature treatment compared to those lacking modification. The mutation ensured a higher viral uptake as shown by immunohistochemistry in the respiratory tract of mice and 25 times lower mouse infectious dose50. Moreover, the reassortants keeping 58K -> I mutation designed as a live attenuated vaccine candidate lacking an NS1 gene induced superior systemic and local antibody response after the intranasal immunization of mice. Conclusion/Significance: Our finding suggests that an efficient intranasal vaccination with a live attenuated H5N1 virus may require a certain level of pH and temperature stability of HA in order to achieve an optimal virus uptake by the nasal epithelial cells and induce a sufficient immune response. The pH of the activation of the H5 HA protein may play a substantial role in the infectivity of HPAIVs for mammals.
Movement of organisms is one of the key mechanisms shaping biodiversity, e.g. the distribution of genes, individuals and species in space and time. Recent technological and conceptual advances have improved our ability to assess the causes and consequences of individual movement, and led to the emergence of the new field of ‘movement ecology’. Here, we outline how movement ecology can contribute to the broad field of biodiversity research, i.e. the study of processes and patterns of life among and across different scales, from genes to ecosystems, and we propose a conceptual framework linking these hitherto largely separated fields of research. Our framework builds on the concept of movement ecology for individuals, and demonstrates its importance for linking individual organismal movement with biodiversity. First, organismal movements can provide ‘mobile links’ between habitats or ecosystems, thereby connecting resources, genes, and processes among otherwise separate locations. Understanding these mobile links and their impact on biodiversity will be facilitated by movement ecology, because mobile links can be created by different modes of movement (i.e., foraging, dispersal, migration) that relate to different spatiotemporal scales and have differential effects on biodiversity. Second, organismal movements can also mediate coexistence in communities, through ‘equalizing’ and ‘stabilizing’ mechanisms. This novel integrated framework provides a conceptual starting point for a better understanding of biodiversity dynamics in light of individual movement and space-use behavior across spatiotemporal scales. By illustrating this framework with examples, we argue that the integration of movement ecology and biodiversity research will also enhance our ability to conserve diversity at the genetic, species, and ecosystem levels.
The integrated stress response (ISR) is a central cellular adaptive program that is activated by diverse stressors including ER stress, hypoxia and nutrient deprivation to orchestrate responses via activating transcription factor 4 (ATF4). We hypothesized that ATF4 is essential for the adaptation of human glioblastoma (GB) cells to the conditions of the tumor microenvironment and is contributing to therapy resistance against chemotherapy. ATF4 induction in GB cells was modulated pharmacologically and genetically and investigated in the context of temozolomide treatment as well as glucose and oxygen deprivation. The relevance of the ISR was analyzed by cell death and metabolic measurements under conditions to approximate aspects of the GB microenvironment. ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.
Species is the fundamental taxonomic unit in biology and its delimitation has implications for conservation. In giraffe (Giraffa spp.), multiple taxonomic classifications have been proposed since the early 1900s.1 However, one species with nine subspecies has been generally accepted,2 likely due to limited in-depth assessments, subspecies hybridizing in captivity,3,4 and anecdotal reports of hybrids in the wild.5 Giraffe taxonomy received new attention after population genetic studies using traditional genetic markers suggested at least four species.6,7 This view has been met with controversy,8 setting the stage for debate.9,10 Genomics is significantly enhancing our understanding of biodiversity and speciation relative to traditional genetic approaches and thus has important implications for species delineation and conservation.11 We present a high-quality de novo genome assembly of the critically endangered Kordofan giraffe (G. camelopardalis antiquorum)12 and a comprehensive whole-genome analysis of 50 giraffe representing all traditionally recognized subspecies. Population structure and phylogenomic analyses support four separately evolving giraffe lineages, which diverged 230–370 ka ago. These lineages underwent distinct demographic histories and show different levels of heterozygosity and inbreeding. Our results strengthen previous findings of limited gene flow and admixture among putative giraffe species6,7,9 and establish a genomic foundation for recognizing four species and seven subspecies, the latter of which should be considered as evolutionary significant units. Achieving a consensus over the number of species and subspecies in giraffe is essential for adequately assessing their threat level and will improve conservation efforts for these iconic taxa.
Quantification of circulating endothelial progenitor cells using the modified ISHAGE protocol
(2010)
Aims: Circulating endothelial progenitor cells (EPC), involved in endothelial regeneration, neovascularisation, and determination of prognosis in cardiovascular disease can be characterised with functional assays or using immunofluorescence and flow cytometry. Combinations of markers, including CD34+KDR+ or CD133+KDR+, are used. This approach, however may not consider all characteristics of EPC. The lack of a standardised protocol with regards to reagents and gating strategies may account for the widespread inter-laboratory variations in quantification of EPC. We, therefore developed a novel protocol adapted from the standardised so-called ISHAGE protocol for enumeration of haematopoietic stem cells to enable comparison of clinical and laboratory data. Methods and Results: In 25 control subjects, 65 patients with coronary artery disease (CAD; 40 stable CAD, 25 acute coronary syndrome/acute myocardial infarction (ACS)), EPC were quantified using the following approach: Whole blood was incubated with CD45, KDR, and CD34. The ISHAGE sequential strategy was used, and finally, CD45dimCD34+ cells were quantified for KDR. A minimum of 100 CD34+ events were collected. For comparison, CD45+CD34+ and CD45-CD34+ were analysed simultaneously. The number of CD45dimCD34+KDR+ cells only were significantly higher in healthy controls compared to patients with CAD or ACS (p = 0.005 each, p<0.001 for trend). An inverse correlation of CD45dimCD34+KDR+ with disease activity (r = -0.475, p<0.001) was confirmed. Only CD45dimCD34+KDR+ correlated inversely with the number of diseased coronaries (r = -0.344; p<0.005). In a second study, a 4-week de-novo treatment of atorvastatin in stable CAD evoked an increase only of CD45dimCD34+KDR+ EPC (p<0.05). CD45+CD34+KDR+ and CD45-CD34+KDR+ were indifferent between the three groups. Conclusion: Our newly established protocol adopted from the standardised ISHAGE protocol achieved higher accuracy in EPC enumeration confirming previous findings with respect to the correlation of EPC with disease activity and the increase of EPC during statin therapy. The data of this study show the CD45dim fraction to harbour EPC.
Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial
(2021)
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration-–time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers (‘average reader’) was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI.
Previous research indicates that anxiety disorders are characterized by an overgeneralization of conditioned fear as compared with healthy participants. Therefore, fear generalization is considered a key mechanism for the development of anxiety disorders. However, systematic investigations on the variance in fear generalization are lacking. Therefore, the current study aims at identifying distinctive phenotypes of fear generalization among healthy participants. To this end, 1175 participants completed a differential fear conditioning phase followed by a generalization test. To identify patterns of fear generalization, we used a k-means clustering algorithm based on individual arousal generalization gradients. Subsequently, we examined the reliability and validity of the clusters and phenotypical differences between subgroups on the basis of psychometric data and markers of fear expression. Cluster analysis reliably revealed five clusters that systematically differed in mean responses, differentiation between conditioned threat and safety, and linearity of the generalization gradients, though mean response levels accounted for most variance. Remarkably, the patterns of mean responses were already evident during fear acquisition and corresponded most closely to psychometric measures of anxiety traits. The identified clusters reliably described subgroups of healthy individuals with distinct response characteristics in a fear generalization test. Following a dimensional view of psychopathology, these clusters likely delineate risk factors for anxiety disorders. As crucial group characteristics were already evident during fear acquisition, our results emphasize the importance of average fear responses and differentiation between conditioned threat and safety as risk factors for anxiety disorders.
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
Pattern recognition approaches to the analysis of neuroimaging data have brought new applications such as the classification of patients and healthy controls within reach. In our view, the reliance on expensive neuroimaging techniques which are not well tolerated by many patient groups and the inability of most current biomarker algorithms to accommodate information about prior class frequencies (such as a disorder's prevalence in the general population) are key factors limiting practical application. To overcome both limitations, we propose a probabilistic pattern recognition approach based on cheap and easy-to-use multi-channel near-infrared spectroscopy (fNIRS) measurements. We show the validity of our method by applying it to data from healthy controls (n = 14) enabling differentiation between the conditions of a visual checkerboard task. Second, we show that high-accuracy single subject classification of patients with schizophrenia (n = 40) and healthy controls (n = 40) is possible based on temporal patterns of fNIRS data measured during a working memory task. For classification, we integrate spatial and temporal information at each channel to estimate overall classification accuracy. This yields an overall accuracy of 76% which is comparable to the highest ever achieved in biomarker-based classification of patients with schizophrenia. In summary, the proposed algorithm in combination with fNIRS measurements enables the analysis of sub-second, multivariate temporal patterns of BOLD responses and high-accuracy predictions based on low-cost, easy-to-use fNIRS patterns. In addition, our approach can easily compensate for variable class priors, which is highly advantageous in making predictions in a wide range of clinical neuroimaging applications. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
Background: Secukinumab [an interleukin (IL)‐17A inhibitor] has demonstrated significantly higher efficacy vs. etanercept (a tumour necrosis factor inhibitor) and ustekinumab (an IL‐12/23 inhibitor) in patients with moderate‐to‐severe plaque psoriasis.
Objectives: To report 52‐week results from a prespecified analysis of patients with active psoriatic arthritis (PsA) having concomitant moderate‐to‐severe plaque psoriasis from the head‐to‐head EXCEED monotherapy study comparing secukinumab with adalimumab.
Methods: Patients were randomized to receive secukinumab 300 mg via subcutaneous injection at baseline, week 1–4, and then every 4 weeks until week 48 or adalimumab 40 mg via subcutaneous injection every 2 weeks from baseline until week 50. Assessments in patients with concomitant moderate‐to‐severe psoriasis, defined as having affected body surface area > 10% or Psoriasis Area and Severity Index (PASI) ≥ 10 at baseline, included musculoskeletal, skin and quality‐of‐life outcomes. Missing data were handled using multiple imputation.
Results: Of the 853 patients [secukinumab (N = 426), adalimumab (N = 427)], 211 (24·7%) had concomitant moderate‐to‐severe psoriasis [secukinumab (N = 110, 25·8%), adalimumab (N = 101, 23·7%)]. Up to week 50, 5·5% of patients discontinued secukinumab vs.17·8% in the adalimumab group. The proportion of patients who achieved American College of Rheumatology (ACR) 20 response was 76·4% with secukinumab vs. 68·3% with adalimumab (P = 0·175), PASI 100 response was 39·1% vs. 23·8% (P = 0·013), and simultaneous improvement in ACR 50 and PASI 100 response at week 52 was 28·2% vs. 17·7%, respectively (P = 0·06). Secukinumab demonstrated consistently higher responses vs. adalimumab across skin endpoints.
Conclusions: This prespecified analysis in PsA patients with concomitant moderate‐to‐severe plaque psoriasis in the EXCEED study provides further evidence that IL‐17 inhibitors offer a comprehensive biological treatment to manage the concomitant features of psoriasis and PsA.
The forest, savanna, and grassland biomes, and the transitions between them, are expected to undergo major changes in the future due to global climate change. Dynamic global vegetation models (DGVMs) are very useful for understanding vegetation dynamics under the present climate, and for predicting its changes under future conditions. However, several DGVMs display high uncertainty in predicting vegetation in tropical areas. Here we perform a comparative analysis of three different DGVMs (JSBACH, LPJ-GUESS-SPITFIRE and aDGVM) with regard to their representation of the ecological mechanisms and feedbacks that determine the forest, savanna, and grassland biomes, in an attempt to bridge the knowledge gap between ecology and global modeling. The outcomes of the models, which include different mechanisms, are compared to observed tree cover along a mean annual precipitation gradient in Africa. By drawing on the large number of recent studies that have delivered new insights into the ecology of tropical ecosystems in general, and of savannas in particular, we identify two main mechanisms that need improved representation in the examined DGVMs. The first mechanism includes water limitation to tree growth, and tree–grass competition for water, which are key factors in determining savanna presence in arid and semi-arid areas. The second is a grass–fire feedback, which maintains both forest and savanna presence in mesic areas. Grasses constitute the majority of the fuel load, and at the same time benefit from the openness of the landscape after fires, since they recover faster than trees. Additionally, these two mechanisms are better represented when the models also include tree life stages (adults and seedlings), and distinguish between fire-prone and shade-tolerant forest trees, and fire-resistant and shade-intolerant savanna trees. Including these basic elements could improve the predictive ability of the DGVMs, not only under current climate conditions but also and especially under future scenarios.
The forest, savanna, and grassland biomes, and the transitions between them, are expected to undergo major changes in the future, due to global climate change. Dynamic Global Vegetation Models (DGVMs) are very useful to understand vegetation dynamics under present climate, and to predict its changes under future conditions. However, several DGVMs display high uncertainty in predicting vegetation in tropical areas. Here we perform a comparative analysis of three different DGVMs (JSBACH, LPJ-GUESS-SPITFIRE and aDGVM) with regard to their representation of the ecological mechanisms and feedbacks that determine the forest, savanna and grassland biomes, in an attempt to bridge the knowledge gap between ecology and global modelling. Model outcomes, obtained including different mechanisms, are compared to observed tree cover along a mean annual precipitation gradient in Africa. Through these comparisons, and by drawing on the large number of recent studies that have delivered new insights into the ecology of tropical ecosystems in general, and of savannas in particular, we identify two main mechanisms that need an improved representation in the DGVMs. The first mechanism includes water limitation to tree growth, and tree-grass competition for water, which are key factors in determining savanna presence in arid and semi-arid areas. The second is a grass-fire feedback, which maintains both forest and savanna occurrences in mesic areas. Grasses constitute the majority of the fuel load, and at the same time benefit from the openness of the landscape after fires, since they recover faster than trees. Additionally, these two mechanisms are better represented when the models also include tree life stages (adults and seedlings), and distinguish between fire-prone and shade-tolerant savanna trees, and fire-resistant and shade-intolerant forest trees. Including these basic elements could improve the predictive ability of the DGVMs, not only under current climate conditions but also and especially under future scenarios.
Comparing projections of future changes in runoff from hydrological and biome models in ISI-MIP
(2013)
Future changes in runoff can have important implications for water resources and flooding. In this study, runoff projections from ISI-MIP (Inter-sectoral Impact Model Intercomparison Project) simulations forced with HadGEM2-ES bias-corrected climate data under the Representative Concentration Pathway 8.5 have been analysed for differences between impact models. Projections of change from a baseline period (1981–2010) to the future (2070–2099) from 12 impacts models which contributed to the hydrological and biomes sectors of ISI-MIP were studied. The biome models differed from the hydrological models by the inclusion of CO2 impacts and most also included a dynamic vegetation distribution. The biome and hydrological models agreed on the sign of runoff change for most regions of the world. However, in West Africa, the hydrological models projected drying, and the biome models a moistening. The biome models tended to produce larger increases and smaller decreases in regionally averaged runoff than the hydrological models, although there is large inter-model spread. The timing of runoff change was similar, but there were differences in magnitude, particularly at peak runoff. The impact of vegetation distribution change was much smaller than the projected change over time, while elevated CO2 had an effect as large as the magnitude of change over time projected by some models in some regions. The effect of CO2 on runoff was not consistent across the models, with two models showing increases and two decreases. There was also more spread in projections from the runs with elevated CO2 than with constant CO2. The biome models which gave increased runoff from elevated CO2 were also those which differed most from the hydrological models. Spatially, regions with most difference between model types tended to be projected to have most effect from elevated CO2, and seasonal differences were also similar, so elevated CO2 can partly explain the differences between hydrological and biome model runoff change projections. Therefore, this shows that a range of impact models should be considered to give the full range of uncertainty in impacts studies.
Projections of future changes in runoff can have important implications for water resources and flooding. In this study, runoff projections from ISI-MIP (Inter-sectoral Impact Model Intercomparison Project) simulations forced with HadGEM2-ES bias-corrected climate data under the Representative Concentration Pathway 8.5 have been analysed. Projections of change from the baseline period (1981–2010) to the future (2070–2099) from a number of different ecosystems and hydrological models were studied. The differences between projections from the two types of model were looked at globally and regionally. Typically, across different regions the ecosystem models tended to project larger increases and smaller decreases in runoff than the hydrological models. However, the differences varied both regionally and seasonally. Sensitivity experiments were also used to investigate the contributions of varying CO2 and allowing vegetation distribution to evolve on projected changes in runoff. In two out of four models which had data available from CO2 sensitivity experiments, allowing CO2 to vary was found to increase runoff more than keeping CO2 constant, while in two models runoff decreased. This suggests more uncertainty in runoff responses to elevated CO2 than previously considered. As CO2 effects on evapotranspiration via stomatal conductance and leaf-area index are more commonly included in ecosystems models than in hydrological models, this may partially explain some of the difference between model types. Keeping the vegetation distribution static in JULES runs had much less effect on runoff projections than varying CO2, but this may be more pronounced if looked at over a longer timescale as vegetation changes may take longer to reach a new state.
Background Drought is the major constraint to increase yield in chickpea (Cicer arietinum). Improving drought tolerance is therefore of outmost importance for breeding. However, the complexity of the trait allowed only marginal progress. A solution to the current stagnation is expected from innovative molecular tools such as transcriptome analyses providing insight into stress-related gene activity, which combined with molecular markers and expression (e)QTL mapping, may accelerate knowledge-based breeding. SuperSAGE, an improved version of the serial analysis of gene expression (SAGE) technique, generating genome-wide, high-quality transcription profiles from any eukaryote, has been employed in the present study. The method produces 26 bp long fragments (26 bp tags) from defined positions in cDNAs, providing sufficient sequence information to unambiguously characterize the mRNAs. Further, SuperSAGE tags may be immediately used to produce microarrays and probes for real-time-PCR, thereby overcoming the lack of genomic tools in non-model organisms. Results We applied SuperSAGE to the analysis of gene expression in chickpea roots in response to drought. To this end, we sequenced 80,238 26 bp tags representing 17,493 unique transcripts (UniTags) from drought-stressed and non-stressed control roots. A total of 7,532 (43%) UniTags were more than 2.7-fold differentially expressed, and 880 (5.0%) were regulated more than 8-fold upon stress. Their large size enabled the unambiguous annotation of 3,858 (22%) UniTags to genes or proteins in public data bases and thus to stress-response processes. We designed a microarray carrying 3,000 of these 26 bp tags. The chip data confirmed 79% of the tag-based results, whereas RT-PCR confirmed the SuperSAGE data in all cases. Conclusion This study represents the most comprehensive analysis of the drought-response transcriptome of chickpea available to date. It demonstrates that – inter alias – signal transduction, transcription regulation, osmolyte accumulation, and ROS scavenging undergo strong transcriptional remodelling in chickpea roots already 6 h after drought stress. Certain transcript isoforms characterizing these processes are potential targets for breeding for drought tolerance. We demonstrate that these can be easily accessed by micro-arrays and RT-PCR assays readily produced downstream of SuperSAGE. Our study proves that SuperSAGE owns potential for molecular breeding also in non-model crops.
Alternative polyadenylation (APA) is a widespread mechanism that contributes to the sophisticated dynamics of gene regulation. Approximately 50% of all protein-coding human genes harbor multiple polyadenylation (PA) sites; their selective and combinatorial use gives rise to transcript variants with differing length of their 3' untranslated region (3'UTR). Shortened variants escape UTR-mediated regulation by microRNAs (miRNAs), especially in cancer, where global 3'UTR shortening accelerates disease progression, dedifferentiation and proliferation. Here we present APADB, a database of vertebrate PA sites determined by 3' end sequencing, using massive analysis of complementary DNA ends. APADB provides (A)PA sites for coding and non-coding transcripts of human, mouse and chicken genes. For human and mouse, several tissue types, including different cancer specimens, are available. APADB records the loss of predicted miRNA binding sites and visualizes next-generation sequencing reads that support each PA site in a genome browser. The database tables can either be browsed according to organism and tissue or alternatively searched for a gene of interest. APADB is the largest database of APA in human, chicken and mouse. The stored information provides experimental evidence for thousands of PA sites and APA events. APADB combines 3' end sequencing data with prediction algorithms of miRNA binding sites, allowing to further improve prediction algorithms. Current databases lack correct information about 3'UTR lengths, especially for chicken, and APADB provides necessary information to close this gap. Database URL: http://tools.genxpro.net/apadb/
Objective: This study was undertaken to quantify epilepsy-related costs of illness (COI) in Germany and identify cost-driving factors.
Methods: COI were calculated among adults with epilepsy of different etiologies and severities. Multiple regression analysis was applied to determine any epilepsy-related and sociodemographic factors that serve as cost-driving factors.
Results: In total, 486 patients were included, with a mean age of 40.5 ± 15.5 years (range = 18–83 years, 58.2% women). Mean 3-month COI were estimated at €4911, €2782, and €2598 for focal, genetic generalized, and unclassified epilepsy, respectively. The mean COI for patients with drug-refractory epilepsy (DRE; €7850) were higher than those for patients with non-DRE (€4720), patients with occasional seizures (€3596), or patients with seizures in remission for >1 year (€2409). Identified cost-driving factors for total COI included relevant disability (unstandardized regression coefficient b = €2218), poorer education (b = €2114), living alone (b = €2612), DRE (b = €1831), and frequent seizures (b = €2385). Younger age groups of 18–24 years (b = −€2945) and 25–34 years (b = −€1418) were found to have lower overall expenditures. A relevant disability (b = €441), DRE (b = €1253), frequent seizures (b = €735), and the need for specialized daycare (b = €749) were associated with higher direct COI, and poorer education (b = €1969), living alone (b = €2612), the presence of a relevant disability (b = €1809), DRE (b = €1831), and frequent seizures (b = €2385) were associated with higher indirect COI.
Significance: This analysis provides up-to-date COI data for use in further health economics analyses, highlighting the high economic impacts associated with disease severity, disability, and disease-related loss of productivity among adult patients with epilepsy. The identified cost drivers could be used as therapeutic and socioeconomic targets for future cost-containment strategies.
Sudden cardiac death (SCD) in adolescents and young adults may be the first manifestation of an inherited arrhythmic syndrome. Thus identification of a genetic origin in sudden death cases deemed inconclusive after a comprehensive autopsy and may help to reduce the risk of lethal episodes in the remaining family. Using next-generation sequencing (NGS), a large number of variants of unknown significance (VUS) are detected. In the majority of cases, there is insufficient evidence of pathogenicity, representing a huge dilemma in current genetic investigations. Misinterpretation of such variants may lead to inaccurate genetic diagnoses and/or the adoption of unnecessary and/or inappropriate therapeutic approaches. In our study, we applied current (ACMG) recommendations for variant classification in post-mortem genetic screening of a cohort of 56 SCD victims. We identified a total 53 rare protein-altering variants (MAF < 0.2%) classified as VUS or worse. Twelve percent of the cases exhibited a clinically actionable variant (pathogenic, likely pathogenic or VUS – potentially pathogenic) that would warrant cascade genetic screening in relatives. Most of the variants detected by means of the post-mortem genetic investigations were VUS. Thus, genetic testing by itself might be fairly meaningless without supporting background data. This data reinforces the need for an experienced multidisciplinary team for obtaining reliable and accountable interpretations of variant significance for elucidating potential causes for SCDs in the young. This enables the early identification of relatives at risk or excludes family members as genetic carriers. Also, development of adequate forensic guidelines to enable appropriate interpretation of rare genetic variants is fundamental.
Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 3-year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. (trial registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)
Binary nucleation of sulphuric acid-water particles is expected to be an important process in the free troposphere at low temperatures. SAWNUC (Sulphuric Acid Water Nucleation) is a model of binary nucleation that is based on laboratory measurements of the binding energies of sulphuric acid and water in charged and neutral clusters. Predictions of SAWNUC are compared for the first time comprehensively with experimental binary nucleation data from the CLOUD chamber at European Organization for Nuclear Research. The experimental measurements span a temperature range of 208–292 K, sulphuric acid concentrations from 1·106 to 1·109 cm−3, and distinguish between ion-induced and neutral nucleation. Good agreement, within a factor of 5, is found between the experimental and modeled formation rates for ion-induced nucleation at 278 K and below and for neutral nucleation at 208 and 223 K. Differences at warm temperatures are attributed to ammonia contamination which was indicated by the presence of ammonia-sulphuric acid clusters, detected by an Atmospheric Pressure Interface Time of Flight (APi-TOF) mass spectrometer. APi-TOF measurements of the sulphuric acid ion cluster distributions (math formula with i = 0, 1, ..., 10) show qualitative agreement with the SAWNUC ion cluster distributions. Remaining differences between the measured and modeled distributions are most likely due to fragmentation in the APi-TOF. The CLOUD results are in good agreement with previously measured cluster binding energies and show the SAWNUC model to be a good representation of ion-induced and neutral binary nucleation of sulphuric acid-water clusters in the middle and upper troposphere.
Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse.
Methods: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel.
Results: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion.
Conclusions: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.
VASP is a member of the Enabled/VASP protein family that is involved in cortical actin dynamics and may also contribute to the formation of gap junctions. In vessels, gap junctional coupling allows the transfer of signals along the vessel wall and coordinates vascular behavior. Moreover, VASP is reportedly a mediator of NO-induced inhibition of platelet aggregation. Therefore, we hypothesized that VASP exerts also important physiologic functions in arterioles. We examined the spread of vasodilations enabled by gap junctional coupling in endothelial cells as well as NO-induced arteriolar dilations in VASP-deficient mice by intravital microscopy of the microcirculation in a skeletal muscle in anesthetized mice. Conducted dilations were initiated by brief, locally confined stimulation of the arterioles with acetylcholine. The maximal diameters of the arterioles under study ranged from 30 to 40 μm. Brief stimulation with acetylcholine induced a short dilation at the local site that was also observed at remote, upstream sites without an attenuation of the amplitude up to a distance of 1.2 mm in control animals (wild-type). In contrast, remote dilations were reduced in VASP-deficient mice despite a similar local dilation indicating an impairment of conducted dilations. Superfusion of NOdonors induced a concentration-dependent dilation in wild-type mice. However, these dilations were slightly reduced in VASP-deficient animals. In contrast, dilations induced by the endothelial stimulator acetylcholine were fully preserved in VASP-deficient mice. In summary, this study suggests that VASP exerts critical functions in arteriolar diameter control. It is crucial for the conduction of dilator signals along the endothelial cell layer. The impairment possibly reflects a perturbed formation of gap junctions in the endothelial cell membrane. VASP also participates in the full dilatory potential of NOdonors although the effect of its deficiency is only subtle. In contrast, VASP is not required for dilations initiated by endothelial stimulation which are mediated in the murine microcirculation by an EDH-mechanism.
Geometrical frustration among interacting spins combined with strong quantum fluctuations destabilize long-range magnetic order in favor of more exotic states such as spin liquids. By following this guiding principle, a number of spin liquid candidate systems were identified in quasi-two-dimensional (quasi-2D) systems. For 3D, however, the situation is less favorable as quantum fluctuations are reduced and competing states become more relevant. Here we report a comprehensive study of thermodynamic, magnetic and dielectric properties on single crystalline and pressed-powder samples of PbCuTe2O6, a candidate material for a 3D frustrated quantum spin liquid featuring a hyperkagome lattice. Whereas the low-temperature properties of the powder samples are consistent with the recently proposed quantum spin liquid state, an even more exotic behavior is revealed for the single crystals. These crystals show ferroelectric order at TFE ≈ 1 K, accompanied by strong lattice distortions, and a modified magnetic response—still consistent with a quantum spin liquid—but with clear indications for quantum critical behavior.
Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner. In contrast to TNFα, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smac mimetic- and TNFα-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation) in FADD-deficient cells. By comparison, Smac mimetic and TNFα trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD.fmk fails to block Smac mimetic- and TNFα-triggered cell death in FADD- or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic- and TNFα-induced cell death in FADD- or caspase-8-deficient. Thus, Smac mimetic enhances TNFα-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNFα-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNFα-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.