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Background: Subarachnoid hemorrhage (SAH) is mainly caused by ruptured cerebral aneurysms but in up to 15% of patients with SAH no bleeding source could be identified. Our objective was to analyze patient characteristics, clinical outcome and prognostic factors in patients suffering from non-aneurysmal SAH.
Methods: From 1999 to 2009, data of 125 patients with non-aneurysmal SAH were prospectively entered into a database. All patients underwent repetitive cerebral angiography. Outcome was assessed according to the modified Rankin Scale (mRS) (mRS 0-2 favorable vs. 3-6 unfavorable). Also, patients were divided in two groups according to the distribution of blood in the CT scan (perimesencephalic and non-perimesencephalic SAH).
Results: 106 of the 125 patients were in good WFNS grade (I-III) at admission (85%). Overall, favorable outcome was achieved in 104 of 125 patients (83%). Favorable outcome was associated with younger age (P < 0.001), good admission status (P < 0.0001), and absence of hydrocephalus (P = 0.001).73 of the 125 patients suffered from perimesencephalic SAH, most patients (90%) were in good grade at admission, and 64 achieved favorable outcome.52 of the 125 patients suffered from non-perimesencephalic SAH and 40 were in good grade at admission. Also 40 patients achieved favorable outcome.
Conclusions: Patients suffering from non-aneurysmal SAH have better prognosis compared to aneurysm related SAH and poor admission status was the only independent predictor of unfavorable outcome in the multivariate analysis. Patients with a non-perimesencephalic SAH have an increased risk of a worse neurological outcome. These patients should be monitored attentively.
Background: Hereditary angioedema (HAE) due to C1 inhibitor deficiency is a rare but serious and potentially life-threatening disease marked by spontaneous, recurrent attacks of swelling. The study objective was to characterize direct and indirect resource utilization associated with HAE from the patient perspective in Europe.
Methods: The study was conducted in Spain, Germany, and Denmark to assess the real-world experience of HAE via a cross-sectional survey of HAE patients, including direct and indirect resource utilization during and between attacks for patients and their caregivers over the past 6 months. A regression model examined predictors of medical resource utilization.
Results: Overall, 164 patients had an attack in the past 6 months and were included in the analysis. The most significant predictor of medical resource utilization was the severity of the last attack (OR 2.6; p < 0.001). Among patients who sought medical care during the last attack (23%), more than half utilized the emergency department. The last attack prevented patients from their normal activities an average of 4-12 hours. Patient and caregiver absenteeism increased with attack severity and frequency. Among patients who were working or in school (n = 120), 72 provided work/school absenteeism data, resulting in an estimated 20 days missing from work/school on average per year; 51% (n = 84) indicated that HAE has hindered their career/educational advancement.
Conclusion: HAE poses a considerable burden on patients and their families in terms of direct medical costs and indirect costs related to lost productivity. This burden is substantial at the time of attacks and in between attacks.
Background: Risk stratification, detection of minimal residual disease (MRD), and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), but survival of adult patients with T-cell acute lymphoblastic leukemia (T-ALL) remains unsatisfactory. Thus, novel molecular insights and therapeutic approaches are urgently needed.
Methods: We studied the impact of B-cell CLL/lymphoma 11b (BCL11b), a key regulator in normal T-cell development, in T-ALL patients enrolled into the German Multicenter Acute Lymphoblastic Leukemia Study Group trials (GMALL; n = 169). The mutational status (exon 4) of BCL11b was analyzed by Sanger sequencing and mRNA expression levels were determined by quantitative real-time PCR. In addition gene expression profiles generated on the Human Genome U133 Plus 2.0 Array (affymetrix) were used to investigate BCL11b low and high expressing T-ALL patients.
Results: We demonstrate that BCL11b is aberrantly expressed in T-ALL and gene expression profiles reveal an association of low BCL11b expression with up-regulation of immature markers. T-ALL patients characterized by low BCL11b expression exhibit an adverse prognosis [5-year overall survival (OS): low 35% (n = 40) vs. high 53% (n = 129), P = 0.02]. Within the standard risk group of thymic T-ALL (n = 102), low BCL11b expression identified patients with an unexpected poor outcome compared to those with high expression (5-year OS: 20%, n = 18 versus 62%, n = 84, P < 0.01). In addition, sequencing of exon 4 revealed a high mutation rate (14%) of BCL11b.
Conclusions: In summary, our data of a large adult T-ALL patient cohort show that low BCL11b expression was associated with poor prognosis; particularly in the standard risk group of thymic T-ALL. These findings can be utilized for improved risk prediction in a significant proportion of adult T-ALL patients, which carry a high risk of standard therapy failure despite a favorable immunophenotype.
Understanding the diverging opinions of academic experts, stakeholders and the public is important for effective conservation management. This is especially so when a consensus is needed for action to minimize future risks but the knowledge upon which to base this action is uncertain or missing. How to manage non-native, invasive species (NIS) is an interesting case in point: the issue has long been controversial among stakeholders, but publicly visible, major disagreement among experts is recent. To characterize the multitude of experts’ understanding and valuation of non-native, NIS we performed structured qualitative interviews with 26 academic experts, 13 of whom were invasion biologists and 13 landscape experts. Within both groups, thinking varied widely, not only about basic concepts (e.g., non-native, invasive) but also about their valuation of effects of NIS. The divergent opinions among experts, regarding both the overall severity of the problem in Europe and its importance for ecosystem services, contrasted strongly with the apparent consensus that emerges from scientific synthesis articles and policy documents. We postulate that the observed heterogeneity of expert judgments is related to three major factors: (1) diverging conceptual understandings, (2) lack of empirical information and high scientific uncertainties due to complexities and contingencies of invasion processes, and (3) missing deliberation of values. Based on theory from science studies, we interpret the notion of an NIS as a boundary object, i.e., concepts that have a similar but not identical meaning to different groups of experts and stakeholders. This interpretative flexibility of a concept can facilitate interaction across diverse groups but bears the risk of introducing misunderstandings. An alternative to seeking consensus on exact definitions and risk assessments would be for invasive species experts to acknowledge uncertainties and engage transparently with stakeholders and the public in deliberations about conflicting opinions, taking the role of honest brokers of policy alternatives rather than of issue advocates.
Climate is frequently used to predict the outcome of species introductions based on the results from species distribution models (SDMs). However, despite the widespread use of SDMs for pre- and post-border risk assessments, data that can be used to validate predictions is often not available until after an invasion has occurred. Here we explore the potential for using historical forestry trials to assess the performance of climate-based SDMs. SDMs were parameterized based on the native range distribution of 36 Australian acacias, and predictions were compared against both the results of 150 years of government forestry trials, and current invasive distribution in southern Africa using true skill statistic, sensitivity and specificity. Classification tree analysis was used to evaluate why some Australian acacias failed in trials while others were successful. Predicted suitability was significantly related to the invaded range (sensitivity = 0.87) and success in forestry trials (sensitivity = 0.80), but forestry trial failures were under-predicted (specificity = 0.35). Notably, for forestry trials, the success in trials was greater for species invasive somewhere in the world. SDM predictions also indicate a considerable invasion potential of eight species that are currently naturalized but not yet widespread. Forestry trial data clearly provides a useful additional source of data to validate and refine SDMs in the context of risk assessment. Our study identified the climatic factors required for successful invasion of acacias, and accentuates the importance of integration of status elsewhere for risk assessment.
A hybrid form of tilapia was introduced into Port Sulphur, Louisiana and was subsequently managed by treatment with rotenone and stocking of native predatory fishes. Measurements of tilapia from before this management event were compared to measurements of tilapia in the two years after the treatment. Post-management tilapia were consistently deeper in body and had greater weight per unit length (condition) when compared to pre-management fish. Procrustes generalized least squares data supported this by consistently finding post-management tilapia to be consistently deeper in body and head shape than pre-management fish. Although this could indicate the effectiveness of stocking native predators, several other factors, including two cold winters, seasonal effects, and less competition, may have contributed to this result.
Ribosome biogenesis in yeast requires 75 small nucleolar RNAs (snoRNAs) and a myriad of cofactors for processing, modification, and folding of the ribosomal RNAs (rRNAs). For the 19 RNA helicases implicated in ribosome synthesis, their sites of action and molecular functions have largely remained unknown. Here, we have used UV cross-linking and analysis of cDNA (CRAC) to reveal the pre-rRNA binding sites of the RNA helicase Rok1, which is involved in early small subunit biogenesis. Several contact sites were identified in the 18S rRNA sequence, which interestingly all cluster in the “foot” region of the small ribosomal subunit. These include a major binding site in the eukaryotic expansion segment ES6, where Rok1 is required for release of the snR30 snoRNA. Rok1 directly contacts snR30 and other snoRNAs required for pre-rRNA processing. Using cross-linking, ligation and sequencing of hybrids (CLASH) we identified several novel pre-rRNA base-pairing sites for the snoRNAs snR30, snR10, U3, and U14, which cluster in the expansion segments of the 18S rRNA. Our data suggest that these snoRNAs bridge interactions between the expansion segments, thereby forming an extensive interaction network that likely promotes pre-rRNA maturation and folding in early pre-ribosomal complexes and establishes long-range rRNA interactions during ribosome synthesis.
Na+/H+ antiporters are integral membrane proteins that are present in almost every cell and in every kingdom of life. They are essential for the regulation of intracellular pH-value, Na+-concentration and cell volume. These secondary active transporters exchange sodium ions against protons via an alternating access mechanism, which is not understood in full detail. Na+/H+ antiporters show distinct species-specific transport characteristics and regulatory properties that correlate with respective physiological functions. Here we present the characterization of the Na+/H+ antiporter NhaA from Salmonella enterica serovar Thyphimurium LT2, the causing agent of food-born human gastroenteritis and typhoid like infections. The recombinant antiporter was functional in vivo and in vitro. Expression of its gene complemented the Na+-sensitive phenotype of an E. coli strain that lacks the main Na+/H+ antiporters. Purified to homogeneity, the antiporter was a dimer in solution as accurately determined by size-exclusion chromatography combined with multi-angle laser-light scattering and refractive index monitoring. The purified antiporter was fully capable of electrogenic Na+(Li+)/H+-antiport when reconstituted in proteoliposomes and assayed by solid-supported membrane-based electrophysiological measurements. Transport activity was inhibited by 2-aminoperimidine. The recorded negative currents were in agreement with a 1Na+(Li+)/2H+ stoichiometry. Transport activity was low at pH 7 and up-regulation above this pH value was accompanied by a nearly 10-fold decrease of KmNa (16 mM at pH 8.5) supporting a competitive substrate binding mechanism. K+ does not affect Na+ affinity or transport of substrate cations, indicating that selectivity of the antiport arises from the substrate binding step. In contrast to homologous E. coli NhaA, transport activity remains high at pH values above 8.5. The antiporter from S. Typhimurium is a promising candidate for combined structural and functional studies to contribute to the elucidation of the mechanism of pH-dependent Na+/H+ antiporters and to provide insights in the molecular basis of species-specific growth and survival strategies.
Colors and odors are associated; for instance, people typically match the smell of strawberries to the color pink or red. These associations are forms of crossmodal correspondences. Recently, there has been discussion about the extent to which these correspondences arise for structural reasons (i.e., an inherent mapping between color and odor), statistical reasons (i.e., covariance in experience), and/or semantically-mediated reasons (i.e., stemming from language). The present study probed this question by testing color-odor correspondences in 6 different cultural groups (Dutch, Netherlands-residing-Chinese, German, Malay, Malaysian-Chinese, and US residents), using the same set of 14 odors and asking participants to make congruent and incongruent color choices for each odor. We found consistent patterns in color choices for each odor within each culture, showing that participants were making non-random color-odor matches. We used representational dissimilarity analysis to probe for variations in the patterns of color-odor associations across cultures; we found that US and German participants had the most similar patterns of associations, followed by German and Malay participants. The largest group differences were between Malay and Netherlands-resident Chinese participants and between Dutch and Malaysian-Chinese participants. We conclude that culture plays a role in color-odor crossmodal associations, which likely arise, at least in part, through experience.
ND3, ND1 and 39kDa subunits are more exposed in the de-active form of bovine mitochondrial complex I
(2014)
An intriguing feature of mitochondrial complex I from several species is the so-called A/D transition, whereby the idle enzyme spontaneously converts from the active (A) form to the de-active (D) form. The A/D transition plays an important role in tissue response to the lack of oxygen and hypoxic deactivation of the enzyme is one of the key regulatory events that occur in mitochondria during ischaemia. We demonstrate for the first time that the A/D conformational change of complex I does not affect the macromolecular organisation of supercomplexes in vitro as revealed by two types of native electrophoresis. Cysteine 39 of the mitochondrially-encoded ND3 subunit is known to become exposed upon de-activation. Here we show that even if complex I is a constituent of the I+III2+IV (S1) supercomplex, cysteine 39 is accessible for chemical modification in only the D-form. Using lysine-specific fluorescent labelling and a DIGE-like approach we further identified two new subunits involved in structural rearrangements during the A/D transition: ND1 (MT-ND1) and 39kDa (NDUFA9). These results clearly show that structural rearrangements during de-activation of complex I include several subunits located at the junction between hydrophilic and hydrophobic domains, in the region of the quinone binding site. De-activation of mitochondrial complex I results in concerted structural rearrangement of membrane subunits which leads to the disruption of the sealed quinone chamber required for catalytic turnover.
Memory Concerns, Memory Performance and Risk of Dementia in Patients with Mild Cognitive Impairment
(2014)
Background: Concerns about worsening memory (“memory concerns”; MC) and impairment in memory performance are both predictors of Alzheimer's dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations. We examined the risk of incident AD by MC and memory performance in patients with mild cognitive impairment (MCI).
Methods: We analyzed data of 417 MCI patients from a longitudinal multicenter observational study. Patients were classified based on presence (n = 305) vs. absence (n = 112) of MC. Risk of incident AD was estimated with Cox Proportional-Hazards regression models.
Results: Risk of incident AD was increased by MC (HR = 2.55, 95%CI: 1.33–4.89), lower memory performance (HR = 0.63, 95%CI: 0.56–0.71) and ApoE4-genotype (HR = 1.89, 95%CI: 1.18–3.02). An interaction effect between MC and memory performance was observed. The predictive power of MC was greatest for patients with very mild memory impairment and decreased with increasing memory impairment.
Conclusions: Our data suggest that the power of MC as a predictor of future dementia at the MCI stage varies with the patients' level of cognitive impairment. While MC are predictive at early stage MCI, their predictive value at more advanced stages of MCI is reduced. This suggests that loss of insight related to AD may occur at the late stage of MCI.
Background: Dengue fever (DF) is the most rapidly spreading mosquito-borne viral disease in the world. In this decade it has expanded to new countries and from urban to rural areas. Nepal was regarded DF free until 2004. Since then dengue virus (DENV) has rapidly expanded its range even in mountain regions of Nepal, and major outbreaks occurred in 2006 and 2010. However, no data on the local knowledge, attitude and practice (KAP) of DF in Nepal exist although such information is required for prevention and control measures.
Methods: We conducted a community based cross-sectional survey in five districts of central Nepal between September 2011 and February 2012. We collected information on the socio-demographic characteristics of the participants and their knowledge, attitude and practice regarding DF using a structured questionnaire. We then statistically compared highland and lowland communities to identify possible causes of observed differences.
Principal findings: Out of 589 individuals interviewed, 77% had heard of DF. Only 12% of the sample had good knowledge of DF. Those living in the lowlands were five times more likely to possess good knowledge than highlanders (P<0.001). Despite low knowledge levels, 83% of the people had good attitude and 37% reported good practice. We found a significantly positive correlation among knowledge, attitude and practice (P<0.001). Among the socio-demographic variables, the education level of the participants was an independent predictor of practice level (P<0.05), and education level and interaction between the sex and age group of the participants were independent predictors of attitude level (P<0.05).
Conclusion: Despite the rapid expansion of DENV in Nepal, the knowledge of people about DF was very low. Therefore, massive awareness programmes are urgently required to protect the health of people from DF and to limit its further spread in this country.
The pharmacokinetic properties and tolerability of a triamcinolone acetonide poloxamer 407 hydrogel for intratympanic application were investigated in a guinea pig model. Evaluation of in vivo release kinetics showed very high initial perilymph drug levels, with clinically relevant levels present for a minimum of 10 days. Assessment of auditory brainstem response thresholds showed a minimal, delayed and transient threshold shift, which was apparent on day 3 and resolved by day 10. No relevant histological changes of the middle and inner ear structures were noted, and hair cell counts showed no significant differences between treated and untreated ears. Thus, the triamcinolone-acetonide-loaded poloxamer 407 hydrogel is an effective vehicle for sustained high-dose inner ear glucocorticoid delivery.
So-called medicanes (Mediterranean hurricanes) are meso-scale, marine, and warm-core Mediterranean cyclones that exhibit some similarities to tropical cyclones. The strong cyclonic winds associated with medicanes threaten the highly populated coastal areas around the Mediterranean basin. To reduce the risk of casualties and overall negative impacts, it is important to improve the understanding of medicanes with the use of numerical models. In this study, we employ an atmospheric limited-area model (COSMO-CLM) coupled with a one-dimensional ocean model (1-D NEMO-MED12) to simulate medicanes. The aim of this study is to assess the robustness of the coupled model in simulating these extreme events. For this purpose, 11 historical medicane events are simulated using the atmosphere-only model, COSMO-CLM, and coupled model, with different setups (horizontal atmospheric grid-spacings of 0.44°, 0.22°, and 0.08°; with/without spectral nudging, and an ocean grid-spacing of 1/12°). The results show that at high-resolution, the coupled model is able to not only simulate most of medicane events but also improve the track length, core temperature, and wind speed of simulated medicanes compared to the atmosphere-only simulations. The results suggest that the coupled model is more proficient for systemic and detailed studies of historical medicane events, and that this model can be an effective tool for future projections.
Background: The aim of this study was to compare outcome of patients with previous cardiac surgery undergoing transapical aortic valve implantation (Redo-TAVI) to those undergoing classic aortic valve replacement (Redo-AVR) by using propensity analysis.
Methods: From January 2005 through May 2012, 52 high-risk patients underwent Redo-TAVI using a pericardial xenograft fixed within a stainless steel, balloon-expandable stent (Edwards SAPIEN™). During the same period of time 167 patients underwent classic Redo-AVR. Logistic regression analysis was used to identify covariates among 11 baseline patient variables including the type of initial surgery. Using the significant regression coefficients, each patient’s propensity score was calculated, allowing selectively matched subgroups of 40 patients each. Initial surgery included coronary artery bypass grafting in 30 patients, aortic valve replacement in 7 patients and mitral valve reconstruction in 3 patients in each group. Follow-up was 4 ± 2 years and was 100% complete.
Results: Postoperative chest tube drainage (163 ± 214 vs. 562 ± 332 ml/24 h, p = 0.02) and incidence of early permanent neurologic deficit (0 vs. 13%, p = 0.04) was lower in patients with Redo-TAVI and there was a trend towards improved 30-day survival (p = 0.06). Also we detected a decreased ventilation time (p = 0.04) and lower transfusion rate of allogenic blood products (p ≤ 0.05) in the Redo-TAVI group. At late follow up differences regarding incidence of major adverse events, including death and permanent neurologic deficits (25% vs. 43%, p = 0.01) statistically supported early postoperative findings.
Conclusion: The encouraging results regarding early and long-term outcomes following TAVI in patients with previous cardiac surgery show, that this evolving approach may be particularly beneficial in this patient cohort.
The role of RNA interference in the developmental separation of blood and lymphatic vasculature
(2014)
Background: Dicer is an RNase III enzyme that cleaves double stranded RNA and generates functional interfering RNAs that act as important regulators of gene and protein expression. Dicer plays an essential role during mouse development because the deletion of the dicer gene leads to embryonic death. In addition, dicer-dependent interfering RNAs regulate postnatal angiogenesis. However, the role of dicer is not yet fully elucidated during vascular development.
Methods: In order to explore the functional roles of the RNA interference in vascular biology, we developed a new constitutive Cre/loxP-mediated inactivation of dicer in tie2 expressing cells.
Results: We show that cell-specific inactivation of dicer in Tie2 expressing cells does not perturb early blood vessel development and patterning. Tie2-Cre; dicerfl/fl mutant embryos do not show any blood vascular defects until embryonic day (E)12.5, a time at which hemorrhages and edema appear. Then, midgestational lethality occurs at E14.5 in mutant embryos. The developing lymphatic vessels of dicer-mutant embryos are filled with circulating red blood cells, revealing an impaired separation of blood and lymphatic vasculature.
Conclusion: Thus, these results show that RNA interference perturbs neither vasculogenesis and developmental angiogenesis, nor lymphatic specification from venous endothelial cells but actually provides evidence for an epigenetic control of separation of blood and lymphatic vasculature.
The recent approval by the US Food and Drug Administration of ocriplasmin for the treatment of symptomatic vitreomacular adhesion (VMA), often associated with vitreomacular traction (VMT) and macular hole (MH), has brought new attention to the field of pharmacologic vitreolysis. The need for an enzyme to split the vitreomacular interface, which is formed by a strong adhesive interaction between the posterior vitreous cortex and the internal limiting membrane, historically stems from pediatric eye surgery. This review summarizes the different anatomic classifications of posterior vitreous detachment or anomalous posterior vitreous detachment and puts these in the context of clinical pathologies commonly observed in clinical practice of the vitreoretinal specialist, such as MH, VMT, age-related macular degeneration, and diabetic macular edema. We revisit the outcome of the Phase II studies that indicated ocriplasmin was a safe and effective treatment for selected cases of symptomatic VMA and MH. Release of VMA at day 28 was achieved by 26.5% of patients in the ocriplasmin group versus 10.1% in the placebo group (P<0.001). Interestingly, for MHs, the numbers were more remarkable. Predictive factors for successful ocriplasmin treatment were identified for VMT (VMA diameter smaller than 1,500 µm) and MH (smaller than 250 µm). In comparison with the highly predictable outcome after vitrectomy, the general success rate of ocriplasmin not under clinical trial conditions has not fully met expectations and needs to be proven in real-world clinical settings. The ocriplasmin data will be compared in the future with observational data on spontaneous VMA release, will help retina specialists make more accurate predictions, and will improve outcome rates.
The investigated haloarchaeal species, Halobacterium salinarum, Haloferax mediterranei, and H. volcanii, have all been shown to be polyploid. They contain several replicons that have independent copy number regulation, and most have a higher copy number during exponential growth phase than in stationary phase. The possible evolutionary advantages of polyploidy for haloarchaea, most of which have experimental support for at least one species, are discussed. These advantages include a low mutation rate and high resistance toward X-ray irradiation and desiccation, which depend on homologous recombination. For H. volcanii, it has been shown that gene conversion operates in the absence of selection, which leads to the equalization of genome copies. On the other hand, selective forces might lead to heterozygous cells, which have been verified in the laboratory. Additional advantages of polyploidy are survival over geological times in halite deposits as well as at extreme conditions on earth and at simulated Mars conditions. Recently, it was found that H. volcanii uses genomic DNA as genetic material and as a storage polymer for phosphate. In the absence of phosphate, H. volcanii dramatically decreases its genome copy number, thereby enabling cell multiplication, but diminishing the genetic advantages of polyploidy. Stable storage of phosphate is proposed as an alternative driving force for the emergence of DNA in early evolution. Several additional potential advantages of polyploidy are discussed that have not been addressed experimentally for haloarchaea. An outlook summarizes selected current trends and possible future developments.
The Paddys River Wetlands in the New South Wales Southern Highlands, southwest of Sydney, are characterised by several watercourses with associated swamps (fens), some of which, on Forestry Corporation of NSW land, have been the focus for removal of Pinus radiata wildings by the Penrose Swamps Conservation Group. In this study we map a population of Eucalyptus aquatica trees in one of these swamps perched above Paddys River (latitude 34.65575o S, longitude 150.21831o E; 600 m elevation). Eucalyptus aquatica is geographically restricted to the Paddys River area and is listed as a threatened species at state and national levels. New findings on the physical characteristics of the swamp in relation to the bedrock geology, stream geomorphology, peat development and the main native plant species, are presented. The occurrence of clumps of Eucalyptus aquatica appears to be independent of the type or thickness of the growing substrate. Rather it is suggested that a continuous supply of water and the shelter afforded by the narrow valley may be key factors determining the distribution of the trees at the study site. An on-going programme of research is underway to study other occurrences of Eucalyptus aquatica.
The Queensland Herbarium Regional Ecosystem Survey and Mapping (QHRESM) program has contributed almost 90000 (89389) specimens to the Queensland Herbarium in Brisbane accounting for 28% of the specimens added to the Herbarium between 1970 and 2011. These specimens have been collected across all bioregions and vegetation communities in Queensland in a systematic sampling program driven by the requirement to sample comprehensively all vegetation communities. The QHRESM’s Queensland Herbarium (BRI) specimens represent more than 79% of the native, and 73% of the naturalised vascular flora of Queensland, as well as making valuable contributions to the bryophytes, lichens and liverworts collections. The data and specimens collected enhance our ability to assess local, state and continental-scale plant diversity, and will be used by botanists, ecologists, governments, business and the public for long into the future.
Natural vegetation of freely draining beach sand ridges in the valley of the Upper Myall River on the lower North Coast of NSW is sclerophyllous open forest or woodland. Based on previous experience on the nearby Eurunderee area, the vegetation on the sand ridges was classified into three types. These were mapped using aerial photographs and field observation. In transects, each 50 m long, the presence of species was scored in 10, 5 X 5 m quadrats. 48 such transects were used sampling all three types of vegetation on the sand ridges and also vegetation in periodically waterlogged sites adjacent to the ridges. Data from the transects, subjected to an ordination using principal components analysis, revealed clear separation between vegetation of the ridges and that of periodically waterlogged sites. In the ordination, vegetation of the ridges formed a continuum with the three types occupying characteristic parts of the continuum, reflecting their respective distributions on sands with different geomorphological histories. The most grassy, tallest forest, termed Dry Sclerophyll Forest (DSF) is on sands either recently disturbed or deposited (Holocene) or closely overlying other substrates. Banksia serrata occurs in DSF. The least grassy, most sclerophyllous, lowest forest or woodland, termed Dry Heath Forest (DHF), occurs on sands apparently little disturbed since they were laid down in the Pleistocene. Banksia aemula occurs in DHF. An intermediate forest, in which Banksia aemula and Banksia serrata occur together, Intermediate Dry Forest (IDF), is most widely found on the sand mass close to Bombah Broadwater. This sand is postulated to have been reworked during the last Glacial Period. In short, the vegetation of these sand ridges largely varies with time since they were laid down or last disturbed in a major way. Preliminary observations indicate the degree of podsolization of their soils is similarly related to this variation in time.
Lysimachia mauritiana Lam. (family Primulaceae), a small short-lived herb native to India, Indian and Pacific Ocean islands, and coastal east Asia, is described as a new naturalised record from the eastern suburbs of Sydney, New South Wales, Australia. It was first recorded in 1981 near Coogee, and grows in exposed rock crevices and seepages on the seacoast, very similar to its natural habitat overseas. Lysimachia mauritiana is known to have been cultivated in the area in 1961 in a home garden, which is the likely source of this introduction; it appears to be spreading locally as a weed.
Vegetation of Little Bora Nature Conservation Trust Agreement, North Western Slopes, New South Wales
(2014)
The vegetation of the Little Bora Nature Conservation Trust Agreement property (560 ha in area), 8 km south east of Bingara (lat 29° 55’S long 150° 37’) in the Gwydir Shire and within the Nandewar Bioregion is described. Eight vegetation communities are defined based on flexible UPGMA analysis of cover-abundance scores of all vascular plant taxa. These communities are mapped based on ground truthing, ADS40 imagery interpretation, topography and substrate. Communities described are: 1) Melaleuca bracteata – Eucalyptus melanophloia – Eucalyptus camaldulensis Woodland, 2) Callitris glaucophylla – Eucalyptus melanophloia – Eucalyptus albens Woodland, 3) Callitris glaucophylla – Eucalyptus melanophloia – Brachychiton populneus Woodland, 4) Eucalyptus albens Woodland, 5) Eucalyptus caleyi – Eucalyptus albens – Callitris glaucophylla Woodland, 6) Callitris glaucophylla – Eucalyptus melanophloia – Eucalyptus albens Woodland, 7) Austrostipa verticillata – Austrostipa scabra Derived Grassland, 8) Eucalyptus melliodora – Eucalyptus dealbata Woodland. A total of 232 vascular plant taxa were found of which 14% were considered exotic in origin. 66 ha of listed threatened communities were mapped along with populations of a currently listed Extinct plant (TSC Act) Dodonaea stenophylla.
A population of 700 Blandfordia cunninghamii Lindl. (family Blandfordiaceae) plants in the Blue Mountains, 100 km west of Sydney, New South Wales was monitored over a period of seven years, during which a part of the population area was burnt in a Hazard Reduction Burn (HRB). The survey measured flowering of Blandfordia cunninghamii in both the burnt and unburnt areas. In part of the unburnt area flowering (in December) was strongly correlated with previous September rainfall, but in another unburnt area there was no flowering at all over the seven years. An enhanced flowering response after fire was found in the burnt area and the diminution of this enhanced response in subsequent years was found to be logarithmic (taking into account potential rainfall effects). No recruitment of juvenile plants after fire was observed. 87% of seeds of Blandfordia cunninghamii were found to be germinable. Slow juvenile growth of Blandfordia cunninghamii in the field was measured over seven years. Seed was collected for two major seedbanks, the NSW Plantbank at the Australian Botanic Garden, Mt Annan and the Millennium Seedbank at Kew in the United Kingdom.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Many studies about endocrine pollution in the aquatic environment reveal changes in the reproduction system of biota. We analysed endocrine activities in two rivers in Southern Germany using three approaches: (1) chemical analyses, (2) in vitro bioassays, and (3) in vivo investigations in fish and snails. Chemical analyses were based on gas chromatography coupled with mass spectrometry. For in vitro analyses of endocrine potentials in water, sediment, and waste water samples, we used the E-screen assay (human breast cancer cells MCF-7) and reporter gene assays (human cell line HeLa-9903 and MDA-kb2). In addition, we performed reproduction tests with the freshwater mudsnail Potamopyrgus antipodarum to analyse water and sediment samples. We exposed juvenile brown trout (Salmo trutta f. fario) to water downstream of a wastewater outfall (Schussen River) or to water from a reference site (Argen River) to investigate the vitellogenin production. Furthermore, two feral fish species, chub (Leuciscus cephalus) and spirlin (Alburnoides bipunctatus), were caught in both rivers to determine their gonadal maturity and the gonadosomatic index. Chemical analyses provided only little information about endocrine active substances, whereas the in vitro assays revealed endocrine potentials in most of the samples. In addition to endocrine potentials, we also observed toxic potentials (E-screen/reproduction test) in waste water samples, which could interfere with and camouflage endocrine effects. The results of our in vivo tests were mostly in line with the results of the in vitro assays and revealed a consistent reproduction-disrupting (reproduction tests) and an occasional endocrine action (vitellogenin levels) in both investigated rivers, with more pronounced effects for the Schussen river (e.g. a lower gonadosomatic index). We were able to show that biological in vitro assays for endocrine potentials in natural stream water reasonably reflect reproduction and endocrine disruption observed in snails and field-exposed fish, respectively.
Mechanisms behind how the immune system signals to the brain in response to systemic inflammation are not fully understood. Transgenic mice expressing Cre recombinase specifically in the hematopoietic lineage in a Cre reporter background display recombination and marker gene expression in Purkinje neurons. Here we show that reportergene expression in neurons is caused by intercellular transfer of functional Cre recombinase messenger RNA from immune cells into neurons in the absence of cell fusion. In vitro purified secreted extracellular vesicles (EVs) from blood cells contain Cre mRNA, which induces recombination in neurons when injected into the brain. Although Cre-mediated recombination events in the brain occur very rarely in healthy animals, their number increases considerably in different injury models, particularly under inflammatory conditions, and extend beyond Purkinje neurons to other neuronal populations in cortex, hippocampus, and substantia nigra. Recombined Purkinje neurons differ in their miRNA profile from their nonrecombined counterparts, indicating physiological significance. These observations reveal the existence of a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain, in response to inflammation.
The exposure to tobacco smoke during pregnancy is considered to be amongst the most harmful avoidable risk factors. In this scientometric and gender study scientific data on smoking and pregnancy was analyzed using a variety of objective scientometric methods like the number of scientific contributions, the number of citations and the modified h-index in combination with gender-specific investigations. Covering a time period from 1900 to 2012, publishing activities of 27,955 authors, institutions and countries, reception within the international scientific community and its reactions were analyzed and interpreted. Out of 10,043 publications the highest number of scientific works were published in the USA (35.5%), followed by the UK (9.9%) and Canada (5.3%). These nations also achieve the highest modified h-indices of 128, 79 and 62 and the highest citation rates of 41.4%, 8.6% and 5.3%, respectively. Out of 12,596 scientists 6,935 are female (55.1%), however they account for no more than 49.7% of publications (12,470) and 42.8% of citations (172,733). The highest percentage of female experts about smoking and pregnancy is found in Australasia (60.7%), while the lowest is found in Asia (41.9%). The findings of the study indicate an increase in gender equality as well as in quantity and quality of international scientific research about smoking and pregnancy in the future.
There are no European recommendations on issues specifically related to lung transplantation (LTX) in cystic fibrosis (CF). The main goal of this paper is to provide CF care team members with clinically relevant CF-specific information on all aspects of LTX, highlighting areas of consensus and controversy throughout Europe. Bilateral lung transplantation has been shown to be an important therapeutic option for end-stage CF pulmonary disease. Transplant function and patient survival after transplantation are better than in most other indications for this procedure. Attention though has to be paid to pretransplant morbidity, time for referral, evaluation, indication, and contraindication in children and in adults. This review makes extensive use of specific evidence in the field of lung transplantation in CF patients and addresses all issues of practical importance. The requirements of pre-, peri-, and postoperative management are discussed in detail including bridging to transplant and postoperative complications, immune suppression, chronic allograft dysfunction, infection, and malignancies being the most important. Among the contributors to this guiding information are 19 members of the ECORN-CF project and other experts. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Christiane Herzog Foundation.
Objective: To analyze Mucograft (MG), a recently introduced collagen matrix, in vitro and in vivo, and compare it with BioGide (BG), a well-established collagen membrane, as control.
Material and methods: A detailed analysis of the materials surface and ultra-structure was performed. Cellular growth patterns and proliferation rates of human fibroblasts on MG and BG were analyzed in vitro. In addition, the early tissue reaction of CD-1 mouse to these materials was analyzed by means of histological and histomorphometrical analysis.
Results: MG showed a three-fold higher thickness both in dry and wet conditions, when compared to BG. The spongy surface of BG significantly differed from that of MG. Cells showed a characteristic proliferation pattern on the different materials in vitro. Fibroblasts tended to proliferate on the compact layers of both collagens, with the highest values on the compact side of BG. In vivo, at day three both materials demonstrated good tissue integration, with a mononuclear cell sheet of fibroblasts on all surfaces, however, without penetrating into the materials.
Conclusions: The findings of this study showed that MG and BG facilitate cell proliferation on both of their surfaces in vitro. In vivo, these two materials induce a comparable early tissue reaction, while serving as cell occlusive barriers.
Background: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) usually presents in middle aged men and shows an indolent clinical behavior. However, up to 30% of the patients present a secondary transformation into aggressive diffuse large B cell lymphoma (DLBCL). The aim of the present study was to characterize morphology and immunophenotype of this kind of DLBCL in detail and compare it with conventional DLBCL.
Methods: Morphology and immunophenotype of 33 cases of NLPHL with simultaneous or sequential transformation into DLBCL were investigated. These cases were compared with 41 de novo DLBCL in Finnish men.
Results: The majority of cases exhibited different immunophenotypes in the NLPHL and the DLBCL components. The immunophenotype of the DLBCL secondary to NLPHL was heterogeneous. However, BCL6, EMA, CD75 and J-chain were usually expressed in both components (≥73% positive). Overall, the NLPHL component was more frequently positive for EMA, CD75 and J-chain than the DLBCL component. In contrast, B cell markers, CD10 and BCL2, were more frequently expressed and were expressed at higher levels in the DLBCL component than in the NLPHL component. In the independent series of de novo DLBCL 4 cases could be identified with a growth pattern and immunophenotype that suggested that they had arisen secondarily from NLPHL.
Conclusions: The morphology and immunophenotype of DLBCL arisen from NLPHL is heterogeneous. Further characterization of the particular molecular features of this subgroup is warranted to be able to better identify these cases among conventional DLBCL.
Increased oxidative stress and reduced nitric oxide (NO) bioavailability play a causal role in endothelial cell dysfunction occurring in the vasculature of diabetic patients. In this review, we summarized the molecular mechanisms underpinning diabetic endothelial and vascular dysfunction. In particular, we focused our attention on the complex interplay existing among NO, reactive oxygen species (ROS), and one crucial regulator of intracellular ROS production, p66Shc protein.
The common aim of transcranial stimulation methods is the induction or alterations of cortical excitability in a controlled way. Significant effects of each individual stimulation method have been published; however, conclusive direct comparisons of many of these methods are rare. The aim of the present study was to compare the efficacy of three widely applied stimulation methods inducing excitability enhancement in the motor cortex: 1 mA anodal transcranial direct current stimulation (atDCS), intermittent theta burst stimulation (iTBS), and 1 mA transcranial random noise stimulation (tRNS) within one subject group. The effect of each stimulation condition was quantified by evaluating motor-evoked-potential amplitudes (MEPs) in a fixed time sequence after stimulation. The analyses confirmed a significant enhancement of the M1 excitability caused by all three types of active stimulations compared to sham stimulation. There was no significant difference between the types of active stimulations, although the time course of the excitatory effects slightly differed. Among the stimulation methods, tRNS resulted in the strongest and atDCS significantly longest MEP increase compared to sham. Different time courses of the applied stimulation methods suggest different underlying mechanisms of action. Better understanding may be useful for better targeting of different transcranial stimulation techniques.
High lipoprotein expression and potent activation of host Toll-like receptor-2 (TLR2) are characteristic features of the staphylococcal species. Expression of TLR2 in the host is important for clearance of Staphylococcus aureus infection and host survival. Thus, we hypothesized that bacterial regulation of its intrinsic TLR2-stimulatory capacity could represent a means for immune evasion or host adaptation. We, therefore, compared clinical S. aureus isolates in regards to their TLR2 activation potential and assessed the bacterial factors that modulate TLR2-mediated recognition. S. aureus isolates displayed considerable variability in TLR2-activity with low to absent TLR2-activity in 64% of the isolates tested (68/106). Notably, strain-specific TLR2-activity was independent of the strain origin, e.g. no differences were found between strains isolated from respiratory specimen from cystic fibrosis patients or those isolated from invasive disease specimen. TLR2-activity correlated with protein A expression but not with the agr status. Capsule expression and small colony variant formation had a negative impact on TLR2-activity but any disruption of cell wall integrity enhanced TLR2 activation. Altogether, heterogeneity in host TLR2-activity reflects differences in metabolic activity and cell wall synthesis and/or remodeling.
Background: There is absence of specific biomarkers and an incomplete understanding of the pathophysiology of exudative age-related macular degeneration (AMD).
Methods and findings: Eighty-eight vitreous samples (73 from patients with treatment naïve AMD and 15 control samples from patients with idiopathic floaters) were analyzed with capillary electrophoresis coupled to mass spectrometry in this retrospective case series to define potential candidate protein markers of AMD. Nineteen proteins were found to be upregulated in vitreous of AMD patients. Most of the proteins were plasma derived and involved in biological (ion) transport, acute phase inflammatory reaction, and blood coagulation. A number of proteins have not been previously associated to AMD including alpha-1-antitrypsin, fibrinogen alpha chain and prostaglandin H2-D isomerase. Alpha-1-antitrypsin was validated in vitreous of an independent set of AMD patients using Western blot analysis. Further systems biology analysis of the data indicated that the observed proteomic changes may reflect upregulation of immune response and complement activity.
Conclusions: Proteome analysis of vitreous samples from patients with AMD, which underwent an intravitreal combination therapy including a core vitrectomy, steroids and bevacizumab, revealed apparent AMD-specific proteomic changes. The identified AMD-associated proteins provide some insight into the pathophysiological changes associated with AMD.
Species' geographical distributions are tracking latitudinal and elevational surface temperature gradients under global climate change. To evaluate the opportunities to track these gradients across space, we provide a first baseline assessment of the steepness of these gradients for the world's terrestrial birds. Within the breeding ranges of 9,014 bird species, we characterized the spatial gradients in temperature along latitude and elevation for all and a subset of bird species, respectively. We summarized these temperature gradients globally for threatened and non-threatened species and determined how their steepness varied based on species' geography (range size, shape, and orientation) and projected changes in temperature under climate change. Elevational temperature gradients were steepest for species in Africa, western North and South America, and central Asia and shallowest in Australasia, insular IndoMalaya, and the Neotropical lowlands. Latitudinal temperature gradients were steepest for extratropical species, especially in the Northern Hemisphere. Threatened species had shallower elevational gradients whereas latitudinal gradients differed little between threatened and non-threatened species. The strength of elevational gradients was positively correlated with projected changes in temperature. For latitudinal gradients, this relationship only held for extratropical species. The strength of latitudinal gradients was better predicted by species' geography, but primarily for extratropical species. Our findings suggest threatened species are associated with shallower elevational temperature gradients, whereas steep latitudinal gradients are most prevalent outside the tropics where fewer bird species occur year-round. Future modeling and mitigation efforts would benefit from the development of finer grain distributional data to ascertain how these gradients are structured within species' ranges, how and why these gradients vary among species, and the capacity of species to utilize these gradients under climate change.
Transcription factor IIS (TFIIS) is a protein known for catalyzing the cleavage reaction of the 3′-end of backtracked RNA transcript, allowing RNA polymerase II (Pol II) to reactivate the transcription process from the arrested state. Recent structural studies have provided a molecular basis of protein-protein interaction between TFIIS and Pol II. However, the detailed dynamic conformational changes of TFIIS upon binding to Pol II and the related thermodynamic information are largely unknown. Here we use computational approaches to investigate the conformational space of TFIIS in the Pol II-bound and Pol II-free (unbound) states. Our results reveal two distinct conformations of TFIIS: the closed and the open forms. The closed form is dominant in the Pol II-free (unbound) state of TFIIS, whereas the open form is favorable in the Pol II-bound state. Furthermore, we discuss the free energy difference involved in the conformational changes between the two forms in the presence or absence of Pol II. Additionally, our analysis indicates that hydrophobic interactions and the protein-protein interactions between TFIIS and Pol II are crucial for inducing the conformational changes of TFIIS. Our results provide novel insights into the functional interplay between Pol II and TFIIS as well as mechanism of reactivation of Pol II transcription by TFIIS.
Vesicle transport is a central process to ensure protein and lipid distribution in eukaryotic cells. The current knowledge on the molecular components and mechanisms of this process is majorly based on studies in Saccharomyces cerevisiae and Arabidopsis thaliana, which revealed 240 different proteinaceous factors either experimentally proven or predicted to be involved in vesicle transport. In here, we performed an orthologue search using two different algorithms to identify the components of the secretory pathway in yeast and 14 plant genomes by using the ‘core-set’ of 240 factors as bait. We identified 4021 orthologues and (co-)orthologues in the discussed plant species accounting for components of COP-II, COP-I, Clathrin Coated Vesicles, Retromers and ESCRTs, Rab GTPases, Tethering factors and SNAREs. In plants, we observed a significantly higher number of (co-)orthologues than yeast, while only 8 tethering factors from yeast seem to be absent in the analyzed plant genomes. To link the identified (co-)orthologues to vesicle transport, the domain architecture of the proteins from yeast, genetic model plant A. thaliana and agriculturally relevant crop Solanum lycopersicum has been inspected. For the orthologous groups containing (co-)orthologues from yeast, A. thaliana and S. lycopersicum, we observed the same domain architecture for 79% (416/527) of the (co-)orthologues, which documents a very high conservation of this process. Further, publically available tissue-specific expression profiles for a subset of (co-)orthologues found in A. thaliana and S. lycopersicum suggest that some (co-)orthologues are involved in tissue-specific functions. Inspection of localization of the (co-)orthologues based on available proteome data or localization predictions lead to the assignment of plastid- as well as mitochondrial localized (co-)orthologues of vesicle transport factors and the relevance of this is discussed.
HIV neutralizing antibodies (nAbs) represent an important tool in view of prophylactic and therapeutic applications for HIV-1 infection. Patients chronically infected by HIV-1 represent a valuable source for nAbs. HIV controllers, including long-term non-progressors (LTNP) and elite controllers (EC), represent an interesting subgroup in this regard, as here nAbs can develop over time in a rather healthy immune system and in the absence of any therapeutic selection pressure. In this study, we characterized two particular antibodies that were selected as scFv antibody fragments from a phage immune library generated from an LTNP with HIV neutralizing antibodies in his plasma. The phage library was screened on recombinant soluble gp140 envelope (Env) proteins. Sequencing the selected peptide inserts revealed two major classes of antibody sequences. Binding analysis of the corresponding scFv-Fc derivatives to various trimeric and monomeric Env constructs as well as to peptide arrays showed that one class, represented by monoclonal antibody (mAb) A2, specifically recognizes an epitope localized in the pocket binding domain of the C heptad repeat (CHR) in the ectodomain of gp41, but only in the trimeric context. Thus, this antibody represents an interesting tool for trimer identification. MAb A7, representing the second class, binds to structural elements of the third variable loop V3 and neutralizes tier 1 and tier 2 HIV-1 isolates of different subtypes with matching critical amino acids in the linear epitope sequence. In conclusion, HIV controllers are a valuable source for the selection of functionally interesting antibodies that can be selected on soluble gp140 proteins with properties from the native envelope spike.
The comeback of the Eurasian beaver (Castor fiber) throughout western and central Europe is considered a major conservation success. Traditionally, several subspecies are recognised by morphology and mitochondrial haplotype, each linked to a relict population. During various reintroduction programs in the 20th century, beavers from multiple source localities were released and now form viable populations. These programs differed in their reintroduction strategies, i.e., using pure subspecies vs. mixed source populations. This inhomogeneity in management actions generated ongoing debates regarding the origin of present beaver populations and appropriate management plans for the future. By sequencing of the mitochondrial control region and microsatellite genotyping of 235 beaver individuals from five selected regions in Germany, Switzerland, Luxembourg, and Belgium we show that beavers from at least four source origins currently form admixed, genetically diverse populations that spread across the study region. While regional occurrences of invasive North American beavers (n = 20) were found, all but one C. fiber bore the mitochondrial haplotype of the autochthonous western Evolutionary Significant Unit (ESU). Considering this, as well as the viability of admixed populations and the fact that the fusion of different lineages is already progressing in all studied regions, we argue that admixture between different beaver source populations should be generally accepted.
During the SHIVA (Stratospheric Ozone: Halogen Impacts in a Varying Atmosphere) project an extensive dataset of all halogen species relevant for the atmospheric budget of total organic bromine has been collected in the West Pacific region using the FALCON aircraft operated by the German Aerospace agency DLR (Deutsches Zentrum für Luft- und Raumfahrt) covering a vertical range from the planetary boundary layer up to the ceiling altitude of the aircraft of 13 km. In total, more than 700 measurements were performed with the newly developed fully-automated in-situ instrument GHOST-MS (Gas cHromatograph for the Observation of Tracers – coupled with a Mass Spectrometer) by the Goethe University of Frankfurt (GUF) and with the onboard whole-air sampler WASP with subsequent ground based state-of-the-art GC/MS analysis by the University of East Anglia (UEA). Both instruments yield good agreement for all major (CHBr3 and CH2Br2) and minor (CHBrCl, CHBrCl2 and CHBr2Cl) VSLS (very short-lived substances), at least at the level of their 2 σ measurement uncertainties. In contrast to the suggestion that the Western Pacific could be a major source region for VSLS (Pyle et al., 2011), we found only slightly enhanced mixing ratios of brominated halogen source gases relative to the levels reported in Montzka et al. (2011) for other tropical regions. A budget for total organic bromine, including all four halons,CH3Br and the VSLS, is derived for the upper troposphere, the input region for the TTL and thus also for the stratosphere, compiled from the SHIVA dataset. With exception of the two minor VSLS CHBrCl2 and CHBr2Cl, excellent agreement with the values reported in Montzka et al. (2011) is found, while being slightly higher than previous studies from our group based on balloon-borne measurements.
Background: With increasing life expectancy the number of people affected by multimorbidity rises. Knowledge of factors associated with health-related quality of life in multimorbid people is scarce. We aimed to identify the factors that are associated with self-rated health (SRH) in aged multimorbid primary care patients.
Methods: Cross-sectional study with 3,189 multimorbid primary care patients aged from 65 to 85 years recruited in 158 general practices in 8 study centers in Germany. Information about morbidity, risk factors, resources, functional status and socio-economic data were collected in face-to-face interviews. Factors associated with SRH were identified by multivariable regression analyses.
Results: Depression, somatization, pain, limitations of instrumental activities (iADL), age, distress and Body Mass Index (BMI) were inversely related with SRH. Higher levels of physical activity, income and self-efficacy expectation had a positive association with SRH. The only chronic diseases remaining in the final model were Parkinson's disease and neuropathies. The final model accounted for 35% variance of SRH. Separate analyses for men and women detected some similarities; however, gender specific variation existed for several factors.
Conclusion: In multimorbid patients symptoms and consequences of diseases such as pain and activity limitations, as well as depression, seem to be far stronger associated with SRH than the diseases themselves. High income and self-efficacy expectation are independently associated with better SRH and high BMI and age with low SRH.
A 48 year old patient with dilated cardiomyopathy and chronic acne inversa underwent implantation of a LVAD system (Heartmate II, Thoratec, USA) March 2011. During 2011 and 2012 the patient was repeatedly readmitted for treatment of driveline infection with MRSA. Colonization was controlled with Linezolid and Rifampicin however reoccurred after discontinuation. In August 2012 the LVAD-system was exchanged due to pump dysfunction (HVAD, HeartWare Inc., USA). Postoperatively, the patient presented with ascites which secreted through the driveline exit. Consequently, the abdominal wall was surgically corrected to prevent exit of peritoneal fluid through the driveline, and the patient was discharged with sterile wound swabs. However 6 weeks after discharge the driveline exit wound started secreting pus showing abundant growth of multi resistant staphylococcus aureus (MRSA). With clinical signs of increasing liver failure with regular need for paracentesis, and clinical signs of local infection, a CT scan of the abdomen was performed revealing an enrichment of contrast medium along the driveline and an abscess-like formation on the abdominal wall. Patient was admitted receiving regular dose Daptomycin and Rifampicin. The latter was discontinued after ten days. The abscess, surrounding driveline exit and abdominal wall cavity was excised and vacuum treatment initiated. Total duration of Daptomycin therapy was 3 weeks. While first week skin and wound swabs were still positive for MRSA, all samples were sterile after the second week. Inflammation was monitored by leucocyte count and IL6. The secretion of pus along the driveline ceased, the wound cavity was closed subsequently. After discharge and stop of antibiotics skin and driveline swabs remained negative for MRSA (10 weeks).
Mechanics has an important role during morphogenesis, both in the generation of forces driving cell shape changes and in determining the effective material properties of cells and tissues. Drosophila dorsal closure has emerged as a reference model system for investigating the interplay between tissue mechanics and cellular activity. During dorsal closure, the amnioserosa generates one of the major forces that drive closure through the apical contraction of its constituent cells. We combined quantitation of live data, genetic and mechanical perturbation and cell biology, to investigate how mechanical properties and contraction rate emerge from cytoskeletal activity. We found that a decrease in Myosin phosphorylation induces a fluidization of amnioserosa cells which become more compliant. Conversely, an increase in Myosin phosphorylation and an increase in actin linear polymerization induce a solidification of cells. Contrary to expectation, these two perturbations have an opposite effect on the strain rate of cells during DC. While an increase in actin polymerization increases the contraction rate of amnioserosa cells, an increase in Myosin phosphorylation gives rise to cells that contract very slowly. The quantification of how the perturbation induced by laser ablation decays throughout the tissue revealed that the tissue in these two mutant backgrounds reacts very differently. We suggest that the differences in the strain rate of cells in situations where Myosin activity or actin polymerization is increased arise from changes in how the contractile forces are transmitted and coordinated across the tissue through ECadherin-mediated adhesion. Altogether, our results show that there is an optimal level of Myosin activity to generate efficient contraction and suggest that the architecture of the actin cytoskeleton and the dynamics of adhesion complexes are important parameters for the emergence of coordinated activity throughout the tissue.
The mitochondrial kinase PINK1 and the ubiquitin ligase Parkin are participating in quality control after CCCP- or ROSinduced mitochondrial damage, and their dysfunction is associated with the development and progression of Parkinson’s disease. Furthermore, PINK1 expression is also induced by starvation indicating an additional role for PINK1 in stress response. Therefore, the effects of PINK1 deficiency on the autophago-lysosomal pathway during stress were investigated. Under trophic deprivation SH-SY5Y cells with stable PINK1 knockdown showed downregulation of key autophagic genes, including Beclin, LC3 and LAMP-2. In good agreement, protein levels of LC3-II and LAMP-2 but not of LAMP-1 were reduced in different cell model systems with PINK1 knockdown or knockout after addition of different stressors. This downregulation of autophagic factors caused increased apoptosis, which could be rescued by overexpression of LC3 or PINK1. Taken together, the PINK1-mediated reduction of autophagic key factors during stress resulted in increased cell death, thus defining an additional pathway that could contribute to the progression of Parkinson’s disease in patients with PINK1 mutations.
Consequences of a human TRPA1 genetic variant on the perception of nociceptive and olfactory stimuli
(2014)
Background: TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity.
Methods: Olfactory function and nociception was compared between carriers (n = 38) and non-carriers (n = 43) of TRPA1 variant rs11988795 G.A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2).
Results: Among the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2) were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049). Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.161.5 versus 12.361.6 correct discriminations) and indicated a higher intensity of the H2S stimuli (29.2613.2 versus 21612.8 mm VAS, p = 0.006), which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced.
Conclusions: The findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants.
Background: Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown.
Methods: Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells.
Results: Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load.
Conclusions: PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.
It was long assumed that translation initiation in prokaryotes generally occurs via the so-called Shine Dalgarno (SD) mechanism. Recently, it became clear that translation initiation in prokaryotes is more heterogeneous. In the haloarchaeon Haloferax volcanii, the majority of transcripts is leaderless and most transcripts with a 5′-UTR lack a SD motif. Nevertheless, a bioinformatic analysis predicted that 20–30% of all genes are preceded by a SD motif in haloarchaea. To analyze the importance of the SD mechanism for translation initiation in haloarchaea experimentally the monocistronic sod gene was chosen, which contains a 5′-UTR with an extensive SD motif of seven nucleotides and a length of 19 nt, the average length of 5′UTRs in this organism. A translational fusion of part of the sod gene with the dhfr reporter gene was constructed. A mutant series was generated that matched the SD motif from zero to eight positions, respectively. Surprisingly, there was no correlation between the base pairing ability between transcripts and 16S rRNA and translational efficiency in vivo under several different growth conditions. Furthermore, complete replacement of the SD motif by three unrelated sequences did not reduce translational efficiency. The results indicate that H. volcanii does not make use of the SD mechanism for translation initiation in 5′-UTRs. A genome analysis revealed that while the number of SD motifs in 5′-UTRs is rare, their fraction within open reading frames is high. Possible biological functions for intragenic SD motifs are discussed, including re-initiation of translation at distal genes in operons.