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Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells
(2014)
The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC) must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.
Use of drug-eluting balloon coronary intervention prior to living donor kidney transplantation
(2014)
Background: Kidney transplantation is the gold standard of therapy in patients with terminal renal insufficiency. Living donor transplantation is a well-established option in this field. Enlarging the donor's pool implicates the acceptance of an increased rate of comorbidities. Among them, coronary artery disease is a growing problem. An increasing number of patients, undergoing living donation, receive antiplatelet therapies due to coronary disease.
Case presentation: Here we report about the perioperative treatment with a drug-eluting balloon in a patient with major cardiac risk factors who underwent kidney transplantation.
Conclusion: At the current time no recommendation can be given for the routine use of drug-eluting balloons.
Linear Ubiquitin chain Assembly Complex (LUBAC) is an E3 ligase complex that generates linear ubiquitin chains and is important for tumour necrosis factor (TNF) signaling activation. Mice lacking Sharpin, a critical subunit of LUBAC, spontaneously develop inflammatory lesions in the skin and other organs. Here we show that TNF receptor 1 (TNFR1)-associated death domain (TRADD)-dependent TNFR1 signaling in epidermal keratinocytes drives skin inflammation in Sharpin-deficient mice. Epidermis-restricted ablation of Fas-associated protein with death domain (FADD) combined with receptor-interacting protein kinase 3 (RIPK3) deficiency fully prevented skin inflammation, while single RIPK3 deficiency only delayed and partly ameliorated lesion development in Sharpin-deficient mice, showing that inflammation is primarily driven by TRADD- and FADD-dependent keratinocyte apoptosis while necroptosis plays a minor role. At the cellular level, Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. Depletion of FADD or TRADD in Sharpin-deficient HaCaT cells suppressed TNF-induced apoptosis, indicating the importance of FADD and TRADD in Sharpin-dependent anti-apoptosis signaling in keratinocytes.
"Great technology, football and ..." : Malaysian language learners' stereotypes about Germany
(2014)
This study focuses on stereotypes about Germany, its culture and people, held by learners of German in a big public university in Malaysia. It examines not only the stereotypical representations of the target language country but also assesses its favourability and salience, which has not been done previously. The findings revealed that the students' stereotypes about Germany were varied and diverse. Also, they were overwhelmingly positive. The top three salient categories of images about Germany were related to technology, famous personalities – for the most part football players and scientists – and cars. The findings also indicated that very few references had been made to German culture and to its great cultural figures. The results of the present study suggest that students could benefit from a wider and deeper exposure to German culture in the language classroom.
Franz Kafka's (1883-1924) "Die Brücke" is one of the less well-known texts by one of the most prolific authors of literary modernity. However, this short prose text embodies prevalent questions of literary modernity and philosophy as it reflects the crisis of language in regard of identity, communication, and literary production. Placed in the context of fin-de-siècle's discourse of language crisis, this article provides a dialogue between Kafka's "Die Brücke" and Hannah Arendt's (1906-1975) philosophy of thinking and speaking in "The Life of the Mind". Contrary to Arendt's understanding of the metaphor as "a carrying over" between the mental activities of the solitude thinker and a reconciliation with the pluralistic world shared with others, this article argues for a deconstructionist reading of "Die Brücke" as a tool to reevaluate Arendt"s notion of a shared human experience ensured through language and illustrates the advantages of poetic texts within philosophical discourses.
Seven years after the launch of the European Paediatric Medicine Regulation, limited progress in paediatric oncology drug development remains a major concern amongst stakeholders – academics, industry, regulatory authorities, parents, patients and caregivers. Restricted increases in early phase paediatric oncology trials, legal requirements and regulatory pressure to propose early Paediatric Investigation Plans (PIPs), missed opportunities to explore new drugs potentially relevant for paediatric malignancies, lack of innovative trial designs and no new incentives to develop drugs against specific paediatric targets are some unmet needs. Better access to new anti-cancer drugs for paediatric clinical studies and improved collaboration between stakeholders are essential. The Cancer Drug Development Forum (CDDF), previously Biotherapy Development Association (BDA), with Innovative Therapy for Children with Cancer Consortium (ITCC), European Society for Paediatric Oncology (SIOPE) and European Network for Cancer Research in Children and Adolescents (ENCCA) has created a unique Paediatric Oncology Platform, involving multiple stakeholders and the European Union (EU) Commission, with an urgent remit to improve paediatric oncology drug development. The Paediatric Oncology Platform proposes to recommend immediate changes in the implementation of the Regulation and set the framework for its 2017 revision; initiatives to incentivise drug development against specific paediatric oncology targets, and repositioning of drugs not developed in adults. Underpinning these changes is a strategy for mechanism of action and biology driven selection and prioritisation of potential paediatric indications rather than the current process based on adult cancer indications. Pre-competitive research and drug prioritisation, early portfolio evaluation, cross-industry cooperation and multi-compound/sponsor trials are being explored, from which guidance for innovative trial designs will be provided.
Structure and regulatory interactions of the cytoplasmic terminal domains of serotonin transporter
(2014)
Uptake of neurotransmitters by sodium-coupled monoamine transporters of the NSS family is required for termination of synaptic transmission. Transport is tightly regulated by protein–protein interactions involving the small cytoplasmic segments at the amino- and carboxy-terminal ends of the transporter. Although structures of homologues provide information about the transmembrane regions of these transporters, the structural arrangement of the terminal domains remains largely unknown. Here, we combined molecular modeling, biochemical, and biophysical approaches in an iterative manner to investigate the structure of the 82-residue N-terminal and 30-residue C-terminal domains of human serotonin transporter (SERT). Several secondary structures were predicted in these domains, and structural models were built using the Rosetta fragment-based methodology. One-dimensional 1H nuclear magnetic resonance and circular dichroism spectroscopy supported the presence of helical elements in the isolated SERT N-terminal domain. Moreover, introducing helix-breaking residues within those elements altered the fluorescence resonance energy transfer signal between terminal cyan fluorescent protein and yellow fluorescent protein tags attached to full-length SERT, consistent with the notion that the fold of the terminal domains is relatively well-defined. Full-length models of SERT that are consistent with these and published experimental data were generated. The resultant models predict confined loci for the terminal domains and predict that they move apart during the transport-related conformational cycle, as predicted by structures of homologues and by the “rocking bundle” hypothesis, which is consistent with spectroscopic measurements. The models also suggest the nature of binding to regulatory interaction partners. This study provides a structural context for functional and regulatory mechanisms involving SERT terminal domains.
Background: Despite improvements in liver surgery over the past decades, hemostasis during hepatic resections remains challenging. This multicenter randomized study compares the hemostatic effect of a collagen hemostat vs. a carrier-bound fibrin sealant after hepatic resection.
Methods: Patients scheduled for elective liver resection were randomized intraoperatively to receive either the collagen hemostat (COLL) or the carrier-bound fibrin sealant (CBFS) for secondary hemostasis. The primary endpoint was the proportion of patients with hemostasis after 3 min. Secondary parameters were the proportions of patients with hemostasis after 5 and 10 min, the total time to hemostasis, and the complication rates during a 3 months follow-up period.
Results: A total of 128 patients were included. In the COLL group, 53 out of 61 patients (86.9 %) achieved complete hemostasis within 3 min after application of the hemostat compared to 52 out of 65 patients (80.0 %) in the CBFS group. The 95 % confidence interval for this difference [−6.0 %, 19.8 %] does not include the lower noninferiority margin (−10 %). Thus, the COLL treatment can be regarded as noninferior to the comparator. The proportions of patients with hemostasis after 3, 5, and 10 min were not significantly different between the two study arms. Postoperative mortality and morbidity were similar in both treatment groups.
Conclusion: The collagen hemostat is as effective as the carrier-bound fibrin sealant in obtaining secondary hemostasis during liver resection with a comparable complication rate.
A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions.
Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol.
Observation and tracking of fluorescently labeled molecules and particles in living cells reveals detailed information about intracellular processes on the molecular level. Whereas light microscopic particle observation is usually limited to two-dimensional projections of short trajectory segments, we report here image-based real-time three-dimensional single particle tracking in an active feedback loop with single molecule sensitivity. We tracked particles carrying only 1-3 fluorophores deep inside living tissue with high spatio-temporal resolution. Using this approach, we succeeded to acquire trajectories containing several hundred localizations. We present statistical methods to find significant deviations from random Brownian motion in such trajectories. The analysis allowed us to directly observe transitions in the mobility of ribosomal (r)RNA and Balbiani ring (BR) messenger (m)RNA particles in living Chironomus tentans salivary gland cell nuclei. We found that BR mRNA particles displayed phases of reduced mobility, while rRNA particles showed distinct binding events in and near nucleoli.
The knowledge of phenotypic variation in the European range of the highly allergenic Ambrosia artemisiifolia L. (common ragweed) is not entirely complete, even though it is an invasive species of utmost concern. We hypothesized the prevalence of phenotypic differentiations between common ragweed populations in the introduced range, and we assumed that those differentiations were related to environmental conditions at the points of origin. Using a common garden experiment, we investigated biomass allocation, growth rates, and flowering phenology of 38 European common ragweed populations originating from a major geographical gradient. We observed considerable phenotypic variation in growth parameters and flowering phenology, e.g. mean aboveground biomass varied from 23.3 to 47.3 g between the populations. We were able to relate most measured traits with environmental parameters prevailing at the points of origin. For example, early growth of ruderal populations was highly correlated with temperature and precipitation at the point of origin. Late growth and flowering phenology were highly correlated with latitude, i.e. individuals from northern populations grew smaller and flowered and dispersed their pollen and seeds up to 5 weeks earlier than individuals from southern populations. We also found a longitudinal gradient in flowering phenology which has not yet been described. The existence of such a high variability in the introduced range may facilitate further range expansion. We suggest that the correlation with environmental variables rests upon genetic variation possibly due to adaptations to the respective environment. To clarify if such adaptation results from multiple events of introduction or as evolutionary response after introduction, genetic investigations are needed.
Molecular tumour targeting has significantly improved anti-cancer protocols. Still, the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. Combined mammalian target of Rapamycin (mTOR) and histone deacetylase (HDAC) inhibition has been shown not only to enhance anti-tumour potential, but also to prevent resistance development seen under mono-drug therapy. This investigation was designed to evaluate whether cross-communication exists between mTOR signalling and epigenetic events regulated by HDAC. DU-145 prostate cancer cells were treated with insulin-like growth factor (IGF) to activate the Akt-mTOR cascade or with the HDAC-inhibitor valproic acid (VPA) to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, mTOR, Rictor, Raptor, p70s6k, Akt (all: total and phosphorylated), H3 and H4 (total and acetylated) were analysed by western blotting. Both techniques revealed a link between mTOR and the epigenetic machinery. IGF activated mTOR, Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, IGFr blockade and knock-down blocked the Akt-mTOR axis, but simultaneously diminished aH3 and aH4. VPA treatment up-regulated histone acetylation, but also activated mTOR-Akt signalling. HDAC1 and 2 knock-down revealed that the interaction with the mTOR system is initiated by histone H3 acetylation. HDAC-mTOR communication, therefore, is apparent whereby tumour-promoting (Akt/mTORhigh, aH3/aH4low) and tumour-suppressing signals (Akt/mTORlow, aH3/aH4high) are activated in parallel. Combined use of an HDAC- and mTOR inhibitor might then diminish pro-tumour effects triggered by the HDAC- (Akt/mTORhigh) or mTOR inhibitor (aH3/aH4low) alone.
Background: Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS.
Design: This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred.
Summary: ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.
Background: HER2 status assessment is a prerequisite for the establishment of an appropriate treatment strategy in gastric cancer. Gastric cancers are very heterogeneous and separate evaluations of gene amplification and protein expression lead to uncertainties in localizing distinct clones and are time consuming. This study evaluates the equivalence of the novel method combining both gene and protein platforms on one slide.
Methods: Immunohistochemistry (IHC) and HER2 dual-colour silver in situ hybridization (SISH) as single methods (IHC/SISH) and gene-protein platform combining both methods on one slide (gene/protein) were performed in randomly collected 100 cases of gastric adenocarcinoma. Results of IHC/SISH were compared with gene/protein staining.
Results: 96 of 100 samples were assessable. In the gene/protein staining, pathologists were able to assess gene amplification and consequent protein expression at the single cell level. In comparison trials, gene amplification was observed in 14.6% by both, conventional SISH and gene/protein platform (agreement 100%; Kappa-coefficient κ = 1.0). Protein expression scores by IHC were 70.8% (0), 10.4% (1+), 9.4% (2+), and 9.4% (3+). Protein expression by gene/protein method were: 70.8% (0), 11.5% (1+), 7.3% (2+) and 10.4% (3+) of patients. There were complete concordances in IHC assessment of cases with score 0 (100.0%; κ = 1). High concordances are shown in score 1+ (98.96%; κ = 0.947) and 3+ (96.88%; κ = 0.825) cases and good concordances in 2+ cases (95.83%; κ = 0.728).
Conclusions: This novel combined platform has the advantage of being able to evaluate both gene and the protein status in the same cancer cell and may be of particular interest for research and patient's care.
Considering the review by Puspitasari and colleagues, an additional discussion of the endpoints of the Se supplementation studies described would be helpful. In our view, selenium can safely be given to selenium-deficient cancer patients prior to and during radiotherapy. Therefore, in order to help the radiation oncologist in decision making, we strongly advocate to determine the selenium status prior to and during a potential adjuvant selenium supplementation, e.g. when trying to ease the side-effects of radiation treatment or in the aftercare situation when the selenium status may become insufficient.
Irrigation intensifies land use by increasing crop yield but also impacts water resources. It affects water and energy balances and consequently the microclimate in irrigated regions. Therefore, knowledge of the extent of irrigated land is important for hydrological and crop modelling, global change research, and assessments of resource use and management. Information on the historical evolution of irrigated lands is limited. The new global Historical Irrigation Dataset (HID) provides estimates of the temporal development of the area equipped for irrigation (AEI) between 1900 and 2005 at 5 arc-minute resolution. We collected subnational irrigation statistics from various sources and found that the global extent of AEI increased from 63 million ha (Mha) in 1900 to 112 Mha in 1950 and 306 Mha in 2005. We developed eight gridded versions of time series of AEI by combining subnational irrigation statistics with different data sets on the historical extent of cropland and pasture. Different rules were applied to maximize consistency of the gridded products to subnational irrigation statistics or to historical cropland and pasture data sets. The HID reflects very well the spatial patterns of irrigated land in the western United States as shown on historical maps. Mean aridity on irrigated land increased and river discharge decreased from 1900–1950 whereas aridity decreased from 1950–2005. The dataset and its documentation are made available in an open data repository at https://mygeohub.org/publications/8 (doi:10.13019/M2MW2G).
We have isolated a cDNA coding for a putative invertebrate-type dopamine receptor (Peadop2) from P. americana brain by using a PCR-based strategy. The mRNA is present in samples from brain and salivary glands. We analyzed the distribution of the PeaDOP2 receptor protein with specific affinity-purified polyclonal antibodies. On Western blots, PeaDOP2 was detected in protein samples from brain, subesophageal ganglion, thoracic ganglia, and salivary glands. In immunocytochemical experiments, we detected PeaDOP2 in neurons with their somata being located at the anterior edge of the medulla bilaterally innervating the optic lobes and projecting to the ventro-lateral protocerebrum. In order to determine the functional and pharmacological properties of the cloned receptor, we generated a cell line constitutively expressing PeaDOP2. Activation of PeaDOP2-expressing cells with dopamine induced an increase in intracellular cAMP. In contrast, a C-terminally truncated splice variant of this receptor did not exhibit any functional property by itself. The molecular and pharmacological characterization of the first dopamine receptor from P. americana provides the basis for forthcoming studies focusing on the significance of the dopaminergic system in cockroach behavior and physiology.
Conventional radar-based image reconstruction techniques fail when they are applied to heterogeneous breast tissue, since the underlying in-breast relative permittivity is unknown or assumed to be constant. This results in a systematic error during the process of image formation. A recent trend in microwave biomedical imaging is to extract the relative permittivity from the object under test to improve the image reconstruction quality and thereby to enhance the diagnostic assessment. In this paper, we present a novel radar-based methodology for microwave breast cancer detection in heterogeneous breast tissue integrating a 3D map of relative permittivity as a priori information. This leads to a novel image reconstruction formulation where the delay-and-sum focusing takes place in time rather than range domain. Results are shown for a heterogeneous dense (class-4) and a scattered fibroglandular (class-2) numerical breast phantom using Bristol's 31-element array configuration.
Multimorbidity is a health issue mostly dealt with in primary care practice. As a result of their generalist and patient-centered approach, long-lasting relationships with patients, and responsibility for continuity and coordination of care, family physicians are particularly well placed to manage patients with multimorbidity. However, conflicts arising from the application of multiple disease oriented guidelines and the burden of diseases and treatments often make consultations challenging. To provide orientation in decision making in multimorbidity during primary care consultations, we developed guiding principles and named them after the Greek mythological figure Ariadne. For this purpose, we convened a two-day expert workshop accompanied by an international symposium in October 2012 in Frankfurt, Germany. Against the background of the current state of knowledge presented and discussed at the symposium, 19 experts from North America, Europe, and Australia identified the key issues of concern in the management of multimorbidity in primary care in panel and small group sessions and agreed upon making use of formal and informal consensus methods. The proposed preliminary principles were refined during a multistage feedback process and discussed using a case example. The sharing of realistic treatment goals by physicians and patients is at the core of the Ariadne principles. These result from i) a thorough interaction assessment of the patient’s conditions, treatments, constitution, and context; ii) the prioritization of health problems that take into account the patient's preferences – his or her most and least desired outcomes; and iii) individualized management realizes the best options of care in diagnostics, treatment, and prevention to achieve the goals. Goal attainment is followed-up in accordance with a re-assessment in planned visits. The occurrence of new or changed conditions, such as an increase in severity, or a changed context may trigger the (re-)start of the process. Further work is needed on the implementation of the formulated principles, but they were recognized and appreciated as important by family physicians and primary care researchers.
Purpose: Prostate specific antigen is not reliable in diagnosing prostate cancer (PCa), making the identification of novel, precise diagnostic biomarkers important. Since chemokines are associated with more aggressive disease and poor prognosis in diverse malignancies, we aimed to investigate the diagnostic relevance of chemokines in PCa.
Materials and methods: Preoperative and early postoperative serum samples were obtained from 39 consecutive PCa patients undergoing radical prostatectomy. Serum from 15 healthy volunteers served as controls. Concentrations of CXCL12, CXCL13, CX3CL1, CCL2, CCL5, and CCL20 were measured in serum by Luminex. The expression activity of CXCR3, CXCR4, CXCR5, CXCR7, CXCL12, CXCL13, CX3CR1, CXCL1, CCR2, CCR5, CCR6, CCR7, CCL2, and CCL5 mRNA was assessed in tumor and adjacent normal tissue of prostatectomy specimens by quantitative real-time polymerase chain reaction. The associations of these chemokines with clinical and histological parameters were tested.
Results: The gene expression activity of CCL2 and CCR6 was significantly higher in tumor tissue compared to adjacent normal tissue. CCL2 was also significantly higher in the blood samples of PCa patients, compared to controls. CCL5, CCL20, and CX3CL1 were lower in patient serum, compared to controls. CCR2 tissue mRNA was negatively correlated with the Gleason score and grading.
Conclusion: Chemokines are significantly modified during tumorigenesis of PCa, and CCL2 is a promising diagnostic biomarker.
A versatile synthetic procedure is described to prepare the benzimidazole-fused 1,2,4-thiadiazoles 2a–c via a methanesulfonyl chloride initiated multistep cyclization involving the intramolecular reaction of an in-situ generated carbodiimide with a thiourea unit. The structure of the intricate heterocycle 2a was confirmed by single-crystal X-ray analysis and its mechanism of formation supported by DFT computations.
Many diseases have been described to be associated with inflammatory processes. The currently available anti-inflammatory drug therapy is often not successful or causes intolerable side effects. Thus, new anti-inflammatory substances are still urgently needed. Plants were the first source of remedies in the history of mankind. Since their chemical characterization in the 19th century, herbal bioactive compounds have fueled drug development. Also, nowadays, new plant-derived agents continuously enrich our drug arsenal (e.g., vincristine, galantamine, and artemisinin). The number of new, pharmacologically active herbal ingredients, in particular that of anti-inflammatory compounds, rises continuously. The major obstacle in this field is the translation of preclinical knowledge into evidence-based clinical progress. Human trials of good quality are often missing or, when available, are frequently not suitable to really prove a therapeutical value. This minireview will summarize the current situation of 6 very prominent plant-derived anti-inflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin-3-gallate (EGCG), and quercetin. We will highlight their clinical potential and/or pinpoint an overestimation. Moreover, we will sum up the planned trials in order to provide insights into the inflammatory disorders that are hypothesized to be beneficially influenced by the compound.
Background: Hypoxia-inducible factor-1α (HIF-1α) and NF-κB play important roles in the inflammatory response after hemorrhagic shock and resuscitation (H/R). Here, the role of myeloid HIF-1α in liver hypoxia, injury, and inflammation after H/R with special regard to NF-κB activation was studied.
Methods: Mice with a conditional HIF-1α knockout (KO) in myeloid cell-line and wild-type (WT) controls were hemorrhaged for 90 min ( mm Hg) and resuscitated. Controls underwent only surgical procedures.
Results: After six hours, H/R enhanced the expression of HIF-1α-induced genes vascular endothelial growth factor (VEGF) and adrenomedullin (ADM). In KO mice, this was not observed. H/R-induced liver injury in HIF-1α KO was comparable to WT. Elevated plasma interleukin-6 (IL-6) levels after H/R were not reduced by HIF-1α KO. Local hepatic hypoxia was not significantly reduced in HIF-1α KO compared to controls after H/R. H/R-induced NF-κB phosphorylation in liver did not significantly differ between WT and KO.
Conclusions: Here, deleting HIF-1α in myeloid cells and thereby in Kupffer cells was not protective after H/R. This data indicates that other factors, such as NF-κB, due to its upregulated phosphorylation in WT and KO mice, contrary to HIF-1α, are rather key modulators of inflammation after H/R in our model.
We study the effects of the recent economic crisis on firms׳ bidding behavior and markups in sealed bid auctions. Using data from Austrian construction procurements, we estimate bidders׳ construction costs within a private value auction model. We find that markups of all bids submitted decrease by 1.5 percentage points in the recent economic crisis, markups of winning bids decrease by 3.3 percentage points. We also find that without the government stimulus package this decrease would have been larger. These two pieces of evidence point to pro-cyclical markups.
Background: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study.
Patients and methods: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA).
Results: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS.
Conclusion: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.
Markets are central to modern society, so their failures can have devastating effects. Here, we examine a prominent failure: price bubbles. We propose that bubbles are affected by ethnic homogeneity in the market and can be thwarted by diversity. Using experimental markets in Southeast Asia and North America, we find a marked difference: Market prices fit true values 58% better in diverse markets. In homogenous markets, overpricing is higher and traders’ errors are more correlated than in diverse markets. The findings suggest that price bubbles arise not only from individual errors or financial conditions, but also from the social context of decision making. Informing public discussion, our findings suggest that diversity facilitates friction that enhances deliberation and upends conformity.
Bacteria communicate via small diffusible molecules to mediate group-coordinated behavior, a process designated as quorum sensing. The basic molecular quorum sensing system of Gram-negative bacteria consists of a LuxI-type autoinducer synthase producing acyl-homoserine lactones (AHLs) as signaling molecules, and a LuxR-type receptor detecting the AHLs to control expression of specific genes. However, many proteobacteria possess one or more unpaired LuxR-type receptors that lack a cognate LuxI-like synthase, referred to as LuxR solos. The enteric and insect pathogenic bacteria of the genus Photorhabdus harbor an extraordinarily high number of LuxR solos, more than any other known bacteria, and all lack a LuxI-like synthase. Here, we focus on the presence and the different types of LuxR solos in the three known Photorhabdus species using bioinformatics analyses. Generally, the N-terminal signal-binding domain (SBD) of LuxR-type receptors sensing AHLs have a motif of six conserved amino acids that is important for binding and specificity of the signaling molecule. However, this motif is altered in the majority of the Photorhabdus-specific LuxR solos, suggesting the use of other signaling molecules than AHLs. Furthermore, all Photorhabdus species contain at least one LuxR solo with an intact AHL-binding motif, which might allow the ability to sense AHLs of other bacteria. Moreover, all three species have high AHL-degrading activity caused by the presence of different AHL-lactonases and AHL-acylases, revealing a high quorum quenching activity against other bacteria. However, the majority of the other LuxR solos in Photorhabdus have a N-terminal so-called PAS4-domain instead of an AHL-binding domain, containing different amino acid motifs than the AHL-sensors, which potentially allows the recognition of a highly variable range of signaling molecules that can be sensed apart from AHLs. These PAS4-LuxR solos are proposed to be involved in host sensing, and therefore in inter-kingdom signaling. Overall, Photorhabdus species are perfect model organisms to study bacterial communication via LuxR solos and their role for a symbiotic and pathogenic life style.
Ternary aerosol nucleation experiments were conducted in the CLOUD chamber at CERN in order to investigate the influence of ions on new particle formation. Neutral and ion-induced nucleation experiments, i.e., with and without the presence of ions, were carried out under precisely controlled conditions. The sulphuric acid concentration was measured with a Chemical Ionization Mass Spectrometer (CIMS) during the new particle formation experiments. The added ternary trace gases were ammonia (NH3), dimethylamine (DMA, C2H7N) or oxidised products of pinanediol (PD, C10H18O2). When pinanediol was introduced into the chamber, an increase in the mass spectrometric signal used to determine the sulphuric acid concentration (m/z 97, i.e., HSO4−) was observed due to ions from the CLOUD chamber. The enhancement was only observed during ion-induced nucleation measurements by using either galactic cosmic rays (GCR) or the proton synchrotron (PS) pion beam for the ion generation, respectively. The ion effect typically involved an increase in the apparent sulphuric acid concentration by a factor of ~2 to 3 and was qualitatively verified by the ion measurements by an Atmospheric Pressure interface-Time Of Flight (APi-TOF) mass spectrometer. By applying a high voltage (HV) clearing field inside the CLOUD chamber the ion effect on the CIMS measurement was completely eliminated since, under these conditions, small ions are swept from the chamber in about one second. In order to exclude the ion effect and to provide corrected sulphuric acid concentrations during the GCR and PS beam nucleation experiments, a parameterisation was derived that utilizes the trace gas concentrations and the UV light intensity as input parameters. Atmospheric sulphuric acid measurements with a CIMS showed an insignificant ion effect.
Ternary aerosol nucleation experiments were conducted in the CLOUD chamber at CERN in order to investigate the influence of ions on new particle formation. Neutral and ion-induced nucleation experiments, i.e. without and with the presence of ions, respectively, were carried out under precisely controlled conditions. The sulfuric acid concentration was measured with a chemical ionisation mass spectrometer (CIMS) during the new particle formation experiments. The added ternary trace gases were ammonia (NH3), dimethylamine (DMA, C2H7N) or oxidised products of pinanediol (PD, C10H18O2). When pinanediol was introduced into the chamber, an increase in the mass spectrometric signal used to determine the sulfuric acid concentration (m/z 97, i.e. HSO4−) was observed due to ions from the CLOUD chamber. The enhancement was only observed during ion-induced nucleation measurements by using either galactic cosmic rays (GCRs) or the proton synchrotron (PS) pion beam for the ion generation, respectively. The ion effect typically involved an increase in the apparent sulfuric acid concentration by a factor of ~ 2 to 3 and was qualitatively verified by the ion measurements with an atmospheric-pressure interface-time of flight (APi-TOF) mass spectrometer. By applying a high-voltage (HV) clearing field inside the CLOUD chamber, the ion effect on the CIMS measurement was completely eliminated since, under these conditions, small ions are swept from the chamber in about 1 s. In order to exclude the ion effect and to provide corrected sulfuric acid concentrations during the GCR and PS beam nucleation experiments, a parameterisation was derived that utilises the trace gas concentrations and the UV light intensity as input parameters. Atmospheric sulfuric acid measurements with a CIMS showed an insignificant ion effect.
The formation of particles from precursor vapors is an important source of atmospheric aerosol. Research at the Cosmics Leaving OUtdoor Droplets (CLOUD) facility at CERN tries to elucidate which vapors are responsible for this new particle formation, and how in detail it proceeds. Initial measurement campaigns at the CLOUD stainless-steel aerosol chamber focused on investigating particle formation from ammonia (NH3) and sulfuric acid (H2SO4). Experiments were conducted in the presence of water, ozone and sulfur dioxide. Contaminant trace gases were suppressed at the technological limit. For this study, we mapped out the compositions of small NH3-H2SO4 clusters over a wide range of atmospherically relevant environmental conditions. We covered [NH3] in the range from <2 to 1400 pptv, [H2SO4] from 3.3 × 106 to 1.4 × 109 cm−3, and a temperature range from −25 to +20 °C. Negatively and positively charged clusters were directly measured by an atmospheric pressure interface time-of-flight (APi-TOF) mass spectrometer, as they initially formed from gas-phase NH3 and H2SO4, and then grew to larger clusters containing more than 50 molecules of NH3 and H2SO4, corresponding to mobility-equivalent diameters greater than 2 nm. Water molecules evaporate from these clusters during sampling and are not observed. We found that the composition of the NH3-H2SO4 clusters is primarily determined by the ratio of gas-phase concentrations [NH3] / [H2SO4], as well as by temperature. Pure binary H2O-H2SO4 clusters (observed as clusters of only H2SO4) only form at [NH3] / [H2SO4]<0.1 to 1. For larger values of [NH3] / [H2SO4], the composition of NH3-H2SO4 clusters was characterized by the number of NH3 molecules m added for each added H2SO4 molecule n (Δm / Δn), where n is in the range 4–18 (negatively charged clusters) or 1–17 (positively charged clusters). For negatively charged clusters, Δm / Δn saturated between 1 and 1.4 for [NH3] / [H2SO4]>10. Positively charged clusters grew on average by Δm / Δn = 1.05 and were only observed at sufficiently high [NH3] / [H2SO4]. The H2SO4 molecules of these clusters are partially neutralized by NH3, in close resemblance to the acid-base bindings of ammonium bisulfate. Supported by model simulations, we substantiate previous evidence for acid-base reactions being the essential mechanism behind the formation of these clusters under atmospheric conditions and up to sizes of at least 2 nm. Our results also suggest that yet unobservable electrically neutral NH3-H2SO4 clusters grow by generally the same mechanism as ionic clusters, particularly for [NH3] / [H2SO4]>10. We expect that NH3-H2SO4 clusters form and grow also mostly by Δm / Δn>1 in the atmosphere's boundary layer, as [NH3] / [H2SO4] is mostly larger than 10. We compared our results from CLOUD with APi-TOF measurements of NH3-H2SO4 anion clusters during new particle formation in the Finnish boreal forest. However, the exact role of NH3-H2SO4 clusters in boundary layer particle formation remains to be resolved.
IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells
(2014)
The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy.
Seven different instruments and measurement methods were used to examine the immersion freezing of bacterial ice nuclei from Snomax® (hereafter Snomax), a product containing ice active protein complexes from non-viable Pseudomonas syringae bacteria. The experimental conditions were kept as similar as possible for the different measurements. Of the participating instruments, some examined droplets which had been made from suspensions directly, and the others examined droplets activated on previously generated Snomax particles, with particle diameters of mostly a few hundred nanometers and up to a few micrometers in some cases. Data were obtained in the temperature range from −2 to −38 °C, and it was found that all ice active protein complexes were already activated above −12 °C. Droplets with different Snomax mass concentrations covering 10 orders of magnitude were examined. Some instruments had very short ice nucleation times down to below 1 s, while others had comparably slow cooling rates around 1 K min−1. Displaying data from the different instruments in terms of numbers of ice active protein complexes per dry mass of Snomax, nm, showed that within their uncertainty the data agree well with each other as well as to previously reported literature results. Two parameterizations were taken from literature for a direct comparison to our results, and these were a time dependent approach based on a contact angle distribution Niedermeier et al. (2014) and a modification of the parameterization presented in Hartmann et~al.~(2013) representing a time independent approach. The agreement between these and the measured data were good, i.e. they agreed within a temperature range of 0.6 K or equivalently a range in nm of a factor of 2. From the results presented herein, we propose that Snomax, at least when carefully shared and prepared, is a suitable material to test and compare different instruments for their accuracy of measuring immersion freezing.
Immersion freezing is the most relevant heterogeneous ice nucleation mechanism through which ice crystals are formed in mixed-phase clouds. In recent years, an increasing number of laboratory experiments utilizing a variety of instruments have examined immersion freezing activity of atmospherically relevant ice nucleating particles (INPs). However, an inter-comparison of these laboratory results is a difficult task because investigators have used different ice nucleation (IN) measurement methods to produce these results. A remaining challenge is to explore the sensitivity and accuracy of these techniques and to understand how the IN results are potentially influenced or biased by experimental parameters associated with these techniques.
Within the framework of INUIT (Ice Nucleation research UnIT), we distributed an illite rich sample (illite NX) as a representative surrogate for atmospheric mineral dust particles to investigators to perform immersion freezing experiments using different IN measurement methods and to obtain IN data as a function of particle concentration, temperature (T), cooling rate and nucleation time. Seventeen measurement methods were involved in the data inter-comparison. Experiments with seven instruments started with the test sample pre-suspended in water before cooling, while ten other instruments employed water vapor condensation onto dry-dispersed particles followed by immersion freezing. The resulting comprehensive immersion freezing dataset was evaluated using the ice nucleation active surface-site density (ns) to develop a representative ns(T) spectrum that spans a wide temperature range (−37 °C < T < −11 °C) and covers nine orders of magnitude in ns.
Our inter-comparison results revealed a discrepancy between suspension and dry-dispersed particle measurements for this mineral dust. While the agreement was good below ~ −26 °C, the ice nucleation activity, expressed in ns, was smaller for the wet suspended samples and higher for the dry-dispersed aerosol samples between about −26 and −18 °C. Only instruments making measurement techniques with wet suspended samples were able to measure ice nucleation above −18 °C. A possible explanation for the deviation between −26 and −18 °C is discussed. In general, the seventeen immersion freezing measurement techniques deviate, within the range of about 7 °C in terms of temperature, by three orders of magnitude with respect to ns. In addition, we show evidence that the immersion freezing efficiency (i.e., ns) of illite NX particles is relatively independent on droplet size, particle mass in suspension, particle size and cooling rate during freezing. A strong temperature-dependence and weak time- and size-dependence of immersion freezing efficiency of illite-rich clay mineral particles enabled the ns parameterization solely as a function of temperature. We also characterized the ns (T) spectra, and identified a section with a steep slope between −20 and −27 °C, where a large fraction of active sites of our test dust may trigger immersion freezing. This slope was followed by a region with a gentler slope at temperatures below −27 °C. A multiple exponential distribution fit is expressed as ns(T) = exp(23.82 × exp(−exp(0.16 × (T + 17.49))) + 1.39) based on the specific surface area and ns(T) = exp(25.75 × exp(−exp(0.13 × (T + 17.17))) + 3.34) based on the geometric area (ns and T in m−2 and °C, respectively). These new fits, constrained by using an identical reference samples, will help to compare IN measurement methods that are not included in the present study and, thereby, IN data from future IN instruments.
Serial quantification of BCR–ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR–ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 106, 1.08±0.11 × 105, 1.03±0.10 × 104, 1.02±0.09 × 103, 1.04±0.10 × 102 and 10.0±1.5 copies/μl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR–ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR–ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).
Myelodysplastic syndromes (MDSs) represent clonal disorders mainly of the elderly that are characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia. The pathogenesis of MDS is thought to evolve from accumulation and selection of specific genetic or epigenetic events. Emerging evidence indicates that MDS is not solely a hematopoietic disease but rather affects the entire bone marrow microenvironment, including bone metabolism. Many of these cells, in particular mesenchymal stem and progenitor cells (MSPCs) and osteoblasts, express a number of adhesion molecules and secreted factors that regulate blood regeneration throughout life by contributing to hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal and differentiation. Several endocrine factors, such as erythropoietin, parathyroid hormone and estrogens, as well as deranged iron metabolism modulate these processes. Thus, interactions between MSPC and HSPC contribute to the pathogenesis of MDS and associated pathologies. A detailed understanding of these mechanisms may help to define novel targets for diagnosis and possibly therapy. In this review, we will discuss the scientific rationale of "osteohematology" as an emerging research field in MDS and outline clinical implications.
Background: In an earlier study we demonstrated the feasibility to create tissue engineered venous scaffolds in vitro and in vivo. In this study we investigated the use of tissue engineered constructs for ureteral replacement in a long term orthotopic minipig model. In many different projects well functional ureretal tissue was established using tissue engineering in animals with short-time follow up (12 weeks). Therefore urothelial cells were harvested from the bladder, cultured, expanded in vitro, labelled with fluorescence and seeded onto the autologous veins, which were harvested from animals during a second surgery. Three days after cell seeding the right ureter was replaced with the cell-seeded matrices in six animals, while further 6 animals received an unseeded vein for ureteral replacement. The animals were sacrificed 12, 24, and 48 weeks after implantation. Gross examination, intravenous pyelogram (IVP), H&E staining, Trichrome Masson's Staining, and immunohistochemistry with pancytokeratin AE1/AE3, smooth muscle alpha actin, and von Willebrand factor were performed in retrieved specimens.
Results: The IVP and gross examination demonstrated that no animals with tissue engineered ureters and all animals of the control group presented with hydronephrosis after 12 weeks. In the 24-week group, one tissue engineered and one unseeded vein revealed hydronephrosis. After 48 weeks all tissue engineered animals and none of the control group showed hydronephrosis on the treated side. Histochemistry and immunohistochemistry revealed a multilayer of urothelial cells attached to the seeded venous grafts.
Comclusions: Venous grafts may be a potential source for ureteral reconstruction. The results of so far published ureteral tissue engineering projects reveal data up to 12 weeks after implantation. Even if the animal numbers of this study are small, there is an increasing rate of hydronephrosis revealing failure of ureteral tissue engineering with autologous matrices in time points longer than 3 months after implantation. Further investigations have to prove adequate clinical outcome and appropriate functional long-term results.
In this study we show how size-resolved measurements of aerosol particles and cloud condensation nuclei (CCN) can be used to characterize the supersaturation of water vapor in a cloud. The method was developed and applied during the ACRIDICON-Zugspitze campaign (17 September to 4 October 2012) at the high-Alpine research station Schneefernerhaus (German Alps, 2650 m a.s.l.). Number size distributions of total and interstitial aerosol particles were measured with a scanning mobility particle sizer (SMPS), and size-resolved CCN efficiency spectra were recorded with a CCN counter system operated at different supersaturation levels.
During the evolution of a cloud, aerosol particles are exposed to different supersaturation levels. We outline and compare different estimates for the lower and upper bounds (Slow, Shigh) and the average value (Savg) of peak supersaturation encountered by the particles in the cloud. A major advantage of the derivation of Slow and Savg from size-resolved CCN efficiency spectra is that it does not require the specific knowledge or assumptions about aerosol hygroscopicity that are needed to derive estimates of Slow, Shigh, and Savg from aerosol size distribution data. For the investigated cloud event, we derived Slow ≈ 0.07–0.25%, Shigh ≈ 0.86–1.31% and Savg ≈ 0.42–0.68%.
The three-dimensional quantification of small scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe and TACTS/ESMVal aircraft campaigns. The focus of this work is on the so-called dynamics mode data characterized by a medium spectral and a very high spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3 and CFC-12) and their spatial resolution are discussed. During ESSenCe, high resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in-situ data indicate a good agreement between the data sets. During TACTS/ESMVal a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere has been performed. This filament could be reconstructed with an unprecedented spatial resolution of better than 500 m vertically and 20 km × 20 km horizontally.
In the present work, three different techniques are used to separate ice-nucleating particles (INP) and ice particle residuals (IPR) from non-ice-active particles: the Ice Selective Inlet (ISI) and the Ice Counterflow Virtual Impactor (Ice-CVI), which sample ice particles from mixed phase clouds and allow for the analysis of the residuals, as well as the combination of the Fast Ice Nucleus Chamber (FINCH) and the Ice Nuclei Pumped Virtual Impactor (IN-PCVI), which provides ice-activating conditions to aerosol particles and extracts the activated ones for analysis. The collected particles were analyzed by scanning electron microscopy and energy-dispersive X-ray microanalysis to determine their size, chemical composition and mixing state. Samples were taken during January/February 2013 at the High Alpine Research Station Jungfraujoch. All INP/IPR-separating techniques had considerable abundances (median 20–70%) of contamination artifacts (ISI: Si-O spheres, probably calibration aerosol; Ice-CVI: Al-O particles; FINCH + IN-PCVI: steel particles). Also, potential measurement artifacts (soluble material) occurred (median abundance < 20%). After removal of the contamination particles, silicates and Ca-rich particles, carbonaceous material and metal oxides were the major INP/IPR particle types separated by all three techniques. Minor types include soot and Pb-bearing particles. Sea-salt and sulfates were identified by all three methods as INP/IPR. Lead was identified in less than 10% of the INP/IPR. It was mainly present as an internal mixture with other particle types, but also external lead-rich particles were found. Most samples showed a maximum of the INP/IPR size distribution at 400 nm geometric diameter. In a few cases, a second super-micron maximum was identified. Soot/carbonaceous material and metal oxides were present mainly in the submicron range. ISI and FINCH yielded silicates and Ca-rich particles mainly with diameters above 1 μm, while the Ice-CVI also sampled many submicron particles. Probably owing to the different meteorological conditions, the INP/IPR composition was highly variable on a sample to sample basis. Thus, some part of the discrepancies between the different techniques may result from the (unavoidable) non-parallel sampling. The observed differences of the particles group abundances as well as the mixing state of INP/IPR point to the need of further studies to better understand the influence of the separating techniques on the INP/IPR chemical composition.
Comparing two methods of determining infiltration rates of permeable interlocking concrete pavers
(2014)
Adequate infiltration through Permeable Interlocking Concrete Pavements (PICPs) is critical to their hydraulic performance. Detected by monitoring infiltration performance, reduced infiltration rates can indicate that maintenance is required. Measurement of infiltration rates has previously been problematic on PICPs because of a lack of accepted standard methodologies and the practical difficulties in modifying existing testing methodologies. On large sites, standard methodologies necessitate multiple measurements to achieve accuracy. Standard methods also contend with practical issues such as sealing the rings to the surface to prevent lateral water flow. This study examined the performance of two PICP surface infiltration rate measurement methods: a modified double-ring infiltrometer (DRIT), and a specially designed rainfall simulation infiltrometer (RSIT). A positive correlation (R2 = 0.85) of results was found between the two, demonstrating that the RSIT was comparable to the DRIT. The modified DRIT produced surface infiltration results approximately 60% higher than the RSIT results. The RSIT provided lower variation between tests, requiring fewer measurements in large sites whilst still maintaining accuracy, thereby improving testing efficiency. The new RSIT method also eliminates some of the practical difficulties with existing methodologies such as unrealistic pressure heads artificially increasing infiltration rates, and the use of sealant under test measurement infiltration rings.
Global warming, changes in the hydrological cycle and enhanced marine primary productivity all have been invoked to have contributed to the occurrence of widespread ocean anoxia during the Cenomanian-Turonian Oceanic Anoxic Event (OAE2; ~ 94 Ma), but disentangling these factors on a regional scale has remained problematic. We generated palynological and organic geochemical records that allow the separation of these forcing factors in a core spanning the OAE2 from Wunstorf, Lower Saxony Basin (LSB; North Gemany), which exhibits cyclic black shale–marl alternations related to the orbital precession cycle.
Despite the widely varying depositional conditions complicating the interpretation of the obtained records, TEX86H indicates that sea-surface temperature (SST) evolution in the LSB during OAE2 resembles that of previously studied sites throughout the proto-North Atlantic. Cooling during the so-called Plenus Cold Event interrupted black shale deposition during the early stages of OAE2. However, TEX86 does not vary significantly across marl–black shale alternations, suggesting that temperature variations did not force the formation of the cyclic black shale horizons. Relative (i.e., with respect to marine palynomorphs) and absolute abundances of pollen and spores are elevated during phases of black shale deposition, indicative of enhanced precipitation and run-off. High abundances of cysts from inferred heterotrophic and euryhaline dinoflagellates supports high run-off, which likely introduced additional nutrients to the epicontinental shelf resulting in elevated marine primary productivity.
We conclude that orbitally-forced enhanced precipitation and run-off, in tandem with elevated marine primary productivity, were critical in cyclic black shale formation on the northwest European epicontinental shelf and potentially for other OAE2 sections in the proto-Atlantic and Western Interior Seaway at similar latitudes as well.
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.
The Tarim River Basin, located in Xinjiang, NW China, is the largest endorheic river basin of China and one of the largest in whole Central Asia. Due to the extremely arid climate with an annual precipitation of less than 100 mm, the water supply along the Aksu and Tarim River solely depends on river water. This applies for anthropogenic activities (e.g. agriculture) as well as for the natural ecosystems so that both compete for water. The on-going increase of water consumption by agriculture and other human activities in this region has been enhancing the competition for water between human needs and nature. Against this background, 11 German and 6 Chinese universities and research institutes formed the consortium SuMaRiO (www.sumario.de), which aims at gaining a holistic picture of the availability of water resources in the Tarim River Basin and the impacts on anthropogenic activities and natural ecosystems caused by the water distribution within the Tarim River Basin. The discharge of the Aksu River, which is the major tributary to the Tarim, has been increasing over the past 6 decades due to enhanced glacier melt. Alone from 1989 to 2011, the area under agriculture more than doubled. Thereby, cotton became the major crop and there was a shift from small-scale farming to large-scale intensive farming. The major natural ecosystems along the Aksu and Tarim River are riparian ecosystems: Riparian (Tugai) forests, shrub vegetation, reed beds, and other grassland. Within the SuMaRiO Cluster the focus was laid on the Tugai forests, with Populus euphratica as dominant tree, because the most productive and species-rich natural ecosystems can be found among those forests. On sites with groundwater distance of less than 7.5 m the annual increments correlated with river runoffs of the previous year. But, the further downstream along the Tarim River, the more the natural river dynamics ceased, which impacts on the recruitment of Populus euphratica. Household surveys revealed that there is a considerable willingness to pay for conservation of those riparian forests with the mitigation of dust and sandstorms considered as the most important ecosystem service. This interdisciplinary project will result in a decision support tool (DST), build on the participation of regional stakeholders and models based on results and field experiments. This DST finally shall assist stakeholders in balancing the water competition acknowledging the major external effects of any water allocation.
The link between atmospheric radicals and newly formed particles at a spruce forest site in Germany
(2014)
It has been claimed for more than a century that atmospheric new particle formation is primarily influenced by the presence of sulfuric acid. However, the activation process of sulfuric acid related clusters into detectable particles is still an unresolved topic. In this study we focus on the PARADE campaign measurements conducted during August/September 2011 at Mt Kleiner Feldberg in central Germany. During this campaign a set of radicals, organic and inorganic compounds and oxidants and aerosol properties were measured or calculated. We compared a range of organic and inorganic nucleation theories, evaluating their ability to simulate measured particle formation rates at 3 nm in diameter (J3) for a variety of different conditions. Nucleation mechanisms involving only sulfuric acid tentatively captured the observed noon-time daily maximum in J3, but displayed an increasing difference to J3 measurements during the rest of the diurnal cycle. Including large organic radicals, i.e. organic peroxy radicals (RO2) deriving from monoterpenes and their oxidation products, in the nucleation mechanism improved the correlation between observed and simulated J3. This supports a recently proposed empirical relationship for new particle formation that has been used in global models. However, the best match between theory and measurements for the site of interest was found for an activation process based on large organic peroxy radicals and stabilised Criegee intermediates (sCI). This novel laboratory-derived algorithm simulated the daily pattern and intensity of J3 observed in the ambient data. In this algorithm organic derived radicals are involved in activation and growth and link the formation rate of smallest aerosol particles with OH during daytime and NO3 during night-time. Because the RO2 lifetime is controlled by HO2 and NO we conclude that peroxy radicals and NO seem to play an important role for ambient radical chemistry not only with respect to oxidation capacity but also for the activation process of new particle formation. This is supposed to have significant impact of atmospheric radical species on aerosol chemistry and should be taken into account when studying the impact of new particles in climate feedback cycles.
We present the application of Time-of-Flight Mass Spectrometry (TOF MS) for the analysis of halocarbons in the atmosphere, after cryogenic sample preconcentration and gas chromatographic separation. For the described field of application, the Quadrupole Mass Spectrometer (QP MS) is the state-of-the-art detector. This work aims at comparing two commercially available instruments, a QP MS and a TOF MS with respect to mass resolution, mass accuracy, sensitivity, measurement precision and detector linearity. Both mass spectrometers are operated on the same gas chromatographic system by splitting the column effluent to both detectors. The QP MS had to be operated in optimised Single Ion Monitoring (SIM) mode to achieve a sensitivity which could compete with the TOF MS. The TOF MS provided full mass range information in any acquired mass spectrum without losing sensitivity. Whilst the QP MS showed the performance already achieved in earlier tests, the sensitivity of the TOF MS was on average higher than that of the QP MS in the "operational" SIM mode by a factor of up to 3 reaching detection limits of less than 0.2 pg. Measurement precision determined for the whole analytical system was up to 0.2% depending on substance and sampled volume. The TOF MS instrument used for this study displayed significant non-linearities of up to 10% for two third of all analysed substances.
Ongoing and predicted global change makes understanding and predicting species’ range shifts an urgent scientific priority. Here, we provide a synthetic perspective on the so far poorly understood effects of interspecific interactions on range expansion rates. We present theoretical foundations for how interspecific interactions may modulate range expansion rates, consider examples from empirical studies of biological invasions and natural range expansions as well as process-based simulations, and discuss how interspecific interactions can be more broadly represented in process-based, spatiotemporally explicit range forecasts. Theory tells us that interspecific interactions affect expansion rates via alteration of local population growth rates and spatial displacement rates, but also via effects on other demographic parameters. The best empirical evidence for interspecific effects on expansion rates comes from studies of biological invasions. Notably, invasion studies indicate that competitive dominance and release from specialized enemies can enhance expansion rates. Studies of natural range expansions especially point to the potential for competition from resident species to reduce expansion rates. Overall, it is clear that interspecific interactions may have important consequences for range dynamics, but also that their effects have received too little attention to robustly generalize on their importance. We then discuss how interspecific interactions effects can be more widely incorporated in dynamic modeling of range expansions. Importantly, models must describe spatiotemporal variation in both local population dynamics and dispersal. Finally, we derive the following guidelines for when it is particularly important to explicitly represent interspecific interactions in dynamic range expansion forecasts: if most interacting species show correlated spatial or temporal trends in their effects on the target species, if the number of interacting species is low, and if the abundance of one or more strongly interacting species is not closely linked to the abundance of the target species.
Channelrhodopsin-2 (ChR2) is a cation-selective light-gated channel from Chlamydomonas reinhardtii (Nagel G, Szellas T, Huhn W, Kateriya S, Adeishvili N, Berthold P, et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci USA 2003;100:13940-5), which has become a powerful tool in optogenetics. Two-dimensional crystals of the slow photocycling C128T ChR2 mutant were exposed to 473 nm light and rapidly frozen to trap the open state. Projection difference maps at 6Å resolution show the location, extent and direction of light-induced conformational changes in ChR2 during the transition from the closed state to the ion-conducting open state. Difference peaks indicate that transmembrane helices (TMHs) TMH2, TMH6 and TMH7 reorient or rearrange during the photocycle. No major differences were found near TMH3 and TMH4 at the dimer interface. While conformational changes in TMH6 and TMH7 are known from other microbial-type rhodopsins, our results indicate that TMH2 has a key role in light-induced channel opening and closing in ChR2.
Translation fidelity and efficiency require multiple ribosomal (r)RNA modifications that are mostly mediated by small nucleolar (sno)RNPs during ribosome production. Overlapping basepairing of snoRNAs with pre-rRNAs often necessitates sequential and efficient association and dissociation of the snoRNPs, however, how such hierarchy is established has remained unknown so far. Here, we identify several late-acting snoRNAs that bind pre-40S particles in human cells and show that their association and function in pre-40S complexes is regulated by the RNA helicase DDX21. We map DDX21 crosslinking sites on pre-rRNAs and show their overlap with the basepairing sites of the affected snoRNAs. While DDX21 activity is required for recruitment of the late-acting snoRNAs SNORD56 and SNORD68, earlier snoRNAs are not affected by DDX21 depletion. Together, these observations provide an understanding of the timing and ordered hierarchy of snoRNP action in pre-40S maturation and reveal a novel mode of regulation of snoRNP function by an RNA helicase in human cells.
Global warming, changes in the hydrological cycle and enhanced marine primary productivity all have been invoked to have contributed to the occurrence of widespread ocean anoxia during the Cenomanian-Turonian Oceanic Anoxic Event (OAE2; ~ 94 Ma), but disentangling these factors on a regional scale has remained problematic. We generated palynological and organic geochemical records that allow the separation of these forcing factors in a core spanning the OAE2 from Wunstorf, Lower Saxony Basin (LSB; North Gemany), which exhibits cyclic black shale–marl alternations related to the orbital precession cycle.
Despite the widely varying depositional conditions complicating the interpretation of the obtained records, TEX86H indicates that sea-surface temperature (SST) evolution in the LSB during OAE2 resembles that of previously studied sites throughout the proto-North Atlantic. Cooling during the so-called Plenus Cold Event interrupted black shale deposition during the early stages of OAE2. However, TEX86 does not vary significantly across marl–black shale alternations, suggesting that temperature variations did not force the formation of the cyclic black shale horizons. Relative (i.e., with respect to marine palynomorphs) and absolute abundances of pollen and spores are elevated during phases of black shale deposition, indicative of enhanced precipitation and run-off. High abundances of cysts from inferred heterotrophic and euryhaline dinoflagellates supports high run-off, which likely introduced additional nutrients to the epicontinental shelf resulting in elevated marine primary productivity.
We conclude that orbitally-forced enhanced precipitation and run-off, in tandem with elevated marine primary productivity, were critical in cyclic black shale formation on the northwest European epicontinental shelf and potentially for other OAE2 sections in the proto-Atlantic and Western Interior Seaway at similar latitudes as well.
One of the most challenging aspects of RT-qPCR data analysis is the identification of reliable reference genes. Ideally, they should be neither induced nor repressed under different experimental conditions. To date, few reference genes have been adequately studied for sugarcane (Saccharum spp.) using statistical approaches. In this work, six candidate genes (αTUB, GAPDH, H1, SAMDC, UBQ, and 25S rRNA) were tested for gene expression normalization of sugarcane root tissues from drought-tolerant and -sensitive accessions after continuous dehydration (24 h). By undergoing different approaches (GeNorm, NormFinder, and BestKeeper), it was shown that most of them could be used in combinations for normalization purposes, with the exception of SAMDC. Nevertheless three of them (H1, αTUB, and GAPDH) were considered the most reliable reference genes. Their suitability as reference genes validated the expression profiles of two targets (AS and PFPα1), related to SuperSAGE unitags, in agreement with results revealed by previous in silico analysis. The other two sugarcane unitags (ACC oxidase and PIP1-1), after salt stress (100 mM NaCl), presented their expressions validated in the same way. In conclusion, these reference genes will be useful for dissecting gene expression in sugarcane roots under abiotic stress, especially in transcriptomic studies using SuperSAGE or RNAseq approaches.
Atherosclerosis is a chronic inflammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. IL-17A is a proinflammatory cytokine, which modulates immune cell trafficking and is involved inflammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study, we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. The 26-wk-old apolipoprotein E–deficient mice were fed a standard chow diet and treated either with IL-17A mAb (n = 15) or irrelevant Ig (n = 10) for 16 wk. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progression (p = 0.001) by reducing inflammatory burden and cellular infiltration (p = 0.01) and improved lesion stability (p = 0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, and sensitization of APCs toward pathogen-derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a proinflammatory milieu and upregulation of molecules expressed by the IL-17A–induced macrophage subtype. In this study, we show that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces plaque stabilization in advanced lesions in apolipoprotein E–deficient mice. The underlying mechanisms involve reduced inflammation and distinct effects of IL-17A on monocyte/macrophage lineage. In addition, translational experiments underline the relevance for the human system.
Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds.
Ursine bears are a mammalian subfamily that comprises six morphologically and ecologically distinct extant species. Previous phylogenetic analyses of concatenated nuclear genes could not resolve all relationships among bears, and appeared to conflict with the mitochondrial phylogeny. Evolutionary processes such as incomplete lineage sorting and introgression can cause gene tree discordance and complicate phylogenetic inferences, but are not accounted for in phylogenetic analyses of concatenated data. We generated a high-resolution data set of autosomal introns from several individuals per species and of Y-chromosomal markers. Incorporating intraspecific variability in coalescence-based phylogenetic and gene flow estimation approaches, we traced the genealogical history of individual alleles. Considerable heterogeneity among nuclear loci and discordance between nuclear and mitochondrial phylogenies were found. A species tree with divergence time estimates indicated that ursine bears diversified within less than 2 My. Consistent with a complex branching order within a clade of Asian bear species, we identified unidirectional gene flow from Asian black into sloth bears. Moreover, gene flow detected from brown into American black bears can explain the conflicting placement of the American black bear in mitochondrial and nuclear phylogenies. These results highlight that both incomplete lineage sorting and introgression are prominent evolutionary forces even on time scales up to several million years. Complex evolutionary patterns are not adequately captured by strictly bifurcating models, and can only be fully understood when analyzing multiple independently inherited loci in a coalescence framework. Phylogenetic incongruence among gene trees hence needs to be recognized as a biologically meaningful signal.
Donald Siegel's 1971 film entitled "The Beguiled" is compared to Tale 1 of Day 3 from Giovanni Boccaccio’s "The Decameron". Both stories are about a man who arrives in a garden setting and finds nine sexually starved women. In Boccaccio's tale, a male gardener finds himself in a convent occupied by nine nuns with whom he proceeds to have sexual relations to everyone's satisfaction. Siegel's film is about a wounded soldier taken in at a girls' finishing school whose nine female residents become the objects of the hero's amorous attention. While Boccaccio adopts a philogynist tone with respect to the material, "The Beguiled" appears to be a virulently misogynist film projecting its female characters as jealous demons who end up mutilating and then killing their male suitor. Findings from evolutionary psychology pertaining to female jealousy and reproductive strategies are used to consider the respective attitudes toward women in the medieval tale and the twentieth-century film. Conclusions are drawn about the difficulty of placing either of the stories within a clear-cut philogynist or misogynist category.
In the article the state of forming of communicative competence of future lawyers in higher education of Ukraine and Germany is analyzed. There is made the comparative description of preparation of the students of law faculty with an accent on forming of communicative competence on the example of the University of modern knowledge (Ukraine) and Frankfort university is named after Goethe (Germany).
It is drawn the conclusion, that the structure of professional preparation of future lawyers is folded educational and cognitive, research constituents, and also productive practice. A main place is taken to conception of communicative preparation of the future lawyers, the essence of it consists in integration of the special courses of the special and professional disciplines, in continuous perfection of skills of the verbal and writing broadcasting, receptions of analytical mental work, that need knowledge. It is also outlined the aim of productive practice of future lawyers in Ukraine that begins from the second course: the forming of professional abilities and skills of acceptance of independent decisions; the education of necessity systematic to proceed the knowledge, to promote a legal culture and professional legal consciousness; to teach to apply knowledge in practical activity. In Germany the practice for future lawyers begins from the first course and lasts two years in legal establishments (from civil cases, court from criminal cases or office of public prosecutor, administrative and managerial establishments, advocacy). The sign line of studies is an active collaboration with the faculties of law of the foreign states. All these factors assist the forming of communicative competence of lawyers.
We show that, under in vitro conditions, the vulnerability of astroglia to hypoxia is reflected by alterations in endothelin (ET)-1 release and capacity of erythropoietin (EPO) to regulate ET-1 levels. Exposure of cells to 24 h hypoxia did not induce changes in ET-1 release, while 48–72 h hypoxia resulted in increase of ET-1 release from astrocytes that could be abolished by EPO. The endothelin receptor type A (ETA) antagonist BQ123 increased extracellular levels of ET-1 in human fetal astroglial cell line (SV-FHAS). The survival and proliferation of rat primary astrocytes, neural precursors, and neurons upon hypoxic conditions were increased upon administration of BQ123. Hypoxic injury and aging affected the interaction between the EPO and ET systems. Under hypoxia EPO decreased ET-1 release from astrocytes, while ETA receptor blockade enhanced the expression of EPO mRNA and EPO receptor in culture-aged rat astroglia. The blockade of ETA receptor can increase the availability of ET-1 to the ETB receptor and can potentiate the neuroprotective effects of EPO. Thus, the new therapeutic use of combined administration of EPO and ETA receptor antagonists during hypoxia-associated neurodegenerative disorders of the central nervous system (CNS) can be suggested.
We enlarge the so-called extended linear Sigma model (eLSM) by including the charm quark according to the global U(4)r × U(4)l chiral symmetry. In the eLSM, besides scalar and pseudoscalar mesons, also vector and axial-vector mesons are present. Almost all the parameters of the model were fixed in a previous study of mesons below 2 GeV. In the extension to the four-flavor case, only three additional parameters (all of them related to the bare mass of the charm quark) appear.We compute the (OZI dominant) strong decays of open charmed mesons. The results are compatible with the experimental data, although the theoretical uncertainties are still large.
The Sahel has been the focus of scientific interest in environmental-human dynamics and interactions. The objective of the present study is to contribute to the recent debate on the re-greening of Sahel. The paper examines the dynamics of barren land in the Sahel of Burkina Faso through analysis of remotely-sensed and rainfall data from 1975–2011. Discussions with farmers and land management staff have helped to understand the anthropogenic efforts toward soil restoration to enable the subsistence farming agriculture. Results showed that area of barren land has been fluctuating during the study period with approximately 10-year cyclicity. Similarly, rainfall, both at national and local levels has followed the same trends. The trends of the area of barren land and rainfall variability suggest that when rainfall increases, the area of barren land decreases and barren land increases when rainfall decreases. This implies that rainfall is one of the main factors driving the change in area of barren land. In addition, humans have contributed positively and negatively to the change by restoring barren lands for agriculture using locally known techniques and by accelerating land degradation through intensive and inappropriate land use practices.
In the framework of an interference setup in which only two outcomes are possible (such as in the case of a Mach–Zehnder interferometer), we discuss in a simple and pedagogical way the difference between a standard, unitary quantum mechanical evolution and the existence of a real collapse of the wavefunction. This is a central and not-yet resolved question of quantum mechanics and indeed of quantum field theory as well. Moreover, we also present the Elitzur–Vaidman bomb, the delayed choice experiment, and the effect of decoherence. In the end, we propose two simple experiments to visualize decoherence and to test the role of an entangled particle.
The ground beetle genus Cymindis is the most species rich amongst genera in the carabid subtribe Cymindidina (tribe Lebiini). Four subgenera are often recognized, i.e. Cymindis (sensu stricto) Latreille, Afrotarus Jeannel, Taridius Chaudoir and Pinacodera Schaum. Cymindis (sensu stricto) has a predominately Holarctic distribution (Hunting 2013) and includes Cymindis alutacea Wollaston, C. dohrnii Wollaston and C. anchomenoides Wollaston (the last one sometimes placed in Tarulus Bedel, either ranked as a genus or a subgenus), all three endemic to the Cape Verde Islands (Geisthardt 1988, 1996).
The abundance of humpback whales occurring around Boa Vista, Cape Verde Islands, was estimated by markrecapture modelling. Photographs of markings on tail flukes of individual whales were collected during the breeding season. Sighting histories were constructed for each individual and an abundance of 171 animals was estimated using a Jolly-Seber mark-recapture model. Correcting for known biases arising due to sex-specific behaviour and temporary emigration insofar as possible, an estimate of 260 whales was obtained. This is significantly higher than the previous estimate of 99 humpback whales from this region. Due to limited survey effort it is not known how representative the study area is of the entire Cape Verde archipelago and this estimate may be considered to be biased low and serves as a minimum estimate. The high recapture probability (0.37) coupled with the low abundance is consistent with a small local population. The low survival rate (0.86) suggests possible emigration and further studies are needed to assess connectivity between humpback whales breeding in Cape Verde and other breeding locations. The amount of exchange between groups of whales breeding in Cape Verde and adjacent areas remains unknown. It is unclear whether the abundance estimate herein applies to part of an isolated population or part of a larger and continuous one.
Black-winged stilt Himantopus himantopus (Linnaeus, 1758) has a wide geographical distribution, including France and southern Iberia to sub-Saharan Africa and Madagascar, and east to central Asia and northern central China, India, Sri Lanka, Indochina and Taiwan (Pierce 1996). On the African mainland, breeding sites nearest to the Cape Verde Islands are in Mauritania and Senegal (Isenmann et al. 2010, Borrow & Demey 2014).
Recent data on status and distribution of resident and migrant birds in the Cape Verde Islands are presented, including records of nine taxa new to the archipelago, viz. Ciconia nigra, Ciconia ciconia, Circus macrourus, Falco naumanni, Chlidonias hybrida, Chlidonias leucopterus, Apus affinis, Ptyonoprogne fuligula and Phylloscopus inornatus. Also presented are data on a number of breeding taxa, including the first record of the endemic Cape Verde purple heron Ardea bournei outside Santiago island. The alarming situation of the magnificent frigatebird Fregata magnificens, of which only three individuals remain in Cape Verde, constituting the entire population in the East Atlantic, remains of great concern. Several species of birds of prey are also highly threatened and have already become extinct in some islands. Following its expansion through Northwest Africa and the Canary Islands, Eurasian collared dove Streptopelia decaocto has now also become established in at least three of the Cape Verde Islands.
The zoogeographic composition of the coastal ichthyofauna of the Cape Verde archipelago shows a predominance of Guinean species, followed by tropical-subtropical (amphi-Atlantic) fishes and several endemic species. Recent taxonomic revisions, new species descriptions, new fish records in the area and recent ecological surveys of intra-specific fish interaction as well as emergent research on seamounts in national waters warrant an up-to-date review of research on the ichthyofauna of Cape Verde. An updated percentage of endemic coastal reef fish of 10.2% attest significant speciation in Cape Verde waters. Almost half of the total cryptobenthic fish species richness in Cape Verde comprises endemic species, some of them newly discovered. Examples of endemism are discussed, notably white seabream Diplodus sargus lineatus, bulldog dentex Dentex (Virididentex) acromegalus, blackfish drummer Girella stuebeli, Lubbock's chromis Chromis lubbocki, Cape Verde damselfish Similiparma hermani and Guinean parrotfish Scarus hoefleri. Cape Verde diverges considerably from the other Macaronesian island groups in terms of its ichthyofauna and its uniqueness warrants special attention by governmental agencies and conservation organizations.
During an entomological survey in Santiago Island, Cape Verde Islands, in November-December 2011 in order to study the bio-ecology and susceptibility to insecticides of Anopheles arabiensis Patton, 1905, Culex tritaeniorhynchus Giles, 1901 was found to be present in the Santa Cruz District. Both adult and immature specimens were collected and a description of both is given. Further confirmation of the taxonomic identity of the specimens was obtained from studying the male genitalia. This is the first known occurrence of Culex tritaeniorhynchus (a primary vector of Japanese encephalitis in eastern and southern Asia and a potential vector of West Nile Virus, Sindbis and Rift Valley Fever Virus) in the Cape Verde Islands.
Background: In primary care, patients with multiple chronic conditions are the rule rather than the exception. The Chronic Care Model (CCM) is an evidence-based framework for improving chronic illness care, but little is known about the extent to which it has been implemented in routine primary care. The aim of this study was to describe how multimorbid older patients assess the routine chronic care they receive in primary care practices in Germany, and to explore the extent to which factors at both the practice and patient level determine their views.
Methods: This cross-sectional study used baseline data from an observational cohort study involving 158 general practitioners (GP) and 3189 multimorbid patients. Standardized questionnaires were employed to collect data, and the Patient Assessment of Chronic Illness Care (PACIC) questionnaire used to assess the quality of care received. Multilevel hierarchical modeling was used to identify any existing association between the dependent variable, PACIC, and independent variables at the patient level (socio-economic factors, weighted count of chronic conditions, instrumental activities of daily living, health-related quality of life, graded chronic pain, no. of contacts with GP, existence of a disease management program (DMP) disease, self-efficacy, and social support) and the practice level (age and sex of GP, years in current practice, size and type of practice).
Results: The overall mean PACIC score was 2.4 (SD 0.8), with the mean subscale scores ranging from 2.0 (SD 1.0, subscale goal setting/tailoring) to 3.5 (SD 0.7, delivery system design). At the patient level, higher PACIC scores were associated with a DMP disease, more frequent GP contacts, higher social support, and higher autonomy of past occupation. At the practice level, solo practices were associated with higher PACIC values than other types of practice.
Conclusions: This study shows that from the perspective of multimorbid patients receiving care in German primary care practices, the implementation of structured care and counseling could be improved, particularly by helping patients set specific goals, coordinating care, and arranging follow-up contacts. Studies evaluating chronic care should take into consideration that a patient’s assessment is associated not only with practice-level factors, but also with individual, patient-level factors.
The exact pathophysiology of contrast-induced nephropathy (CIN) is not fully clarified, yet the osmotic characteristics of contrast media (CM) have been a significant focus in many investigations of CIN. Osmotic effects of CM specific to the kidney include transient decreases in blood flow, filtration fraction, and glomerular filtration rate. Potentially significant secondary effects include an osmotically induced diuresis with a concomitant dehydrating effect. Clinical experiences that have compared the occurrence of CIN between the various classes of CM based on osmolality have suggested a much less than anticipated advantage, if any, with a lower osmolality. Recent animal experiments actually suggest that induction of a mild osmotic diuresis in association with iso-osmolar agents tends to offset potentially deleterious renal effects of high viscosity-mediated intratubular CM stagnation.
Carinostoma elegans new to the Slovakian harvestmen fauna (Opiliones, Dyspnoi, Nemastomatidae)
(2014)
A new genus and species of small harvestman was found for the first time in Slovakia – Carinostoma elegans (Sorensen, 1894). One male and two females were collected in the Mlyňany arboretum of the Slovak Academy of Science (western Slovakia). Descriptions and photographs of both sexes of C. elegans are provided. Additional comments, and a map of distribution of all species of this genus, are provided.
Sauron rayi (Simon, 1881) is recorded in Austria for the first time. Male and female specimens of this rare European spider were found in two “Austrian pine forests” in Lower Austria. Data on distribution, habitat, phenology and Red List status from the Austrian localities and from published records in other countries are presented.
Examination of the type material of the forgotten species Liocranum ochraceum Simon, 1867 reveals this species has to be transferred to the genus Anagraphis comb. nov. and that Anagraphis pallida (Hadjissarantos, 1940) is its junior synonym (syn. nov.). Furthermore, the monotypic genus Macedoniella Drensky, 1935 is a junior synonym of Anagraphis and M. karamani a junior synonym of Anagraphis ochraceum (L. Koch, 1867) (syn. nov.).
A survey of spiders of the genus Scytodes Latreille, 1804 in Iran resulted in six species occurring in this country: Scytodes fusca Walckenaer, 1837, S. strandi Spassky, 1941, S. thoracica (Latreille, 1802), S. univittata Simon, 1882 and – recorded for the first time – S. arwa Rheims, Brescovit & van Harten, 2006 and S. makeda Rheims, Brescovit & van Harten, 2006. Illustrations of the newly recorded species and a key to all known Iranian species are presented.
Carniella brignolii Thaler & Steinberger, 1988 was first described based on a male from Austria and still belongs to the rare, scarcely studied species. Based on material from Germany and Switzerland the hitherto unknown female now can be assigned and presented. In this context a new synonymy is also proposed: The cave-dwelling, troglomorphic C. mihaili (Georgescu, 1989) from Romania, originally established as new genus Marianana, is synonymised with C. brignolii.
The spitting spider Scytodes fusca Walckenaer, 1837 is recorded for the first time in Central Europe from both Germany and Slovakia. The species was found in two localities, within the Botanical Garden in Bratislava (Slovakia), specifically from a heated greenhouse with high humidity, and the "Tropical Islands", a tropical holiday resort in Krausnick (Germany). It seems that this Pantropical species has probably been introduced here along with imported plants. A description of diagnostic characters, as well as figures, is given.
An annotated catalogue of the rare mesothele spiders (Araneae: Mesothelae: Liphistiidae) held in the Museum für Naturkunde Berlin is presented. The museum hosts non-type specimens of nine species representing all three currently recognised genera, namely: Liphistius desultor Schiödte, 1849, L. malayanus cameroni Haupt, 1983, L. cf. thaleban Schwendinger, 1990, Heptathela kikuyai Ono, 1998, H. kimurai (Kishida, 1920), H. yanbaruensis Haupt, 1983, Ryuthela ishigakiensis Haupt, 1983, R. nishihirai (Haupt, 1979) and R. tanikawai Ono, 1997 (spec. reval.). The geographical focus of this collection is Malaysia and Japan, and most of the material was collected by the Berlin-based zoologist Joachim Haupt.
Silometopus ambiguus (O. Pickard-Cambridge, 1905) is a species occurring in coastal habitats from northeastern to western Europe. S. curtus (Simon, 1881), occurring in southern France and north-eastern Spain, was for a long time mixed up with S. ambiguus, even though corrections have been published very early and several times. This contribution summarizes publications on this topic, discusses doubtful records of both species and proposes corrections for the World Spider Catalog; and thus tries to avoid repetitions of the mistake in the future.
The African species Cheiracanthium furculatum Karsch, 1879 was recognised as being introduced to Germany and is re-described and illustrated in the present study. C. tenuipes Roewer, 1961 is recognised as a junior synonym of C. africanum Lessert, 1921 (new synonymy); both subspecies of C. strasseni Strand, 1915, namely C. strasseni strasseni Strand, 1915 and C. strasseni aharonii Strand, 1915, are recognised as junior synonyms of C. mildei L. Koch, 1864 (new synonymies). Photographic images of the copulatory organs of the types of C. cretense Roewer, 1928, recently synonymised with C. mildei, are provided and discussed in the course of intraspecific variation in C. mildei. The female holotype of C. rehobothense Strand, 1915 is re-described and illustrated. Relations of C. rehobothense to other Cheiracanthium species are discussed.
Desertification is a major problem in Sudano-sahelian West Africa, including the loss of biodiversity and vegetation cover. The loss of related ecosystem services is having a severe impact on human wellbeing. To facilitate assessments of these aspects of desertification, we decided to find plant species suitable as indicators. Based on a large database of vegetation plot data for Burkina Faso, we identified species associated with high or low levels of species richness and vegetation cover by calculating average values of these measures from vegetation plots on which they occur. To account for the differences between the dry Sahel and the more humid Sudan, we separated the plots of our study area in three vegetation zones (Sahel, North Sudan, South Sudan). Furthermore, herbs and woody plants were analysed separately, as they were usually represented in different plot sizes in the primary data. For each combination of species richness or vegetation cover, vegetation zone and growth form we identified ten species indicating low and another ten species indicating high values and assigned indicator values based on the average values of these species in the relevés.
Knowledge about useful plants and their various applications in West Africa is scattered over many publications and often in form of grey literature difficult to access. Several online-databases compile large scale information from these sources and provide comprehensive summarized descriptions of plant usages. Our aim is to additionally build up a database (UseDa) for primary ethnobotanical interview data. Thus, quantitative data can be extracted and synthesized and data sets can be treated according to different research questions analyzing for example uses in specific areas, of different ethnic groups or user groups, which is essential for practical applications on a local level. In this article we give an overview on the technical structure and the content of the database and discuss at the end the possible output for practical application. The database was set up in the frame of the EU-funded Project UNDESERT.
Dynamics of juvenile woody plant communities on termite mounds in a West African savanna landscape
(2014)
Termites are keystone species in savanna ecology, and their mounds are thought to be an important source of habitat heterogeneity and structural complexity of the savanna. Macrotermes termitaria have been shown to allow woody plant colonisation of landscapes otherwise dominated by C4 grasses. In this study, we assess how resource-rich Macrotermes mounds affect juvenile woody plant and non-woody plant species diversity, community composition, biomass and population dynamics. We repeatedly sampled paired termite mound and savanna plots in Pendjari National Park (Sudanian vegetation zone, North Benin, West Africa) over the course of two years. Despite considerable overlap in their species pools, plant communities of mound and savanna plots were clearly separated in ordinations. Species richness and diversity of juvenile woody plants was consistently higher on termite mounds, while no differences could be detected for non-woody plants. Evenness of juvenile woody plants was generally lower on mounds, whereas density and basal area were higher on mounds. In contrast, we did not detect any influence of the mound microhabitat on colonisation, mortality and turnover of woody juveniles. Therefore, we suggest that differences in the communities on and off mounds should be strongly influenced by directed diaspore dispersal through zoochory.
Background: Although childhood sexual and/or physical abuse (CSA/CPA) is known to have severe psychopathological consequences, there is little evidence on psychotherapeutic interventions for adolescents and young adults suffering from post-traumatic stress disorder (PTSD). Equally sparse are data on moderators of treatment response on PTSD-related epigenetic changes, health care costs and loss of productivity, alterations in cognitive processing, and on how successful interventions affect all of these factors. Early treatment may prevent later (co)morbidity. In this paper, we present a study protocol for the evaluation of a newly developed psychotherapeutic manual for PTSD after CSA/CPA in adolescents and young adults – the Developmentally Adapted Cognitive Processing Therapy (D-CPT).
Methods/design: In a multicenter randomized controlled trial (RCT) D-CPT is compared to treatment as usual (TAU). A sample of 90 adolescent outpatients aged 14 to 21 years will be randomized to one of these conditions. Four assessments will be carried out at baseline, at end of treatment, and 3 and 6 months after end of therapy. Each time, patients will be assessed via clinical interviews and a wide range of questionnaires. In addition to PTSD symptoms and comorbidities, we will evaluate moderators of treatment response, epigenetic profiles, direct and indirect costs of this disorder, and neurophysiological processing of threat cues in PTSD and their respective changes in the course of these two treatments (D-CPT and TAU).
Discussion: The study will provide new insights in the understudied field of PTSD in adolescents and young adults. A newly developed intervention will be evaluated in this therapeutically underserved population. Results will provide data on treatment efficacy, direct and indirect treatment costs, as well as on associations of treatment outcome and PTSD intensity both to epigenetic profiles and to the neurobiological processing of threat cues. Besides, they will help to learn more about the psychopathology and possible new objective correlates of PTSD.
Trial registration: Germanctr.de identifier: DRKS00004787.
Dendritic cells (DCs) are the cutting edge in innate and adaptive immunity. The major functions of these antigen-presenting cells are the capture, endosomal processing and presentation of antigens, providing them an exclusive ability to provoke adaptive immune responses and to induce and control tolerance. Immature DCs capture and process antigens, migrate towards secondary lymphoid organs where they present antigens to naive T cells in a well-synchronized sequence of procedures referred to as maturation. Indeed, recent research indicated that sphingolipids are modulators of essential steps in DC homeostasis. It has been recognized that sphingolipids not only modulate the development of DC subtypes from precursor cells but also influence functional activities of DCs such as antigen capture, and cytokine profiling. Thus, it is not astonishing that sphingolipids and sphingolipid metabolism play a substantial role in inflammatory diseases that are modulated by DCs. Here we highlight the function of sphingosine 1-phosphate (S1P) on DC homeostasis and the role of S1P and S1P metabolism in inflammatory diseases.
Myocardial infarction (MI) induces a complex inflammatory immune response, followed by the remodelling of the heart muscle and scar formation. The rapid regeneration of the blood vessel network system by the attraction of hematopoietic stem cells is beneficial for heart function. Despite the important role of chemokines in these processes, their use in clinical practice has so far been limited by their limited availability over a long time-span in vivo. Here, a method is presented to increase physiological availability of chemokines at the site of injury over a defined time-span and simultaneously control their release using biodegradable hydrogels. Two different biodegradable hydrogels were implemented, a fast degradable hydrogel (FDH) for delivering Met-CCL5 over 24 hrs and a slow degradable hydrogel (SDH) for a gradual release of protease-resistant CXCL12 (S4V) over 4 weeks. We demonstrate that the time-controlled release using Met-CCL5-FDH and CXCL12 (S4V)-SDH suppressed initial neutrophil infiltration, promoted neovascularization and reduced apoptosis in the infarcted myocardium. Thus, we were able to significantly preserve the cardiac function after MI. This study demonstrates that time-controlled, biopolymer-mediated delivery of chemokines represents a novel and feasible strategy to support the endogenous reparatory mechanisms after MI and may compliment cell-based therapies.
Focus on quantum efficiency
(2014)
Technologies which convert light into energy, and vice versa, rely on complex, microscopic transport processes in the condensed phase, which obey the laws of quantum mechanics, but hitherto lack systematic analysis and modeling. Given our much improved understanding of multicomponent, disordered, highly structured, open quantum systems, this ‘focus on’ collection collects cuttingedge research on theoretical and experimental aspects of quantum transport in truly complex systems as defined, e.g., by the macromolecular functional complexes at the heart of photosynthesis, by organic quantum wires, or even photovoltaic devices. To what extent microscopic quantum coherence effects can (be made to) impact on macroscopic transport behavior is an equally challenging and controversial question, and this "focus on" collection provides a setting for the present state of affairs, as well as for the "quantum opportunities" on the horizon.
This paper deals with the control exerted by the mitochondrial translocator FLX1, which catalyzes the movement of the redox cofactor FAD across the mitochondrial membrane, on the efficiency of ATP production, ROS homeostasis, and lifespan of S. cerevisiae. The deletion of the FLX1 gene resulted in respiration-deficient and small-colony phenotype accompanied by a significant ATP shortage and ROS unbalance in glycerol-grown cells. Moreover, the flx1Δ strain showed H2O2 hypersensitivity and decreased lifespan. The impaired biochemical phenotype found in the flx1Δ strain might be justified by an altered expression of the flavoprotein subunit of succinate dehydrogenase, a key enzyme in bioenergetics and cell regulation. A search for possible cis-acting consensus motifs in the regulatory region upstream SDH1-ORF revealed a dozen of upstream motifs that might respond to induced metabolic changes by altering the expression of Flx1p. Among these motifs, two are present in the regulatory region of genes encoding proteins involved in flavin homeostasis. This is the first evidence that the mitochondrial flavin cofactor status is involved in controlling the lifespan of yeasts, maybe by changing the cellular succinate level. This is not the only case in which the homeostasis of redox cofactors underlies complex phenotypical behaviours, as lifespan in yeasts.
Background: The phagocytic enzyme myeloperoxidase (MPO) acts as a front-line defender against microorganisms. However, increased MPO levels have been found to be associated with complex and calcified atherosclerotic lesions and incident cardiovascular disease. Therefore, this study aimed to investigate a predictive role of MPO, a biomarker of inflammation and oxidative stress, for total and cardiovascular mortality in patients referred to coronary angiography.
Methods and results: MPO plasma concentrations along with eight MPO polymorphisms were determined in 3036 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up 7.75 years). MPO concentrations were positively associated with age, diabetes, smoking, markers of systemic inflammation (interleukin-6, fibrinogen, C-reactive protein, serum amyloid A) and vascular damage (vascular cellular adhesion molecule-1 and intercellular adhesion molecule-1) but negatively associated with HDL-cholesterol and apolipoprotein A-I. After adjustment for cardiovascular risk factors MPO concentrations in the highest versus the lowest quartile were associated with a 1.34-fold risk (95% CI: 1.09–1.67) for total mortality. In the adjusted model the hazard ratio for cardiovascular mortality in the highest MPO quartile was 1.42 (95% CI: 1.07–1.88). Five MPO polymorphisms were positively associated with MPO concentrations but not with mortality. Using Mendelian randomization, we did not obtain evidence for a causal association of MPO with either total or cardiovascular mortality.
Conclusions: MPO concentrations but not genetic variants at the MPO locus are independently associated with risk for total and cardiovascular mortality in coronary artery disease patients.
Here we present a formal description of Biremis panamae Barka, Witkowski et Weisenborn sp. nov., which was isolated from the marine littoral environment of the Pacific Ocean coast of Panama. The description is based on morphology (light and electron microscopy) and the rbcL, psbC and SSU sequences of one clone of this species. The new species is included in Biremis due to its morphological features; i.e. two marginal rows of foramina, chambered striae, and girdle composed of numerous punctate copulae. The new species also possesses a striated valve face which is not seen in most known representatives of marine littoral Biremis species. In this study we also present the relationship of Biremis to other taxa using morphology, DNA sequence data and observations of auxosporulation. Our results based on these three sources point to an evolutionary relationship between Biremis, Neidium and Scoliopleura. The unusual silicified incunabular caps present in them are known otherwise only in Muelleria, which is probably related to the Neidiaceae and Scoliotropidaceae. We also discuss the relationship between Biremis and the recently described Labellicula and Olifantiella.
Glioblastoma multiforme (GBM) is a deadly primary brain malignancy. Glioblastoma stem cells (GSC), which have the ability to self-renew and differentiate into tumor lineages, are believed to cause tumor recurrence due to their resistance to current therapies. A subset of GSCs is marked by cell surface expression of CD133, a glycosylated pentaspan transmembrane protein. The study of CD133-expressing GSCs has been limited by the relative paucity of genetic tools that specifically target them. Here, we present CD133-LV, a lentiviral vector presenting a single chain antibody against CD133 on its envelope, as a vehicle for the selective transduction of CD133-expressing GSCs. We show that CD133-LV selectively transduces CD133+ human GSCs in dose-dependent manner and that transduced cells maintain their stem-like properties. The transduction efficiency of CD133-LV is reduced by an antibody that recognizes the same epitope on CD133 as the viral envelope and by shRNA-mediated knockdown of CD133. Conversely, the rate of transduction by CD133-LV is augmented by overexpression of CD133 in primary human GBM cultures. CD133-LV selectively transduces CD133-expressing cells in intracranial human GBM xenografts in NOD.SCID mice, but spares normal mouse brain tissue, neurons derived from human embryonic stem cells and primary human astrocytes. Our findings indicate that CD133-LV represents a novel tool for the selective genetic manipulation of CD133-expressing GSCs, and can be used to answer important questions about how these cells contribute to tumor biology and therapy resistance.
MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy
(2014)
Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1) were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.
Sleep is regulated in a time-of-day dependent manner and profits working memory. However, the impact of the circadian timing system as well as contributions of specific sleep properties to this beneficial effect remains largely unexplored. Moreover, it is unclear to which extent inter-individual differences in sleep-wake regulation depend on circadian phase and modulate the association between sleep and working memory. Here, sleep electroencephalography (EEG) was recorded during a 40-h multiple nap protocol, and working memory performance was assessed by the n-back task 10 times before and after each scheduled nap sleep episode. Twenty-four participants were genotyped regarding a functional polymorphism in adenosine deaminase (rs73598374, 12 G/A-, 12 G/G-allele carriers), previously associated with differences in sleep-wake regulation. Our results indicate that genotype-driven differences in sleep depend on circadian phase: heterozygous participants were awake longer and slept less at the end of the biological day, while they exhibited longer non rapid eye movement (NREM) sleep and slow wave sleep concomitant with reduced power between 8–16 Hz at the end of the biological night. Slow wave sleep and NREM sleep delta EEG activity covaried positively with overall working memory performance, independent of circadian phase and genotype. Moreover, REM sleep duration benefitted working memory particularly when occurring in the early morning hours and specifically in heterozygous individuals. Even though based on a small sample size and thus requiring replication, our results suggest genotype-dependent differences in circadian sleep regulation. They further indicate that REM sleep, being under strong circadian control, boosts working memory performance according to genotype in a time-of-day dependent manner. Finally, our data provide first evidence that slow wave sleep and NREM sleep delta activity, majorly regulated by sleep homeostatic mechanisms, is linked to working memory independent of the timing of the sleep episode within the 24-h cycle.
Escherichia coli α-hemolysin (HlyA) is a pore-forming protein of 110 kDa belonging to the family of RTX toxins. A hydrophobic region between the amino acid residues 238 and 410 in the N-terminal half of HlyA has previously been suggested to form hydrophobic and/or amphipathic α-helices and has been shown to be important for hemolytic activity and pore formation in biological and artificial membranes. The structure of the HlyA transmembrane channel is, however, largely unknown. For further investigation of the channel structure, we deleted in HlyA different stretches of amino acids that could form amphipathic β-strands according to secondary structure predictions (residues 71–110, 158–167, 180–203, and 264–286). These deletions resulted in HlyA mutants with strongly reduced hemolytic activity. Lipid bilayer measurements demonstrated that HlyAΔ71–110 and HlyAΔ264–286 formed channels with much smaller single-channel conductance than wildtype HlyA, whereas their channel-forming activity was virtually as high as that of the wildtype toxin. HlyAΔ158–167 and HlyAΔ180–203 were unable to form defined channels in lipid bilayers. Calculations based on the single-channel data indicated that the channels generated by HlyAΔ71–110 and HlyAΔ264–286 had a smaller size (diameter about 1.4 to 1.8 nm) than wildtype HlyA channels (diameter about 2.0 to 2.6 nm), suggesting that in these mutants part of the channel-forming domain was removed. Osmotic protection experiments with erythrocytes confirmed that HlyA, HlyAΔ71–110, and HlyAΔ264–286 form defined transmembrane pores and suggested channel diameters that largely agreed with those estimated from the single-channel data. Taken together, these results suggest that the channel-forming domain of HlyA might contain β-strands, possibly in addition to α-helical structures.
Previously we reported modulation of endothelial prostacyclin and interleukin-8 production, cyclooxygenase-2 expression and vasorelaxation by oleoyl-lysophosphatidylcholine (LPC 18:1). In the present study, we examined the impact of this LPC on nitric oxide (NO) bioavailability in vascular endothelial EA.hy926 cells. Basal NO formation in these cells was decreased by LPC 18:1. This was accompanied with a partial disruption of the active endothelial nitric oxide synthase (eNOS)-dimer, leading to eNOS uncoupling and increased formation of reactive oxygen species (ROS). The LPC 18:1-induced ROS formation was attenuated by the superoxide scavenger Tiron, as well as by the pharmacological inhibitors of eNOS, NADPH oxidases, flavin-containing enzymes and superoxide dismutase (SOD). Intracellular ROS-formation was most prominent in mitochondria, less pronounced in cytosol and undetectable in endoplasmic reticulum. Importantly, Tiron completely prevented the LPC 18:1-induced decrease in NO bioavailability in EA.hy926 cells. The importance of the discovered findings for more in vivo like situations was analyzed by organ bath experiments in mouse aortic rings. LPC 18:1 attenuated the acetylcholine-induced, endothelium dependent vasorelaxation and massively decreased NO bioavailability. We conclude that LPC 18:1 induces eNOS uncoupling and unspecific superoxide production. This results in NO scavenging by ROS, a limited endothelial NO bioavailability and impaired vascular function.
Coevolution of viruses and their hosts represents a dynamic molecular battle between the immune system and viral factors that mediate immune evasion. After the abandonment of smallpox vaccination, cowpox virus infections are an emerging zoonotic health threat, especially for immunocompromised patients. Here we delineate the mechanistic basis of how cowpox viral CPXV012 interferes with MHC class I antigen processing. This type II membrane protein inhibits the coreTAP complex at the step after peptide binding and peptide-induced conformational change, in blocking ATP binding and hydrolysis. Distinct from other immune evasion mechanisms, TAP inhibition is mediated by a short ER-lumenal fragment of CPXV012, which results from a frameshift in the cowpox virus genome. Tethered to the ER membrane, this fragment mimics a high ER-lumenal peptide concentration, thus provoking a trans-inhibition of antigen translocation as supply for MHC I loading. These findings illuminate the evolution of viral immune modulators and the basis of a fine-balanced regulation of antigen processing.
Myotonic dystrophy type 1 (DM1) lacks non-invasive and easy to measure biomarkers, still largely relying on semi-quantitative tests for diagnostic and prognostic purposes. Muscle biopsies provide valuable data, but their use is limited by their invasiveness. microRNA (miRNAs) are small non-coding RNAs regulating gene expression that are also present in biological fluids and may serve as diseases biomarkers. Thus, we tested plasma miRNAs in the blood of 36 DM1 patients and 36 controls. First, a wide miRNA panel was profiled in a patient subset, followed by validation using all recruited subjects. We identified a signature of nine deregulated miRNAs in DM1 patients: eight miRNAs were increased (miR-133a, miR-193b, miR-191, miR-140-3p, miR-454, miR-574, miR-885-5p, miR-886-3p) and one (miR-27b) was decreased. Next, the levels of these miRNAs were used to calculate a "DM1-miRNAs score". We found that both miR-133a levels and DM1-miRNAs score discriminated DM1 from controls significantly and Receiver-Operator Characteristic curves displayed an area under the curve of 0.94 and 0.97, respectively. Interestingly, both miR-133a levels and DM1-miRNAs score displayed an inverse correlation with skeletal muscle strength and displayed higher values in more compromised patients. In conclusion, we identified a characteristic plasma miRNA signature of DM1. Although preliminary, this study indicates miRNAs as potential DM1 humoral biomarkers.
As part of a wider study of floodplain vegetation along the River Murray, we carried out a field survey in 1987–1988 involving collection of floristic and vegetation condition data from 335 sample plots (each 400 m2 in area), between Hume Dam and Lake Alexandrina (including the Edward-Wakool anabranch system). The floodplain vegetation is dominated by just two tree species, River Red Gum (Eucalyptus camaldulensis) and Black Box (Eucalyptus largiflorens), but the composition of the understorey shows much greater variation, both along the river and across the floodplain. A total of 499 plant species, subspecies and varieties were recorded from the survey plots, of which 316 (63%) were native and 183 (37%) were exotic. From analysis of the floristic data we identified 37 vegetation communities, not including the vegetation of permanent wetlands and cleared areas; 21 communities were distinguished in the River Red Gum zone, 12 communities in the Black Box zone, and 4 communities on rises within the floodplain. The main floristic division among the River Red Gum communities was between Riverine Plain/ Headwaters Zone communities of the upper Murray, and Mallee Zone communities of the lower Murray. Among the Black Box communities, the main floristic division was between inner floodplain communities and outer floodplain communities, with a further division between South Australian communities and New South Wales/Victorian communities. Major factors influencing the floristic patterns included flooding frequency/duration and soil salinity.
Eucalypt health declined steadily downstream and was poorest in the lower reaches of the river below the Darling Junction, where 60% of the trees were healthy, 18% unhealthy (at least 40% of the canopy dead) and 22% dead. By comparison, at the upper end of the river, above Tocumwal, 84% of the trees were healthy, 14% unhealthy and only 2% dead. Overall, the condition of Black Box trees (44% unhealthy or dead) was worse than the condition of River Red Gum trees (29% unhealthy or dead). Eucaypt regeneration was also poorest below the Darling Junction, with regenerants present in 77% of plots upstream of the Darling but only 35% of plots downstream. The findings of poor tree health and sparse regeneration below the Darling coincide with the most heavily regulated part of the Murray, where the reduction in flooding due to upstream storages and water extraction, mainly for irrigation, has been greatest. Black Box regeneration was much sparser overall than River Red Gum regeneration (regenerants present in 69% of River Red Gum plots but only 29% of Black Box plots). The poor condition of the Black Box trees, coupled with their poor regeneration, suggests that the long-term future of this species along the Murray, particularly below the Darling Junction, is tenuous, even though it is a dominant component of the vegetation.
The integrity of floodplain vegetation along the Murray has been severely compromised by weed invasion. Weeds were common throughout the survey area, but were most prevalent in the climatically wetter sections of the river, at both the downstream and upstream ends (below Mannum and above Tocumwal). The median number of exotic species per plot equalled or exceeded the number of native species in these sections of the river, whereas native species outnumbered exotic species in the other river sections. Communities of the River Red Gum zone and the rises were generally weedier than those of the Black Box zone. Exotic species strongly influenced the community classification. They were the dominant overstorey species in two communities (Salix species – willows) and outnumbered native species in the understorey of another eight communities. At the lower end of the river, below Mannum, the River Red Gums that originally fringed the river had been mostly replaced by dense thickets of the exotic Weeping Willow, Salix babylonica.
Other factors that have impacted on the floodplain vegetation at the plant community level have been river regulation and soil salinisation. Stabilization of water levels in the lower Murray by construction of a series of weirs and barrages has favoured the spread of some communities at the expense of others. The favoured communities, which are characterised by stands of Common Reed, Phragmites australis, along the water’s edge, appear to be artefacts of river regulation. Salinisation has resulted in death of eucalypts and replacement of eucalypt communities by shrub communities dominated by samphires, Tecticornia species. The samphire community characteristic of the most saline sites is one of the most species-poor communities on the Murray floodplain.
Logging along the Murray in New South Wales and Victoria has resulted in extensive replacement of old growth River Red Gum forests and woodlands by more even-aged stands of straight young trees. Following the recent conversion of many areas of State Forest along the Murray in both New South Wales and Victoria to National Park or Regional Park, and thus the cessation of logging in these areas, they should now revert gradually to mature forest and woodland.
This study is the first to describe broad scale floristic patterns in the floodplain vegetation of the Murray covering most of the length of the river. It also provides data on the vegetation condition in the 1980s, and provides a benchmark of conditions before the prolonged Millenium Drought in south-eastern Australia from 1997 to 2010. More recent surveys of vegetation condition have reported a severe decline in tree health during the drought. The results from our 1987–88 survey are important because they show that the deteriorating condition of the vegetation was already evident in the 1980s and although exacerbated by the subsequent drought, it is not just a consequence of that drought. The results are consistent with the conclusion that the primary cause of the decline has been river regulation and water extraction for irrigation. The rate of deterioration has increased rapidly since the 1980s because of the drought. There has been some improvement since the breaking of the drought, but the poor condition of the River Murray floodplain vegetation, an Australian icon, remains a major conservation and management issue. The impacts of climate change – higher temperatures and reduced rainfall – have compounded the problem and will continue to do so at an increasing rate. The results of the study support listing of the floodplain vegetation of the lower reaches of the river as a critically endangered ecological community.
The riparian rainforest on the streamside levees of the coastal floodplain of the Clarence River on the North Coast of New South Wales was cleared during the 1860s by small landholders seeking fertile land. Only three small remnants remain. Using a combination of historical species lists, corner trees from surveyors’ portion plans, habitat information and the NSW Scientific Committee’s (1999) determination for lowland rainforest on floodplain a conceptual model of the original distribution of rainforest suballiances on the levees of the Clarence River coastal floodplain is proposed.
Population size, and flowering and fruiting developmental stages in the Critically Endangered species Corunastylis sp. ‘Charmhaven’ (Family Orchidaceae, formerly included within genus Genoplesium), were investigated in the Warnervale-Charmhaven area over a three year period. Population size in 2012 was 11 plants, in 2013, 14 plants and in 2014 increased to 26 plants, with new plants appearing near the original plants. Proactive management, including mowing and erecting wire protective cages around groups of orchids was partly responsible for this increase in numbers because it prevented browsing by rabbits but only ten plants carried fruits to maturity in the 2014 season to produce seed. Despite an increase in numbers over a couple of years, a population of 26 individuals is very small and warrants maintaining the current conservation listing of Critically Endangered. The population began to flower between 15th and 29th February in 2012 and from 3rd to 14th March in 2013. However in 2014 flowering began on 11th February and extended to 19th March but it took until 17th June to reach the seed dispersal stage. 2014 involved two phases of flowering; whether climatic factors were responsible for this event is not known.