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West African Savanna ecosystems are undergoing severe changes in their vegetation composition due to the impact of human land use and changes in climatic conditions. This study aims to examine the effect of climate, land use, and their interaction on species richness and composition of West African herbaceous vegetation. Plot based vegetation sampling was done in Burkina Faso. Specific richness and diversity indices were used to determine the effect of land use, climate, and their interaction. An importance value was computed to determine herbaceous species dominating the communities. Frequency of species is used to examine their distribution pattern. The results showed that climate significantly influenced herbaceous specific richness more than land use. However, land use had a significant effect on herbaceous vegetation composition. Herbaceous species diversity changed with environmental conditions. The floristic composition of dominant species is driven by both climate and land use. The frequency of distribution demonstrated that herbaceous species occurrences were more influenced by the mixed effect of climate and land use than their separate effects. Occasional and rare species are the most important part of herbaceous vegetation. Thus heterogeneity of Savanna ecosystem and vulnerability of herbaceous species are high.
The paper titled "Cure of Chronic Viral Infection and Virus-Induced Type 1 Diabetes by Neutralizing Antibodies" has been retracted as it was found that the paper was unintentionally published twice by the journal’s former publisher. The version of record of this paper is available at http://dx.doi.org/10.1080/17402520600800721.
Evading innate immunity is a prerequisite for pathogenic microorganisms in order to survive in their respective hosts. Concerning Lyme disease spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato group, a broad range of diverse vertebrates serve as reservoir or even as incidental hosts, including humans. The capability to infect multiple hosts implies that spirochetes have developed sophisticated means to counter the destructive effects of complement of humans and various animals. While the means by which spirochetes overcome the hosts immune defense are far from being completely understood, there is a growing body of evidence suggesting that binding of the key regulator of the alternative pathway, Factor H, plays a pivotal role for immune evasion and that Factor H is an important determinant of host specificity. This review covers (i) the contribution of complement in host-specificity and transmissibility of Lyme disease spirochetes; (ii) the involvement of borrelial-derived determinants to host specificity; (iii) the interplay of human and animal Factor H with complement-acquiring surface proteins of diverse borrelial species; and (iv) the potential role of additional animal complement proteins in the immune evasion of spirochetes.
Background: This study evaluated the effects of a combined innovative training regime consisting of stochastic resonance whole-body vibration (SR-WBV) and a dance video game (DVG) on physical performance and muscle strength in long-term-care dwelling elderly.
Methods: Thirthy long-term-care elderly were randomly allocated to an intervention group (IG; n = 16) receiving combined SR-WBV training and DVG, or a sham group (SG; n = 14). IG performed five sets one minute of SR-WBV, with one minute rest between sets (base frequency 3 Hz up to 6 Hz, Noise 4) during the first five weeks on three days per week. From week five to eight a DVG was added to SR-WBV for IG on three days per week. SG performed a five-set SR-WBV program (1 Hz, Noise 1) lasting five times one minute, with one minute rest in between, three days a week. From week five to eight stepping exercises on a trampoline were added on three days per week. Primary outcome: Short physical performance battery (SPPB). Secondary outcome: isometric maximal voluntary contraction (IMVC), and sub phases of IMVC (Fsub), isometric rate of force development (IRFD) and sub time phases of IRFD (IRFDsub) were measured at baseline, after four and eight weeks. ANOVA with repeated measures was used for analyses of time and interaction effects and MANOVA determined between group intervention effects.
Results: Between group effects revealed significant effects on the SPPB primary outcome after four weeks F(1, 27) = 6.17; p = 0.02) and after eight weeks F(1,27) = 11.8; p = 0.002). Secondary muscle function related outcome showed significant between group effects in IG on IRFD, Fsub 30 ms, 100 ms, 200 ms and IRFDsub 0-30 ms, 0-50 ms, 0-100 ms and 100-200 ms compared to SG (all p < 0.05).
Conclusions: Eight weeks SR-WBV and DVG intervention improved lower extremity physical function and muscle strength compared to a sham intervention in long-term-care elderly. SR-WBV and DVG seems to be effective as a training regime for skilling up in long-term-care elderly.
Interaction of gold nanoparticles (AuNPs) in the vicinity of cells’ membrane with a pulsed laser (λ = 532 nm, τ = 1 ns) leads to perforation of the cell membrane, thereby allowing extracellular molecules to diffuse into the cell. The objective of this study was to develop an experimental setting to deliver molecules into primary human gingival fibroblasts (pHFIB-G) by using ns-laser pulses interacting with AuNPs (study group). To compare the parameters required for manipulation of pHFIB-G with those needed for cell lines, a canine pleomorphic adenoma cell line (ZMTH3) was used (control group). Non-laser-treated cells incubated with AuNPs and the delivery molecules served as negative control. Laser irradiation (up to 35 mJ/cm2) resulted in a significant proportion of manipulated fibroblasts (up to 85%, compared to non-irradiated cells: p < 0.05), while cell viability (97%) was not reduced significantly. pHFIB-G were perforated as efficiently as ZMTH3. No significant decrease of metabolic cell activity was observed up to 72 h after laser treatment. The fibroblasts took up dextrans with molecular weights up to 500 kDa. Interaction of AuNPs and a pulsed laser beam yields a spatially selective technique for manipulation of even primary cells such as pHFIB-G in high throughput.
The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC‐induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X‐linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B‐cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event‐free survival in patients treated with spindle poison‐containing chemotherapy. Accordingly, aggressive B‐cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ‐Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B‐cell lymphoma.
The excellent results of dispersion‐corrected density functional theory (DFT‐D) calculations for static systems have been well established over the past decade. The introduction of dynamics into DFT‐D calculations is a target, especially for the field of molecular NMR crystallography. Four 13C ss‐NMR calibration compounds are investigated by single‐crystal X‐ray diffraction, molecular dynamics and DFT‐D calculations. The crystal structure of 3‐methylglutaric acid is reported. The rotator phases of adamantane and hexamethylbenzene at room temperature are successfully reproduced in the molecular dynamics simulations. The calculated 13C chemical shifts of these compounds are in excellent agreement with experiment, with a root‐mean‐square deviation of 2.0 ppm. It is confirmed that a combination of classical molecular dynamics and DFT‐D chemical shift calculation improves the accuracy of calculated chemical shifts.
Background: Neurotoxic envenomation following bites by kraits (Bungarus species) is a leading cause of snakebite mortality in South Asia. Over a long time, this had been attributed only to one species, the common krait (Bungarus caeruleus). However, recent research has provided increasing evidence of the involvement of several krait species. Here, we report a fatal case of neurotoxic envenomation following the bite of a greater black krait (Bungarus niger) in Nepal.
Case presentation: A 33-year-old man was bitten in the outdoor corridor of his home in the eastern hills of Ilam district while handling a snake he thought to be non-venomous. He subsequently developed severe abdominal pain, frequent vomiting, and signs of neurotoxic envenomation leading to respiratory paralysis. The patient did not respond to Indian polyvalent antivenom given 4 h after the bite and died under treatment 8 h after the bite. This is the second time that a B. niger was observed in Nepal, the first documented case of envenomation by this species in the country and the sixth reported case worldwide.
Conclusions: Previous distribution records – from eastern India and western Nepal, from western hills in Nepal, and from lowland localities in India and Bangladesh – indicate risk of envenomation by B. niger throughout the low and intermediate elevations of Nepal up to at least 1,500 m above sea level. As very few people in Nepal bring killed snakes to healthcare centers and because there is a general belief among local people that there are no kraits in the hills, bites by B. niger are likely to be misdiagnosed and underreported.
Altitude training and respiratory muscle training (RMT) have been reported to improve performance in elite and well-trained athletes. Several devices (altitude and RMT) have been developed to help athletes gain the competitive edge. The Elevation Training Mask 2.0 (ETM) purportedly simulates altitude training and has been suggested to increase aerobic capacity (VO2max), endurance performance, and lung function. Twenty-four moderately trained subjects completed 6 weeks of high-intensity cycle ergometer training. Subjects were randomized into a mask (n = 12) or control (n = 12) group. Pre and post-training tests included VO2max, pulmonary function, maximal inspiration pressure, hemoglobin and hematocrit. No significant differences were found in pulmonary function or hematological variables between or within groups. There was a significant improvement in VO2max and PPO in both the control (13.5% and 9.9%) and mask (16.5% and 13.6%) groups. There was no difference in the magnitude of improvement between groups. Only the mask group had significant improvements in ventilatory threshold (VT) (13.9%), power output (PO) at VT (19.3%), respiratory compensation threshold (RCT) (10.2%), and PO at RCT (16.4%) from pre to post-testing. The trends for improvements in VT and PO at VT between groups were similar to improvements in RCT and PO at RCT, but did not reach statistical significance (VT p = 0.06, PO at VT p = 0.170). Wearing the ETM while participating in a 6-week high-intensity cycle ergometer training program does not appear to act as a simulator of altitude, but more like a respiratory muscle training device. Wearing the ETM may improve specific markers of endurance performance beyond the improvements seen with interval training alone.
Background: Multidrug-resistant Gram-negative bacteria (MRGN) and the infections they cause are a serious threat and a challenge to the healthcare system. This particularly applies to carbapenem-resistant Gram-negative bacteria (CRGN). Currently, the introduction of a nationwide mandatory notification system for CRGN in Germany is under consideration. Against this background, this paper presents an analysis of the mandatory reporting system for CRGN in effect since November 2011 in the federal state of Hesse (Germany).
Materials and methods: All carbapenem-resistant Gram-negative bacteria and the detected carbapenemases reported to the public health department of the city of Frankfurt am Main, Hesse, Germany, on the basis of the mandatory notification system were analyzed.
Results: 827 CRGN cases were reported to the public health department of Frankfurt/Main between April 2012 and December 2015. The following bacterial species were reported: Pseudomonas spp. (n=268), Acinetobacter spp. (n=183), Klebsiella spp. (n=195), Enterobacter spp. (n=77), Escherichia coli (n=75) and others (n=29). Between 2012 and 2015, a reduction of the CRGN reports was noticed, mainly due to changes in the reporting of Pseudomonas spp. Between 2012 and 2015, the total number of notifications decreased slightly, although the number of reported CRGN in screening samples increased, thus giving no indication of a decreased testing frequency. For 10.5% of the patients, the place of residence was not Germany, 18.0% of the patients had previously stayed in hospitals abroad, often in countries with a high CRGN prevalence. CRGN bacteria were reported from all of Frankfurt’s hospitals, and 3.9% were reported from out-patient care facilities. Carbapenemases were detected and reported in 251 CRGN bacteria, including 73 OXA-48, 76 OXA-23, 56 NDM subtypes, and 21 KPC subtypes. There have been no major epidemiological signs of outbreak scenarios.
Discussion: CRGN bacteria are already widespread in patients from hospitals and out-patient care facilities. Clearly, infection control measurements should therefore not only include hospital patients but also those receiving out-patient care. Screening strategies focused on patients from foreign countries with high MRGN prevalence is not sufficient, as only 10.5% of MRGN patients resided in those countries, and only 18% of the patients had been previously treated in a foreign hospital. In a public health context, infection control measures should therefore encompass broader screening strategies.
Live-cell labelling techniques to visualize proteins with minimal disturbance are important; however, the currently available methods are limited in their labelling efficiency, specificity and cell permeability. We describe high-throughput protein labelling facilitated by minimalistic probes delivered to mammalian cells by microfluidic cell squeezing. High-affinity and target-specific tracing of proteins in various subcellular compartments is demonstrated, culminating in photoinduced labelling within live cells. Both the fine-tuned delivery of subnanomolar concentrations and the minimal size of the probe allow for live-cell super-resolution imaging with very low background and nanometre precision. This method is fast in probe delivery (∼1,000,000 cells per second), versatile across cell types and can be readily transferred to a multitude of proteins. Moreover, the technique succeeds in combination with well-established methods to gain multiplexed labelling and has demonstrated potential to precisely trace target proteins, in live mammalian cells, by super-resolution microscopy.
Background: Resistance to temozolomide (TMZ) greatly limits chemotherapeutic effectiveness in glioblastoma (GBM). Here we analysed the ability of the Inhibitor-of-apoptosis-protein (IAP) antagonist birinapant to enhance treatment responses to TMZ in both commercially available and patient-derived GBM cells.
Methods: Responses to TMZ and birinapant were analysed in a panel of commercial and patient-derived GBM cell lines using colorimetric viability assays, flow cytometry, morphological analysis and protein expression profiling of pro- and antiapoptotic proteins. Responses in vivo were analysed in an orthotopic xenograft GBM model.
Results: Single-agent treatment experiments categorised GBM cells into TMZ-sensitive cells, birinapant-sensitive cells, and cells that were insensitive to either treatment. Combination treatment allowed sensitisation to therapy in only a subset of resistant GBM cells. Cell death analysis identified three principal response patterns: Type A cells that readily activated caspase-8 and cell death in response to TMZ while addition of birinapant further sensitised the cells to TMZ-induced cell death; Type B cells that readily activated caspase-8 and cell death in response to birinapant but did not show further sensitisation with TMZ; and Type C cells that showed no significant cell death or moderately enhanced cell death in the combined treatment paradigm. Furthermore, in vivo, a Type C patient-derived cell line that was TMZ-insensitive in vitro and showed a strong sensitivity to TMZ and TMZ plus birinapant treatments.
Conclusions: Our results demonstrate remarkable differences in responses of patient-derived GBM cells to birinapant single and combination treatments, and suggest that therapeutic responses in vivo may be greatly affected by the tumour microenvironment.
Retrograde transport of NF-κB from the synapse to the nucleus in neurons is mediated by the dynein/dynactin motor complex and can be triggered by synaptic activation. The caliber of axons is highly variable ranging down to 100 nm, aggravating the investigation of transport processes in neurites of living neurons using conventional light microscopy. We quantified for the first time the transport of the NF-κB subunit p65 using high-density single-particle tracking in combination with photoactivatable fluorescent proteins in living mouse hippocampal neurons. We detected an increase of the mean diffusion coefficient (Dmean) in neurites from 0.12±0.05 to 0.61±0.03 μm2/s after stimulation with glutamate. We further observed that the relative amount of retrogradely transported p65 molecules is increased after stimulation. Glutamate treatment resulted in an increase of the mean retrograde velocity from 10.9±1.9 to 15±4.9 μm/s, whereas a velocity increase from 9±1.3 to 14±3 μm/s was observed for anterogradely transported p65. This study demonstrates for the first time that glutamate stimulation leads to an increased mobility of single NF-κB p65 molecules in neurites of living hippocampal neurons.
About half of present-day cloud condensation nuclei originate from atmospheric nucleation, frequently appearing as a burst of new particles near midday1. Atmospheric observations show that the growth rate of new particles often accelerates when the diameter of the particles is between one and ten nanometres2,3. In this critical size range, new particles are most likely to be lost by coagulation with pre-existing particles4, thereby failing to form new cloud condensation nuclei that are typically 50 to 100 nanometres across. Sulfuric acid vapour is often involved in nucleation but is too scarce to explain most subsequent growth5,6, leaving organic vapours as the most plausible alternative, at least in the planetary boundary layer7,8,9,10. Although recent studies11,12,13 predict that low-volatility organic vapours contribute during initial growth, direct evidence has been lacking. The accelerating growth may result from increased photolytic production of condensable organic species in the afternoon2, and the presence of a possible Kelvin (curvature) effect, which inhibits organic vapour condensation on the smallest particles (the nano-Köhler theory)2,14, has so far remained ambiguous. Here we present experiments performed in a large chamber under atmospheric conditions that investigate the role of organic vapours in the initial growth of nucleated organic particles in the absence of inorganic acids and bases such as sulfuric acid or ammonia and amines, respectively. Using data from the same set of experiments, it has been shown15 that organic vapours alone can drive nucleation. We focus on the growth of nucleated particles and find that the organic vapours that drive initial growth have extremely low volatilities (saturation concentration less than 10−4.5 micrograms per cubic metre). As the particles increase in size and the Kelvin barrier falls, subsequent growth is primarily due to more abundant organic vapours of slightly higher volatility (saturation concentrations of 10−4.5 to 10−0.5 micrograms per cubic metre). We present a particle growth model that quantitatively reproduces our measurements. Furthermore, we implement a parameterization of the first steps of growth in a global aerosol model and find that concentrations of atmospheric cloud concentration nuclei can change substantially in response, that is, by up to 50 per cent in comparison with previously assumed growth rate parameterizations.
Multidrug-resistant Gram-negative bacteria (MDR GNB) were found to colonise 60.8% (95% confidence interval: 52.3–68.9) of 143 refugee patients mainly from Syria (47), Afghanistan (29), and Somalia (14) admitted to the University Hospital Frankfurt, Germany, between June and December 2015. This percentage exceeds the prevalence of MDR GNB in resident patients four–fold. Healthcare personnel should be aware of this and the need to implement or adapt adequate infection control measures.
Repetitive transcranial magnetic stimulation (rTMS) is used as a therapeutic tool in neurology and psychiatry. While repetitive magnetic stimulation (rMS) has been shown to induce plasticity of excitatory synapses, it is unclear whether rMS can also modify structural and functional properties of inhibitory inputs. Here we employed 10-Hz rMS of entorhinohippocampal slice cultures to study plasticity of inhibitory neurotransmission on CA1 pyramidal neurons. Our experiments reveal a rMS-induced reduction in GABAergic synaptic strength (2–4 h after stimulation), which is Ca2+-dependent and accompanied by the remodelling of postsynaptic gephyrin scaffolds. Furthermore, we present evidence that 10-Hz rMS predominantly acts on dendritic, but not somatic inhibition. Consistent with this finding, a reduction in clustered gephyrin is detected in CA1 stratum radiatum of rTMS-treated anaesthetized mice. These results disclose that rTMS induces coordinated Ca2+-dependent structural and functional changes of specific inhibitory postsynapses on principal neurons.
Background: Guidelines for the control of hospital-acquired MRSA include decolonization measures to end MRSA carrier status in colonized and infected patients. Successful decolonization typically requires up to 22 days of treatment, which is longer than the average hospital length of stay (LOS). Incomplete decolonization is therefore common, with long-term MRSA carriage as a consequence. To overcome this, we developed an integrated MRSA Management (IMM) by extending MRSA decolonization to the outpatient and domestic setting. The protocol makes use of polyhexanide-based products, in view of reported qac-mediated resistance to chlorhexidine in S. aureus and MRSA.
Methods: This is a prospective, single centre, controlled, non-randomized, open-label study to evaluate the efficiency of the IMM concept. The outcome of guideline-approved decolonization during hospital stay only (control group; n = 201) was compared to the outcome following IMM treatment whereby decolonization was continued after discharge in the domestic setting or in a long-term care facility (study group; n = 99). As a secondary outcome, the effect of MRSA-status of skin alterations was assessed.
Results: The overall decolonization rate was 47 % in the IMM patient group compared to 12 % in the control group (p < 0.01). The continued treatment after hospital discharge was as effective as treatment completed during hospitalization, with microbiologically-confirmed decolonization (patients with completed regimes only) obtained with 55 % for the IMM group and 43 % for the control group (p > 0.05). For patients with skin alterations (e.g. wounds and entry sites), decolonization success was 50 % if the skin alterations were MRSA-negative at baseline, compared to 22 % success for patients entering the study with MRSA-positive skin alterations (p < 0.01).
Conclusions: The IMM strategy offers an MRSA decolonization protocol that is feasible in the domestic setting and is equally effective compared with inpatient decolonization treatment when hospital LOS is long enough to complete the treatment. Moreover, for patients with average LOS, decolonization rates obtained with IMM are significantly higher than for in-hospital treatment. IMM is a promising concept to improve decolonization rates of MRSA-carriers for patients who leave the hospital before decolonization is completed.
Acute calculus cholecystitis is a very common disease with several area of uncertainty. The World Society of Emergency Surgery developed extensive guidelines in order to cover grey areas. The diagnostic criteria, the antimicrobial therapy, the evaluation of associated common bile duct stones, the identification of “high risk” patients, the surgical timing, the type of surgery, and the alternatives to surgery are discussed. Moreover the algorithm is proposed: as soon as diagnosis is made and after the evaluation of choledocholitiasis risk, laparoscopic cholecystectomy should be offered to all patients exception of those with high risk of morbidity or mortality. These Guidelines must be considered as an adjunctive tool for decision but they are not substitute of the clinical judgement for the individual patient.
The production of K∗(892)0 and ϕ(1020) mesons has been measured in p–Pb collisions at √sNN = 5.02 TeV. K∗0 and ϕ are reconstructed via their decay into charged hadrons with the ALICE detector in the rapidity range - 0.5 < y < 0. The transverse momentum spectra, measured as a function of the multiplicity, have a pT range from 0 to 15 GeV/c for K∗0 and from 0.3 to 21 GeV/c for ϕ. Integrated yields, mean transverse momenta and particle ratios are reported and compared with results in pp collisions at √s = 7 TeV and Pb–Pb collisions at √sNN = 2.76 TeV. In Pb–Pb and p–Pb collisions, K∗0 and ϕ probe the hadronic phase of the system and contribute to the study of particle formation mechanisms by comparison with other identified hadrons. For this purpose, the mean transverse momenta and the differential proton-to-ϕ ratio are discussed as a function of the multiplicity of the event. The short-lived K∗0 is measured to investigate re-scattering effects, believed to be related to the size of the system and to the lifetime of the hadronic phase.
The essay, originally written in German as an introduction to a volume of collected papers, shows the influence of the Historical School of Law on legal, historical and social sciences in Germany throughout the 19th and even 20th centuries – a time span running contrary to the dominate view that sees the end of the School in the middle of the 19th century. In my view the School constitutes not only a method for developing norms of private law out of the historical materials of Roman and German-Germanic laws, but is based on a wider conception of culture, law and history that is also connected to the political positions of that time. In Savigny’s founding pamphlet, "The vocation of our time ...", two major theoretical topics for this long-lasting influence can be found: The Romantic one, which views law as a part of culture and parallel to language and custom, based on the "spirit of the people", and, on the other side, the rationality of the European tradition of Roman law, which was developed and administered by jurists. These two basic points, in part standing in contradiction to one another, form a fertile tension that provides an impulse to the intellectual discussions and new movements in jurisprudence and history analysed in the text. Realism, founded in the connection of both sciences to political and social life, builds a kind of "basso continuo" and acts as a counterbalance to the former two. And it is in this context that the works of Jacob Grimm, Puchta and Beseler, Heinrich Brunner, Georg von Below and others are analysed, in particular the works of Otto von Gierke and Max Weber. Finally, evidence is furnished that a new image of the medieval period, and its impact on law, as a centre of Western identity was outlined in the 20th century by authors like Ernst Kantorowicz, Fritz Kern, Otto Brunner and, last but not least, by Harold J. Berman (walking in the footsteps of Eugen Rosenstock- Huessy), all of whom were situated in different ways within the tradition of the broader, cultural-based Romantic view.
Relativistic hydrodynamics has been quite successful in explaining the collective behaviour of the QCD matter produced in high energy heavy-ion collisions at RHIC and LHC. We briefly eview the latest developments in the hydrodynamical modeling of relativistic heavy-ion collisions. Essential ingredients of the model such as the hydrodynamic evolution equations, dissipation, initial conditions, equation of state, and freeze-out process are reviewed. We discuss observable quantities such as particle spectra and anisotropic flow and effect of viscosity on these observables. Recent developments such as event-by-event fluctuations, flow in small systems (proton-proton and proton-nucleus collisions), flow in ultracentral collisions, longitudinal fluctuations, and correlations and flow in intense magnetic field are also discussed.
The discovery of antibiotics represented a key milestone in the history of medicine. However, with the rise of these life-saving drugs came the awareness that bacteria deploy defense mechanisms to resist these antibiotics, and they are good at it. Today, we appear at a crossroads between discovery of new potent drugs and omni-resistant superbugs. Moreover, the misuse of antibiotics in different industries has increased the rate of resistance development by providing permanent selective pressure and, subsequently, enrichment of multidrug resistant pathogens. As a result, antimicrobial resistance has now become an urgent threat to public health worldwide (http:// www.who.int/drugresistance/documents/surveillancereport/en/). The development of multidrug resistance (MDR) in an increasing number of pathogens, including Pseudomonas, Acinetobacter, Klebsiella, Salmonella, Burkholderia, and other Gram-negative bacteria is a serious issue. Membrane efflux pump complexes of the Resistance-Nodulation-Division (RND) superfamily play a key role in the development of MDR in these bacteria. These pumps, together with other transporters, contribute to intrinsic and acquired resistance of bacteria toward most, if not all, of the compounds available in our antimicrobial arsenal. Given the enormous drug polyspecificity of MDR efflux pumps, studies on their mechanism of action are extremely challenging, and this has negatively impacted both on the development of new antibiotics that are able to evade these efflux pumps and on the design of pump inhibitors. The collection of articles in this eBook, published as a Research Topic in Frontiers in Microbiology, section of Antimicrobials, Resistance, and Chemotherapy, aims to update the reader about the latest advances on the structure and function of RND efflux transporters, their roles in the overall multidrug resistance phenotype of Gram-negative pathogens, and on the strategies to inhibit their activities. ...
Unique features of a global human ectoparasite identified through sequencing of the bed bug genome
(2016)
The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host–symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human–bed bug and symbiont–bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite.
Background: Use of blood oxygenation level-dependent cardiovascular magnetic resonance (BOLD-CMR) to assess perfusion in the lower limb has been hampered by poor reproducibility and a failure to reliably detect post-revascularization improvements in patients with critical limb ischemia (CLI).
Objectives: This study sought to develop BOLD-CMR as an objective, reliable clinical tool for measuring calf muscle perfusion in patients with CLI.
Methods: The calf was imaged at 3-T in young healthy control subjects (n = 12), age-matched control subjects (n = 10), and patients with CLI (n = 34). Signal intensity time curves were generated for each muscle group and curve parameters, including signal reduction during ischemia (SRi) and gradient during reactive hyperemia (Grad). BOLD-CMR was used to assess changes in perfusion following revascularization in 12 CLI patients. Muscle biopsies (n = 28), obtained at the level of BOLD-CMR measurement and from healthy proximal muscle of patients undergoing lower limb amputation (n = 3), were analyzed for capillary-fiber ratio.
Results: There was good interuser and interscan reproducibility for Grad and SRi (all p < 0.0001). The ischemic limb had lower Grad and SRi compared with the contralateral asymptomatic limb, age-matched control subjects, and young control subjects (p < 0.001 for all comparisons). Successful revascularization resulted in improvement in Grad (p < 0.0001) and SRi (p < 0.0005). There was a significant correlation between capillary-fiber ratio (p < 0.01) in muscle biopsies from amputated limbs and Grad measured pre-operatively at the corresponding level.
Conclusions: BOLD-CMR showed promise as a reliable tool for assessing perfusion in the lower limb musculature and merits further investigation in a clinical trial.
Acetaminophen (APAP, N-acetyl-p-aminophenol, or paracetamol) overdosing is a prevalent cause of acute liver injury. While clinical disease is initiated by overt parenchymal hepatocyte necrosis in response to the analgetic, course of intoxication is substantially influenced by associated activation of innate immunity. This process is supposed to be set in motion by release of danger-associated molecular patterns (DAMPs) from dying hepatocytes and is accompanied by an inflammatory cytokine response. Murine models of APAP-induced liver injury emphasize the complex role that DAMPs and cytokines play in promoting either hepatic pathogenesis or resolution and recovery from intoxication. Whereas the function of key inflammatory cytokines is controversially discussed, a subclass of specific cytokines capable of efficiently activating the hepatocyte signal transducer and activator of transcription (STAT)-3 pathway stands out as being consistently protective in murine models of APAP intoxication. Those include foremost interleukin (IL)-6, IL-11, IL-13, and IL-22. Above all, activation of STAT3 under the influence of these cytokines has the capability to drive hepatocyte compensatory proliferation, a key principle of the regenerating liver. Herein, the role of these specific cytokines during experimental APAP-induced liver injury is highlighted and discussed in a broader perspective. In hard-to-treat or at-risk patients, standard therapy may fail and APAP intoxication can proceed toward a fatal condition. Focused administration of recombinant STAT3-activating cytokines may evolve as novel therapeutic approach under those ill-fated conditions.
The growth of freshly formed aerosol particles can be the bottleneck in their survival to cloud condensation nuclei. It is therefore crucial to understand how particles grow in the atmosphere. Insufficient experimental data has impeded a profound understanding of nano-particle growth under atmospheric conditions. Here we study nano-particle growth in the CLOUD (Cosmics Leaving OUtdoors Droplets) chamber, starting from the formation of molecular clusters. We present measured growth rates at sub-3 nm sizes with different atmospherically relevant concentrations of sulphuric acid, water, ammonia and dimethylamine. We find that atmospheric ions and small acid-base clusters, which are not generally accounted for in the measurement of sulphuric acid vapour, can participate in the growth process, leading to enhanced growth rates. The availability of compounds capable of stabilizing sulphuric acid clusters governs the magnitude of these effects and thus the exact growth mechanism. We bring these observations into a coherent framework and discuss their significance in the atmosphere.
Gene targeting in embryonic stem (ES) cells remains best practice for introducing complex mutations into the mouse germline. One aspect in this multistep process that has not been streamlined with regard to the logistics and ethics of mouse breeding is the efficiency of germline transmission: the transmission of the ES cell-derived genome through the germline of chimeras to their offspring. A method whereby male chimeras transmit exclusively the genome of the injected ES cells to their offspring has been developed. The new technology, referred to as goGermline, entails injecting ES cells into blastocysts produced by superovulated homozygous Tsc22d3 floxed females mated with homozygous ROSA26-Cre males. This cross produces males that are sterile due to a complete cell-autonomous defect in spermatogenesis. The resulting male chimeras can be sterile but when fertile, they transmit the ES cell-derived genome to 100% of their offspring. The method was validated extensively and in two laboratories for gene-targeted ES clones that were derived from the commonly used parental ES cell lines Bruce4, E14, and JM8A3. The complete elimination of the collateral birth of undesired, non-ES cell-derived offspring in goGermline technology fulfills the reduction imperative of the 3R principle of humane experimental technique with animals. genesis 54:326-333, 2016. © 2016 The Authors. Genesis Published by Wiley Periodicals, Inc.
Efficient derivation of extraembryonic endoderm stem cell lines from mouse postimplantation embryos
(2016)
Various types of stem cell lines have been derived from preimplantation or postimplantation mouse embryos: embryonic stem cell lines, epiblast stem cell lines, and trophoblast stem cell lines. It is not known if extraembryonic endoderm stem (XEN) cell lines can be derived from postimplantation mouse embryos. Here, we report the derivation of 77 XEN cell lines from 85 postimplantation embryos at embryonic day E5.5 or E6.5, in parallel to the derivation of 41 XEN lines from 69 preimplantation embryos at the blastocyst stage. We attain a success rate of 100% of XEN cell line derivation with our E5.5 whole-embryo and E6.5 disaggregated-embryo methods. Immunofluorescence and NanoString gene expression analyses indicate that the XEN cell lines that we derived from postimplantation embryos (post-XEN) are very similar to the XEN cell lines that we derived from preimplantation embryos (pre-XEN) using a conventional method. After injection into blastocysts, post-XEN cells contribute to extraembryonic endoderm in chimeras at E6.5 and E7.5.
Background: Among cancer care providers (CCPs), lack of knowledge constitutes an important barrier to the discussion of complementary and alternative medicine (CAM) use with patients. This study assessed CCPs’ needs and preferences regarding CAM information and training (I&T).
Methods: An online survey was completed by 209 general practitioners, 437 medical specialists, 159 oncology nurses and medical assistants, and 244 psychologists and social workers engaged in cancer care. Latent class analysis (LCA) was used to identify subgroups of individuals with distinct preference patterns regarding I&T content.
Results: CCPs prefer CAM I&T to be provided as lectures, information platforms on the internet, workshops, and e-mail newsletters. Concerning subject matters, many CCPs considered CAM therapy options for the treatment of a variety of cancer disease- and therapy-related symptoms to be very important (75%-72% of the sample); the same applies to an "overview of different CAM therapies" (74%). LCA identified 5 latent classes (LCs) of CCPs. All of them attached considerable importance to "medical indication," "potential side effects," and "tips for usage." LCs differed, however, in terms of overall importance ratings, the perceived importance of "patients’ reasons" for using specific CAM therapies, "case examples," and "scientific evidence." Notably, the 5 LCs were clearly present in all 4 occupational groups.
Conclusions: CAM I&T should provide CCPs with an overview of different CAM therapies and show how CAM might help in treating symptoms cancer patients frequently demonstrate (eg, fatigue). Moreover, I&T programs should be flexible and take into account that individual information needs vary even within the same occupational group.
Smith (1968) argues that poems may end with formal changes which produce an experience of closure in the reader. I argue that formal changes do not directly cause an experience of closure. Instead, changes in poetic form always demand increased processing effort from the reader, whether they involve new forms, shifts from more to less regular form, or from less to more regular form. I use relevance theory (Sperber and Wilson 1995) to argue that the increased processing effort encourages the reader to formulate rich and relevant thoughts, including the thought "this poem has closure". Closure is thus the content of a thought rather than a type of experience. I further argue that "closure" is a term whose meaning cannot be fully understood, which makes the thought "this poem has closure" into a schematic belief of the kind which Sperber shows has great richness and productivity. This is one of the reasons that the thought "this poem has closure" achieves sufficient relevance to justify the effort put into processing the end of the poem.
The article addresses the question of who reports the dialogue in fictional texts featuring an unreliable narrator. Since no human being can remember and reproduce lengthy conversations accurately, some narrative theorists attribute direct speech representation to the author instead of the character narrator. This means that the speech of other characters may be reported reliably even if the narrator is totally unreliable. The narrator’s version of the events may then be contradicted by others, which allows the reader to perceive his biases. However, Kazuo Ishiguro’s An Artist of the Floating World illustrates the fact that direct speech reports, too, can be distorted by the narrator’s subjectivity, especially his emotions. In Ishiguro’s novel, the narrator’s grief and depression lead him to misremember and invent past conversations. Following Meir Sternberg, the article argues that the reliability of speech reporting in unreliable narration must be determined on a case-by-case basis. The text must signal that the narrator’s speech reporting is unreliable. In the absence of a signal, the reader is supposed to disregard any deviations from verbatim reproduction and to accept the transgression of the limits of human memory.
This article approaches literary translation from a contact-linguistic perspective and views translation as a language contact situation in which the translator "moves" between the source and target language. The study touches upon the possible linguistic effects of the source text on the translated text and relates the translation-mediated cross-linguistic influence to other language-contact situations. The study investigates the use of Finnish passive in a corpus of literary texts consisting of Finnish translations from Estonian and German and comparable non-translated Finnish literary texts. The translated texts are compared with non-translated ones by using corpus-linguistic tools, and the results are related to a previous contact-linguistic study on the use of the Finnish passive in spoken interviews of Finnish migrants in Estonia. The main objective is to test methodological tools that could be used for this kind of comparative purposes.
In addition, the study approaches the question whether translation as a type of language contact affects the use of the Finnish passive in a similar way as an oral language contact situation. All in all, the study shows that there are some features that differentiate the investigated literary translations from non-translated Finnish texts but the evidence is not unambiguous. The article discusses the possible reasons for the mainly non-conclusive results of the analysis and points out factors that should be taken into account in future studies, such as the size of the sub-corpora and the possibly biased text or genre specific stylistic characteristics. The methodology clearly has to be adjusted and more in-depth methods developed in order to acquire a fuller picture of the Finnish passive in literary texts and to confirm what is author, translator, genre or source-language specific in the use of the Finnish passive.
This article analyzes the representation of linguistic variation in the Finnish translations of four Swedish coming-of-age stories depicting migrant or minority perspectives: Mikael Niemi’s 2000 Popular Music from Vittula, Jonas Hassen Khemiri’s 2003 Ett öga rött, Marjaneh Bakhtiari’s 2005 Kalla det vad fan du vill, and Susanna Alakoski’s 2006 Svinalängorna. Through an analysis of speech and thought representation techniques and focalization, the article explores the role played by literature and translation in the materialization of dialects and sociolects as bounded entities. The paper argues that linguistic and social hybridity, on which the reception of minority and migrant literatures often focuses, is accompanied by the reification of new varieties conceived as authentic expressions of migrant and minority experience. Literature and translation are active agents in such processes, which are largely based on cultural, discursive, and cognitive constraints that condition the interpretation of each text.
C’est trop auch! the translation of contemporary French literature featuring urban youth slang
(2016)
The French post-colonial novel has recently been witnessing the emergence of urban youth language or français contemporain des cités (Goudaillier 2001). This linguistic variety allows underprivileged youths from multi-ethnic suburbs to rebel against authority by deliberately violating standard language norms. Its characteristics include frequent lexical input from immigrant languages, in particular Arabic and English, and the use of verlan at the morphological level, with the latter involving a form of back slang using syllabic inversion, which can be recurrently applied to heighten its coding function. In view of the social rejection of this ‘antilanguage’ (Halliday 1978), it has had difficulty penetrating into literature. However, this is now beginning to change, with urban youth discourse appearing in a number of novels, mostly by young ‘post-migration’ writers (Geiser 2008), such as Faïza Guène, Insa Sané and Rachid Djaïdani. While this language variety has mainly been dealt with by sociolinguists, some of the novels concerned are now crossing borders, and a multi-disciplinary approach to this phenomenon is now called for, combining linguistic, literary and translatological tools.
The transfer of this heterolingual genre does indeed raise a number of issues. For example, if we assume that translation is a cultural-political practice (Venuti 2008), what options do translators have to convey the resistant discourse of young immigrant slang users? How will the relationship between language use and social identity manifest itself in the target text? And how can a contrastive linguistic analysis of the features of urban youth language help to resolve translation problems? I will draw on a corpus of French and Dutch novels as well as some translations from French in an attempt to answer these questions.
Several translation scholars have recognised translation as a form of discourse mediation or discourse presentation (see, for example, Mossop 1998). In line with this, "universals" of translation have also been re-framed in the larger context of discourse mediation, as mediation universals rather than something strictly translationspecific (Ulrych 2009). In the present article, this line of enquiry is developed by comparing some of the alleged universals of translation, namely standardization and explicitation, with insights from literary and narratological studies on the nature of discourse presentation. The notion of reportive or interpretative interference (Sternberg 1982) and Fludernik’s (1993) claim that all represented discourse is typical and schematic in nature seem to bear curious resemblance to the notion of standardization or normalization, posited as a possible universal of translation (Mauranen & Kujamäki 2004). Drawing on the results of my earlier research (Kuusi 2011), I present examples of free indirect discourse (FID) used in Dostoevsky’s novel Crime and Punishment with their translations into Finnish. Analyzing the translations, I demonstrate how in
translations, the narratological and literary-theoretical notions of reportive interference and typification/schematization coincide with the translation-theoretical notions of explicitation and standardization.
The article deals with Finnish translations of varieties of spoken language in fiction from the late 19th century to the beginning of the 2000s. It presents the central findings of a comprehensive study on the changes and developments of translational norms in Finnish literature. The study is based on a corpus consisting of 200 literary works (the original and its translations are counted as one work), representing various genres: literary fiction, young-adult fiction, as well as genre fiction (romance and crime). During this 100-year period, the use of colloquial variants in translations has strongly increased, influenced by the changing literary and linguistic norms of original Finnish literature. The norms of different literary genres, however, vary, and rich, non-standard variation can be found in translated works from different periods.
This article is a linguistic study of David Bellos’ indirect translation of Ismail Kadare’s The File on H (1997), a novel first published in 1980-1981 in the Albanian literary review Nëntori, and translated into English on the basis of Jusuf Vrioni’s French version, Le Dossier H (1989). Also called "double", "mediated" or "second-hand", indirect translation is an understudied phenomenon, often criticised by scholars because of its greater distance to the original. Cay Dollerup (2000: 23), for example, argues that the grammatical structure of the mediating language (ML) obscures the distinctions made in the source language (SL), and that possible "mistakes" in the ML may be repeated in the target language (TL). Do fidelity and loyalty to the author become weakened in Bellos’ indirect translation? To what extent is such weakening discernible linguistically? And does this particular case of indirect translation reveal notable patterns or recurring types of linguistic shifts between ST and TT? Showing that some of the features specific to Kadare’s Albanian writing are tempered in the doubly-translated English text, yet highlighting that similar shifts occur in the three language directions involved, this article demonstrates that changes between ST and TT may occur in indirect translation regardless of the strategies adopted by MT – thus challenging the hypothesis that linguistic shifts in indirect translation follow a single or consistent pattern.
Thomas Mann’s Der Tod in Venedig (1912) owes much of its fame in English to a translation from 1928 by Helen Tracy Lowe-Porter. The novella however has in fact been translated many times – first by Burke (1924, with a revised edition following in 1970), and, after Lowe-Porter, by Luke (1988), Koelb (1994), Appelbaum (1995), Neugroschel (1998), Chase (1999), Heim (2004), Doege (2007) and Hansen & Hansen (2012). Most of these versions are neither known to readers nor discussed in academic literature. This paper, which comes as part of a larger study on linguistic creativity in Der Tod in Venedig, focuses on the use of neologisms by Mann and what happens to them in (re)translation. Relying on a digital corpus composed of the complete set of English retranslations and a corpus-based methodology, the paper argues that, despite the extended time period between the publications and different translation conditions, neologisms are treated uniformly by the translators. Mann’s coinages are nearly always obliterated through normalisation and, if preserved, demonstrate less creativity overall than in the ST, raising questions about the Retranslation Hypothesis (RH) which proposes that early TT versions tend to domesticate while later ones increasingly foreignise.
This special issue of the International Journal of Literary Linguistics offers seven state-of-the-art contributions on the current linguistic study of literary translation. Although the articles are based on similar data – literary source texts and their translations – they focus on diverse aspects of literary translation, study a range of linguistic phenomena and utilize different methodologies. In other words, it is an important goal of this special issue to illuminate the current diversity of possible approaches in the linguistic study of translated literary texts within the discipline of translation studies. At the same time, new theoretical and empirical insights are opened to the study of the linguistic phenomena chosen by the authors of the articles and their representation or use in literary texts and translations. The analyzed features range from neologisms to the category of passive and from spoken language features to the representation of speech and multilingualism in writing. Therefore, the articles in this issue are not only relevant for the study of literary translation or translation theory in general, but also for the disciplines of linguistics and literary studies – or most importantly, for the cross-disciplinary co-operation between these three fields of study.
The common theme that all these articles share is how the translation process shapes, transfers and changes the linguistic properties of literary texts as compared to their sources texts, other translations or non-translated literary texts in the same language and how this question can be approached in research. All articles provide new information about the forces that direct and affect translators’ textual choices and the previously formulated hypotheses about the functioning of such forces. The articles illustrate how translators may perform differently from authors and how translators’ and authors’ norms may diverge at different times and in different cultures. The question of how translation affects the linguistic properties of literary translations is approached from the viewpoint of previously proposed claims or hypotheses about translation. In the following, we will introduce these viewpoints for readers who are not familiar with the recent developments in translation studies. At the same time, we will shortly present the articles in this issue.
This article analyzes the dynamics of fictional dialogue in three short stories by the Finnish author Rosa Liksom. These stories are constructed almost entirely of dialogue, with minimal involvement on the part of the narrator. We adopt two different approaches to dialogue. First, we analyze dialogue from a micro level, as interaction between the characters within the storyworlds, then from a more holistic perspective, paying attention to how dialogue contributes to the rhetorical structure and ethical interpretation of the stories. We show that resorting mainly to dialogue as a narrative mode works as a way of depicting tensions between Liksom’s characters, and between them and the surrounding fictional world. This, in turn, engages the reader in an interpretative process to understand the story’s logic both within the fictional worlds and on the level of communication between the implied author and the authorial audience.
This article explores the uses and functions of dialogue in Frank McCourt’s memoir Angela’s Ashes. Taking conversational dialogue and fictional dialogue as points of comparison, the article argues that dialogue in autobiographical writing is essentially constructed, albeit not in the same way as fictional dialogue is. Dialogue as a means of dramatisation raises questions regarding factuality and fictionality. In McCourt’s memoir, dialogue is shown to serve numerous functions: characterisation and stereotyping; selfpositioning and indirect stance-marking; the creation of verisimilitude, humour and reader involvement.
This special issue is devoted to a cross-disciplinary investigation of a specific literary phenomenon, fictional dialogue. Fictional dialogue is used to refer to passages of character-character conversation within a literary text. More specifically, the articles of the issue deal with fictional dialogue as a narrative mode in prose fiction. The issue aims to engender an appreciation and a better understanding of the workings of dialogue by drawing on the insights and methods from both literary studies and linguistics. These methods include a rhetorical-ethical approach to narrative, cognitive and “natural” narratology, the study of everyday conversational storytelling, and Conversation Analysis (CA). Combining these methods helps us to understand that while dialogue is a central means to depict character-character relationships it also serves other levels of communication in a narrative and thus contributes to the reader's comprehension of the narrative design's rhetorical and ethical dimensions. The articles also suggest that while understanding dialogue depends partly on the reader’s experiences of real-life conversation, the interpretation of dialogue is determined by the overall design of a literary text and the historically changing conventions.
Metaphors we may not live by
(2016)
Metaphors We Live By created an immediate stir in 1980, and it continues to spur interest in cognitive linguistics, cognitive stylistics, and metaphor theory. This article uses both collocations and random samples of words used in conceptual metaphors to search for corpus evidence of the pervasiveness of conceptual metaphor that was unavailable to Lakoff and Johnson. Some metaphors, such as TIME IS MONEY, are pervasive in giant natural language corpora. Others, such as MORE IS UP, are frequent in clearly and consciously metaphorical forms, but relatively rare in the basic forms that would clearly show that we use metaphor to understand more abstract concepts in terms of concrete ones. Some, including ARGUMENT IS WAR, that Lakoff and Johnson discuss throughout their book, are poorly represented. Some gaps in evidence probably result from multiple ways of expressing a complex conceptual metaphors, but others suggest that intuitive plausibility is an insecure basis for argument.
Ribosome recycling orchestrated by the ATP binding cassette (ABC) protein ABCE1 can be considered as the final—or the first—step within the cyclic process of protein synthesis, connecting translation termination and mRNA surveillance with re-initiation. An ATP-dependent tweezer-like motion of the nucleotide-binding domains in ABCE1 transfers mechanical energy to the ribosome and tears the ribosome subunits apart. The post-recycling complex (PRC) then re-initiates mRNA translation. Here, we probed the so far unknown architecture of the 1-MDa PRC (40S/30S·ABCE1) by chemical cross-linking and mass spectrometry (XL-MS). Our study reveals ABCE1 bound to the translational factor-binding (GTPase) site with multiple cross-link contacts of the helix–loop–helix motif to the S24e ribosomal protein. Cross-linking of the FeS cluster domain to the ribosomal protein S12 substantiates an extreme lever-arm movement of the FeS cluster domain during ribosome recycling. We were thus able to reconstitute and structurally analyse a key complex in the translational cycle, resembling the link between translation initiation and ribosome recycling.
The endoplasmic reticulum–mitochondria encounter structure (ERMES) connects the mitochondrial outer membrane with the ER. Multiple functions have been linked to ERMES, including maintenance of mitochondrial morphology, protein assembly and phospholipid homeostasis. Since the mitochondrial distribution and morphology protein Mdm10 is present in both ERMES and the mitochondrial sorting and assembly machinery (SAM), it is unknown how the ERMES functions are connected on a molecular level. Here we report that conserved surface areas on opposite sides of the Mdm10 β-barrel interact with SAM and ERMES, respectively. We generated point mutants to separate protein assembly (SAM) from morphology and phospholipid homeostasis (ERMES). Our study reveals that the β-barrel channel of Mdm10 serves different functions. Mdm10 promotes the biogenesis of α-helical and β-barrel proteins at SAM and functions as integral membrane anchor of ERMES, demonstrating that SAM-mediated protein assembly is distinct from ER-mitochondria contact sites.
Imaging non-adherent cells by super-resolution far-field fluorescence microscopy is currently not possible because of their rapid movement while in suspension. Holographic optical tweezers (HOTs) enable the ability to freely control the number and position of optical traps, thus facilitating the unrestricted manipulation of cells in a volume around the focal plane. Here we show that immobilizing non-adherent cells by optical tweezers is sufficient to achieve optical resolution well below the diffraction limit using localization microscopy. Individual cells can be oriented arbitrarily but preferably either horizontally or vertically relative to the microscope’s image plane, enabling access to sample sections that are impossible to achieve with conventional sample preparation and immobilization. This opens up new opportunities to super-resolve the nanoscale organization of chromosomal DNA in individual bacterial cells.
To crack the neural code and read out the information neural spikes convey, it is essential to understand how the information is coded and how much of it is available for decoding. To this end, it is indispensable to derive from first principles a minimal set of spike features containing the complete information content of a neuron. Here we present such a complete set of coding features. We show that temporal pairwise spike correlations fully determine the information conveyed by a single spiking neuron with finite temporal memory and stationary spike statistics. We reveal that interspike interval temporal correlations, which are often neglected, can significantly change the total information. Our findings provide a conceptual link between numerous disparate observations and recommend shifting the focus of future studies from addressing firing rates to addressing pairwise spike correlation functions as the primary determinants of neural information.
The p300/CBP‐associated factor (PCAF) and related GCN5 bromodomain‐containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine‐based L‐45 (dubbed L‐Moses) as the first potent, selective, and cell‐active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)‐(−)‐norephedrine furnished L‐45 in enantiopure form. L‐45 was shown to disrupt PCAF‐Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co‐crystal structure of L‐45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L‐45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell‐permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.
The present study aims to investigate how foreign language learners at the German for Academic Purposes (GAP) program at a Brazilian federal university interact in their mother tongue about their motivations to learn a foreign language as well as their motivations to participate in study abroad programs. Data were collected using focus group methodology with three focus groups of six students each (A1, A2 and B1 levels). We chose to analyze the A1 group. We conducted metaphor-led discourse analysis of the data in order to examine metaphors and metonymies, which emerged in the focus group interactions. We were able to identify the presence of systematic metaphors such as learning is hard work and learning is jumping hurdles, intertwined with conceptual metaphors such as education is a journey and difficulties are weights, which point at the motivation for learning verbalized by Brazilian foreign language learners who took part in the study.
This paper focuses on the Heimat (home) metaphor of the Pit Bull bitch in Yilmaz Arslan's Brudermord/Fratricide (2005), a film about Turkish migrants in Germany. Updating the genre for a world of fluid boundaries, this is a Heimatfilm of the German margin. Arslan's film self-reflexively posits transnational Heimat film as a possible bridge between "Others", as a means to facilitate conversations which might decrease the violence of the present dog eat dog world of the margin the film portrays.
Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1α induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies.
Serum levels of the lipid mediator sphingosine-1-phosphate (S1P) are reduced in septic patients and are inversely associated with disease severity. We show that serum S1P is reduced in human sepsis and in murine models of sepsis. We then investigated whether pharmacological or genetic approaches that alter serum S1P may attenuate cardiac dysfunction and whether S1P signaling might serve as a novel theragnostic tool in sepsis. Mice were challenged with lipopolysaccharide and peptidoglycan (LPS/PepG). LPS/PepG resulted in an impaired systolic contractility and reduced serum S1P. Administration of the immunomodulator FTY720 increased serum S1P, improved impaired systolic contractility and activated the phosphoinositide 3-kinase (PI3K)-pathway in the heart. Cardioprotective effects of FTY720 were abolished following administration of a S1P receptor 2 (S1P2) antagonist or a PI3K inhibitor. Sphingosine kinase-2 deficient mice had higher endogenous S1P levels and the LPS/PepG-induced impaired systolic contractility was attenuated in comparison with wild-type mice. Cardioprotective effects of FTY720 were confirmed in polymicrobial sepsis. We show here for the first time that the impaired left ventricular systolic contractility in experimental sepsis is attenuated by FTY720. Mechanistically, our results indicate that activation of S1P2 by increased serum S1P and the subsequent activation of the PI3K-Akt survival pathway significantly contributes to the observed cardioprotective effect of FTY720.
In her article, Karin Littau proposes a material or medial turn in the humanities and social sciences to end the neglect of the material basis to every act of communication, including translation. This proposal is warmly welcomed. As a comparatist who has for some time been trying to build bridges between literary studies and book history, I strongly support Littau's point of view – all the more since I am less optimistic regarding the general acceptance of such ideas in the humanities, and especially in literary and translation studies. I am not so sure that McLuhan and the other authorities for the importance of mediality and technicity whom Littau quotes (e.g. Kittler, Ong, and Gumbrecht) have really provoked a "crisis in the self-understanding of the human sciences". For brevity's sake, in my response below, I leave aside literary studies to focus on translation studies.
Characterization of blunt chest trauma in a long-term porcine model of severe multiple trauma
(2016)
Chest trauma has a significant relevance on outcome after severe trauma. Clinically, impaired lung function typically occurs within 72 hours after trauma. However, the underlying pathophysiological mechanisms are still not fully elucidated. Therefore, we aimed to establish an experimental long-term model to investigate physiological, morphologic and inflammatory changes, after severe trauma. Male pigs (sus scrofa) sustained severe trauma (including unilateral chest trauma, femur fracture, liver laceration and hemorrhagic shock). Additionally, non-injured animals served as sham controls. Chest trauma resulted in severe lung damage on both CT and histological analyses. Furthermore, severe inflammation with a systemic increase of IL-6 (p = 0.0305) and a local increase of IL-8 in BAL (p = 0.0009) was observed. The pO2/FiO2 ratio in trauma animals decreased over the observation period (p < 0.0001) but not in the sham group (p = 0.2967). Electrical Impedance Tomography (EIT) revealed differences between the traumatized and healthy lung (p < 0.0001). In conclusion, a clinically relevant, long-term model of blunt chest trauma with concomitant injuries has been developed. This reproducible model allows to examine local and systemic consequences of trauma and is valid for investigation of potential diagnostic or therapeutic options. In this context, EIT might represent a radiation-free method for bedside diagnostics.
The detailed biophysical mechanisms through which transcranial magnetic stimulation (TMS) activates cortical circuits are still not fully understood. Here we present a multi-scale computational model to describe and explain the activation of different cell types in motor cortex due to transcranial magnetic stimulation. Our model determines precise electric fields based on an individual head model derived from magnetic resonance imaging and calculates how these electric fields activate morphologically detailed models of different neuron types. We predict detailed neural activation patterns for different coil orientations consistent with experimental findings. Beyond this, our model allows us to predict activation thresholds for individual neurons and precise initiation sites of individual action potentials on the neurons’ complex morphologies. Specifically, our model predicts that cortical layer 3 pyramidal neurons are generally easier to stimulate than layer 5 pyramidal neurons, thereby explaining the lower stimulation thresholds observed for I-waves compared to D-waves. It also predicts differences in the regions of activated cortical layer 5 and layer 3 pyramidal cells depending on coil orientation. Finally, it predicts that under standard stimulation conditions, action potentials are mostly generated at the axon initial segment of corctial pyramidal cells, with a much less important activation site being the part of a layer 5 pyramidal cell axon where it crosses the boundary between grey matter and white matter. In conclusion, our computational model offers a detailed account of the mechanisms through which TMS activates different cortical cell types, paving the way for more targeted application of TMS based on individual brain morphology in clinical and basic research settings.
Natural sounds contain information on multiple timescales, so the auditory system must analyze and integrate acoustic information on those different scales to extract behaviorally relevant information. However, this multi-scale process in the auditory system is not widely investigated in the literature, and existing models of temporal integration are mainly built upon detection or recognition tasks on a single timescale. Here we use a paradigm requiring processing on relatively ‘local’ and ‘global’ scales and provide evidence suggesting that the auditory system extracts fine-detail acoustic information using short temporal windows and uses long temporal windows to abstract global acoustic patterns. Behavioral task performance that requires processing fine-detail information does not improve with longer stimulus length, contrary to predictions of previous temporal integration models such as the multiple-looks and the spectro-temporal excitation pattern model. Moreover, the perceptual construction of putatively ‘unitary’ auditory events requires more than hundreds of milliseconds. These findings support the hypothesis of a dual-scale processing likely implemented in the auditory cortex.
The present paper aims to elucidate the conceptual structure of the aesthetics of literature.Following Fechner's "aesthetics from below" (1876) and adopting a method introduced by Jacobsen, Buchta, Kohler, and Schroeger (2004), we asked 1544 German-speaking research participants to list adjectives that they use to label aesthetic dimensions of literature in general and of individual literary forms and genres in particular (novels, short stories, poems, plays, comedies). According to our analyses of frequency, mean list rank, and the Cognitive Salience Index, beautiful and suspenseful rank highest across all target categories. For plays/comedies, funny and sad turned out to be the most relevant terms; for novels and short stories, suspenseful, interesting and romantic; and for poetry romantic, along with the music-related terms harmonious, rhythmic, and melodious. A comparison of our results with analogous studies for visual aesthetics and music yielded a comprehensive map of the distribution of aesthetic appeal dimensions across sensory modalities and aesthetic domains, with poetry and music showing the greatest overlap.
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism which is characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca2+ release in myotubes via the ryanodine receptor type 1 (RyR1). As RyR1 is also expressed in B–lymphocytes, this study investigated whether cellular metabolism of native B–lymphocytes was also altered in MH susceptible (MHS) individuals. A potent activator of RyR1, 4–chloro–m–cresol (4-CmC) was used to challenge native B-lymphocytes in a real–time, metabolic assay based on a pH–sensitive silicon biosensor chip. At the cellular level, a dose–dependent, phasic acidification occurred with 4–CmC. The acidification rate, an indicator of metabolic activation, was significantly higher in B–lymphocytes from MHS patients and required 3 to 5 fold lower concentrations of 4–CmC to evoke similar acidification rates to MHN. Native B–lymphocytes from MHS individuals are more sensitive to 4–CmC than those from MHN, reflecting a greater Ca2+ turnover. The acidification response, however, was less pronounced than in muscle cells, presumably reflecting the lower expression of RyR1 in B–lymphocytes.
The human sense of smell is often analyzed as being composed of three main components comprising olfactory threshold, odor discrimination and the ability to identify odors. A relevant distinction of the three components and their differential changes in distinct disorders remains a research focus. The present data-driven analysis aimed at establishing a cluster structure in the pattern of olfactory subtest results. Therefore, unsupervised machine-learning was applied onto olfactory subtest results acquired in 10,714 subjects with nine different olfactory pathologies. Using the U-matrix, Emergent Self-organizing feature maps (ESOM) identified three different clusters characterized by (i) low threshold and good discrimination and identification, (ii) very high threshold associated with absent to poor discrimination and identification ability, or (iii) medium threshold, i.e., in the mid-range of possible thresholds, associated with reduced discrimination and identification ability. Specific etiologies of olfactory (dys)function were unequally represented in the clusters (p < 2.2 · 10−16). Patients with congenital anosmia were overrepresented in the second cluster while subjects with postinfectious olfactory dysfunction belonged frequently to the third cluster. However, the clusters provided no clear separation between etiologies. Hence, the present verification of a distinct cluster structure encourages continued scientific efforts at olfactory test pattern recognition.
Plant regeneration is essential for maintaining forest biodiversity and ecosystem functioning, which are globally threatened by human disturbance. Here we present the first integrative meta-analysis on how forest disturbance affects multiple ecological processes of plant regeneration including pollination, seed dispersal, seed predation, recruitment and herbivory. We analysed 408 pairwise comparisons of these processes between near-natural and disturbed forests. Human impacts overall reduced plant regeneration. Importantly, only processes early in the regeneration cycle that often depend on plant-animal interactions, i.e. pollination and seed dispersal, were negatively affected. Later processes, i.e. seed predation, recruitment and herbivory, showed overall no significant response to human disturbance. Conserving pollination and seed dispersal, including the animals that provide these services to plants, should become a priority in forest conservation efforts globally.
H2S is an important signalling molecule involved in diverse biological processes. It mediates the formation of cysteine persulfides (R-S-SH), which affect the activity of target proteins. Like thiols, persulfides show reactivity towards electrophiles and behave similarly to other cysteine modifications in a biotin switch assay. In this manuscript, we report on qPerS-SID a mass spectrometry-based method allowing the isolation of persulfide containing peptides in the mammalian proteome. With this method, we demonstrated that H2S donors differ in their efficacy to induce persulfides in HEK293 cells. Furthermore, data analysis revealed that persulfide formation affects all subcellular compartments and various cellular processes. Negatively charged amino acids appeared more frequently adjacent to cysteines forming persulfides. We confirmed our proteomic data using pyruvate kinase M2 as a model protein and showed that several cysteine residues are prone to persulfide formation finally leading to its inactivation. Taken together, the site-specific identification of persulfides on a proteome scale can help to identify target proteins involved in H2S signalling and enlightens the biology of H2S and its releasing agents.
Investigating three-dimensional (3D) structures of proteins in living cells by in-cell nuclear magnetic resonance (NMR) spectroscopy opens an avenue towards understanding the structural basis of their functions and physical properties under physiological conditions inside cells. In-cell NMR provides data at atomic resolution non-invasively, and has been used to detect protein-protein interactions, thermodynamics of protein stability, the behavior of intrinsically disordered proteins, etc. in cells. However, so far only a single de novo 3D protein structure could be determined based on data derived only from in-cell NMR. Here we introduce methods that enable in-cell NMR protein structure determination for a larger number of proteins at concentrations that approach physiological ones. The new methods comprise (1) advances in the processing of non-uniformly sampled NMR data, which reduces the measurement time for the intrinsically short-lived in-cell NMR samples, (2) automatic chemical shift assignment for obtaining an optimal resonance assignment, and (3) structure refinement with Bayesian inference, which makes it possible to calculate accurate 3D protein structures from sparse data sets of conformational restraints. As an example application we determined the structure of the B1 domain of protein G at about 250 μM concentration in living E. coli cells.
As a centerpiece of antigen processing, the ATP-binding cassette transporter associated with antigen processing (TAP) became a main target for viral immune evasion. The herpesviral ICP47 inhibits TAP function, thereby suppressing an adaptive immune response. Here, we report on a thermostable ICP47-TAP complex, generated by fusion of different ICP47 fragments. These fusion complexes allowed us to determine the direction and positioning in the central cavity of TAP. ICP47-TAP fusion complexes are arrested in a stable conformation, as demonstrated by MHC I surface expression, melting temperature, and the mutual exclusion of herpesviral TAP inhibitors. We unveiled a conserved region next to the active domain of ICP47 as essential for the complete stabilization of the TAP complex. Binding of the active domain of ICP47 arrests TAP in an open inward facing conformation rendering the complex inaccessible for other viral factors. Based on our findings, we propose a dual interaction mechanism for ICP47. A per se destabilizing active domain inhibits the function of TAP, whereas a conserved C-terminal region additionally stabilizes the transporter. These new insights into the ICP47 inhibition mechanism can be applied for future structural analyses of the TAP complex.
UPF1 regulates myeloid cell functions and S100A9 expression by the hnRNP E2/miRNA-328 balance
(2016)
UPF1 is a key player in nonsense mediated mRNA decay (NMD) but also involved in posttranscriptional gene regulation. In this study we found that UPF1 regulates the expression of genes with functions in inflammation and myeloid cell differentiation via hnRNP E2. The majority of the UPF1-regulated genes identified in monocytic cells contain a binding site for hnRNP E2 within 5′ UTR located introns with hnRNP E2 acting here as splicing regulator. We found that miRNA-328 which is significantly induced during monocytic cell differentiation acts independently from its gene silencing function as RNA decoy for hnRNP E2. One representative gene controlled by the hnRNP E2/miRNA-328 balance is S100A9 which plays an important role in cell differentiation and oxidative stress response of monocytes. Induction of miRNA-328 expression during cell differentiation antagonizes the blockade by hnRNP E2 which results in the upregulation of CD11b expression and ROS production in monocytic cells. Taken together, our data indicate that upregulation of miR-328 is responsible for the induction of hnRNP E2 target genes during myeloid cell differentiation.
This commentary on Edwin Carels’ essay “Revisiting Tom Tom: Performative anamnesis and autonomous vision in Ken Jacobs’ appropriations of Tom Tom the Piper’s Son” broadens up the media-archaeological framework in which Carels places his text. Notions such as Huhtamo’s topos and Zielinski’s “deep time” are brought into the discussion in order to point out the difficulty to see what there is to see and to question the position of the viewer in front of experimental films like Tom Tom the Piper’s Son and its remakes.
Streptococcus pneumoniae is the most frequent cause of community-acquired pneumonia. The infection process involves bacterial cell surface receptors, which interact with host extracellular matrix components to facilitate colonization and dissemination of bacteria. Here, we investigated the role of host-derived extracellular RNA (eRNA) in the process of pneumococcal alveolar epithelial cell infection. Our study demonstrates that eRNA dose-dependently increased S. pneumoniae invasion of alveolar epithelial cells. Extracellular enolase (Eno), a plasminogen (Plg) receptor, was identified as a novel eRNA-binding protein on S. pneumoniae surface, and six Eno eRNA-binding sites including a C-terminal 15 amino acid motif containing lysine residue 434 were characterized. Although the substitution of lysine 434 for glycine (K434G) markedly diminished the binding of eRNA to Eno, the adherence to and internalization into alveolar epithelial cells of S. pneumoniae strain carrying the C-terminal lysine deletion and the mutation of internal Plg-binding motif were only marginally impaired. Accordingly, using a mass spectrometric approach, we identified seven novel eRNA-binding proteins in pneumococcal cell wall. Given the high number of eRNA-interacting proteins on pneumococci, treatment with RNase1 completely inhibited eRNA-mediated pneumococcal alveolar epithelial cell infection. Our data support further efforts to employ RNAse1 as an antimicrobial agent to combat pneumococcal infectious diseases.
Next-generation sequencing (NGS) provides unrestricted access to the genome, but it produces ‘big data’ exceeding in amount and complexity the classical analytical approaches. We introduce a bioinformatics-based classifying biomarker that uses emergent properties in genetics to separate pain patients requiring extremely high opioid doses from controls. Following precisely calculated selection of the 34 most informative markers in the OPRM1, OPRK1, OPRD1 and SIGMAR1 genes, pattern of genotypes belonging to either patient group could be derived using a k-nearest neighbor (kNN) classifier that provided a diagnostic accuracy of 80.6±4%. This outperformed alternative classifiers such as reportedly functional opioid receptor gene variants or complex biomarkers obtained via multiple regression or decision tree analysis. The accumulation of several genetic variants with only minor functional influences may result in a qualitative consequence affecting complex phenotypes, pointing at emergent properties in genetics.
ANGIOGENES : knowledge database for protein-coding and noncoding RNA genes in endothelial cells
(2016)
Increasing evidence indicates the presence of long noncoding RNAs (lncRNAs) is specific to various cell types. Although lncRNAs are speculated to be more numerous than protein-coding genes, the annotations of lncRNAs remain primitive due to the lack of well-structured schemes for their identification and description. Here, we introduce a new knowledge database “ANGIOGENES” (http://angiogenes.uni-frankfurt.de) to allow for in silico screening of protein-coding genes and lncRNAs expressed in various types of endothelial cells, which are present in all tissues. Using the latest annotations of protein-coding genes and lncRNAs, publicly-available RNA-seq data was analyzed to identify transcripts that are expressed in endothelial cells of human, mouse and zebrafish. The analyzed data were incorporated into ANGIOGENES to provide a one-stop-shop for transcriptomics data to facilitate further biological validation. ANGIOGENES is an intuitive and easy-to-use database to allow in silico screening of expressed, enriched and/or specific endothelial transcripts under various conditions. We anticipate that ANGIOGENES serves as a starting point for functional studies to elucidate the roles of protein-coding genes and lncRNAs in angiogenesis.
Obesity-associated insulin resistance is driven by inflammatory processes in response to metabolic overload. Obesity-associated inflammation can be recapitulated in cell culture by exposing macrophages to saturated fatty acids (SFA), and endoplasmic reticulum (ER) stress responses essentially contribute to pro-inflammatory signalling. AMP-activated protein kinase (AMPK) is a central metabolic regulator with established anti-inflammatory actions. Whether pharmacological AMPK activation suppresses SFA-induced inflammation in a human system is unclear. In a setting of hypoxia-potentiated inflammation induced by SFA palmitate, we found that the AMP-mimetic AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) potently suppressed upregulation of ER stress marker mRNAs and pro-inflammatory cytokines. Furthermore, AICAR inhibited macrophage ER stress responses triggered by ER-stressors thapsigargin or tunicamycin. Surprisingly, AICAR acted independent of AMPK or AICAR conversion to 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate (ZMP) while requiring intracellular uptake via the equilibrative nucleoside transporter (ENT) ENT1 or the concentrative nucleoside transporter (CNT) CNT3. AICAR did not affect the initiation of the ER stress response, but inhibited the expression of major ER stress transcriptional effectors. Furthermore, AICAR inhibited autophosphorylation of the ER stress sensor inositol-requiring enzyme 1α (IRE1α), while activating its endoribonuclease activity in vitro. Our results suggest that AMPK-independent inhibition of ER stress responses contributes to anti-inflammatory and anti-diabetic effects of AICAR.
The charged particle community is looking for techniques exploiting proton interactions instead of X-ray absorption for creating images of human tissue. Due to multiple Coulomb scattering inside the measured object it has shown to be highly non-trivial to achieve sufficient spatial resolution. We present imaging of biological tissue with a proton microscope. This device relies on magnetic optics, distinguishing it from most published proton imaging methods. For these methods reducing the data acquisition time to a clinically acceptable level has turned out to be challenging. In a proton microscope, data acquisition and processing are much simpler. This device even allows imaging in real time. The primary medical application will be image guidance in proton radiosurgery. Proton images demonstrating the potential for this application are presented. Tomographic reconstructions are included to raise awareness of the possibility of high-resolution proton tomography using magneto-optics.
Purpose: To determine the value of the 2D multiple-echo data image combination (MEDIC) sequence relative to the short-tau inversion recovery (STIR) sequence regarding the depiction of chondral lesions in the patellofemoral joint.
Materials and methods: During a period of 6 month patients with acute pain at the anterior aspect of the knee, joint effusion and suspected chondral lesion defect in the patellofemoral joint underwent MRI including axial MEDIC and STIR imaging. Patients with chondral lesions in the patellofemoral joint on at least one sequence were included. The MEDIC and STIR sequence were quantitatively compared regarding the patella cartilage-to-effusion contrast-to-noise ratio (CNR) and qualitatively regarding the depiction of chondral lesions independently scored by two radiologists on a 3-point scale (1 = not depicted; 2 = blurred depicted; 3 = clearly depicted) using the Wilcoxon-Mann-Whitney-Test. For the analysis of inter-observer agreement the Cohen's Weighted Kappa test was used.
Results: 30 of 58 patients (male: female, 21:9; age: 44 ± 12 yrs) revealed cartilage lesions (fissures, n = 5 including fibrillation; gaps, n = 15; delamination, n = 7; osteoarthritis, n = 3) and were included in this study. The STIR-sequence was significantly (p < 0.001) superior to the MEDIC-sequence regarding both, the patella cartilage-to-effusion CNR (mean CNR: 232 ± 61 vs. 40 ± 16) as well as the depiction of chondral lesion (mean score: 2.83 ± 0.4 vs. 1.75 ± 0.7) with substantial inter-observer agreement in the rating of both sequences (κ = 0.76–0.89).
Conclusion: For the depiction of chondral lesions in the patellofemoral joint, the axial STIR-sequence should be chosen in preference to the axial MEDIC-sequence.
Background: Computed tomography (CT) low-dose (LD) imaging is used to lower radiation exposure, especially in vascular imaging; in current literature, this is mostly on latest generation high-end CT systems.
Purpose: To evaluate the effects of reduced tube current on objective and subjective image quality of a 15-year-old 16-slice CT system for pulmonary angiography (CTPA).
Material and Methods: CTPA scans from 60 prospectively randomized patients (28 men, 32 women) were examined in this study on a 15-year-old 16-slice CT scanner system. Standard CT (SD) settings were 100 kV and 150 mAs, LD settings were 100 kV and 50 mAs. Attenuation of the pulmonary trunk, various anatomic landmarks, and image noise were quantitatively measured; contrast-to-noise ratios (CNR) and signal-to-noise ratios (SNR) were calculated. Three independent blinded radiologists subjectively rated each image series using a 5-point grading scale.
Results: CT dose index (CTDI) in the LD series was 66.46% lower compared to the SD settings (2.49 ± 0.55 mGy versus 7.42 ± 1.17 mGy). Attenuation of the pulmonary trunk showed similar results for both series (SD 409.55 ± 91.04 HU; LD 380.43 HU ± 93.11 HU; P = 0.768). Subjective image analysis showed no significant differences between SD and LD settings regarding the suitability for detection of central and peripheral PE (central SD/LD, 4.88; intra-class correlation coefficients [ICC], 0.894/4.83; ICC, 0.745; peripheral SD/LD, 4.70; ICC, 0.943/4.57; ICC, 0.919; all P > 0.4).
Conclusion: The LD protocol, on a 15-year-old CT scanner system without current high-end hardware or post-processing tools, led to a dose reduction of approximately 67% with similar subjective image quality and delineation of central and peripheral pulmonary arteries.
Aims: The primary safety and efficacy endpoints of the randomized FIRE AND ICE trial have recently demonstrated non-inferiority of cryoballoon vs. radiofrequency current (RFC) catheter ablation in patients with drug-refractory symptomatic paroxysmal atrial fibrillation (AF). The aim of the current study was to assess outcome parameters that are important for the daily clinical management of patients using key secondary analyses. Specifically, reinterventions, rehospitalizations, and quality-of-life were examined in this randomized trial of cryoballoon vs. RFC catheter ablation.
Methods and results: Patients (374 subjects in the cryoballoon group and 376 subjects in the RFC group) were evaluated in the modified intention-to-treat cohort. After the index ablation, log-rank testing over 1000 days of follow-up demonstrated that there were statistically significant differences in favour of cryoballoon ablation with respect to repeat ablations (11.8% cryoballoon vs. 17.6% RFC; P = 0.03), direct-current cardioversions (3.2% cryoballoon vs. 6.4% RFC; P = 0.04), all-cause rehospitalizations (32.6% cryoballoon vs. 41.5% RFC; P = 0.01), and cardiovascular rehospitalizations (23.8% cryoballoon vs. 35.9% RFC; P < 0.01). There were no statistical differences between groups in the quality-of-life surveys (both mental and physical) as measured by the Short Form-12 health survey and the EuroQol five-dimension questionnaire. There was an improvement in both mental and physical quality-of-life in all patients that began at 6 months after the index ablation and was maintained throughout the 30 months of follow-up.
Conclusion: Patients treated with cryoballoon as opposed to RFC ablation had significantly fewer repeat ablations, direct-current cardioversions, all-cause rehospitalizations, and cardiovascular rehospitalizations during follow-up. Both patient groups improved in quality-of-life scores after AF ablation.
Clinical trial registration: ClinicalTrials.gov identifier: NCT01490814.
Marine nematodes of the genus Anisakis are common parasites of a wide range of aquatic organisms. Public interest is primarily based on their importance as zoonotic agents of the human Anisakiasis, a severe infection of the gastro-intestinal tract as result of consuming live larvae in insufficiently cooked fish dishes. The diverse nature of external impacts unequally influencing larval and adult stages of marine endohelminth parasites requires the consideration of both abiotic and biotic factors. Whereas abiotic factors are generally more relevant for early life stages and might also be linked to intermediate hosts, definitive hosts are indispensable for a parasite’s reproduction. In order to better understand the uneven occurrence of parasites in fish species, we here use the maximum entropy approach (Maxent) to model the habitat suitability for nine Anisakis species accounting for abiotic parameters as well as biotic data (definitive hosts). The modelled habitat suitability reflects the observed distribution quite well for all Anisakis species, however, in some cases, habitat suitability exceeded the known geographical distribution, suggesting a wider distribution than presently recorded. We suggest that integrative modelling combining abiotic and biotic parameters is a valid approach for habitat suitability assessments of Anisakis, and potentially other marine parasite species.
Cellular informational and metabolic processes are propagated with specific membrane fusions governed by soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNARE). SNARE protein Ykt6 is highly expressed in brain neurons and plays a critical role in the membrane-trafficking process. Studies suggested that Ykt6 undergoes a conformational change at the interface between its longin domain and the SNARE core. In this work, we study the conformational state distributions and dynamics of rat Ykt6 by means of single-molecule Förster Resonance Energy Transfer (smFRET) and Fluorescence Cross-Correlation Spectroscopy (FCCS). We observed that intramolecular conformational dynamics between longin domain and SNARE core occurred at the timescale ~200 μs. Furthermore, this dynamics can be regulated and even eliminated by the presence of lipid dodecylphoshpocholine (DPC). Our molecular dynamic (MD) simulations have shown that, the SNARE core exhibits a flexible structure while the longin domain retains relatively stable in apo state. Combining single molecule experiments and theoretical MD simulations, we are the first to provide a quantitative dynamics of Ykt6 and explain the functional conformational change from a qualitative point of view.
Summary: This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5–2 times higher and risk of discontinuation was significantly lower (P < 0.0001) with denosumab.
Introduction: Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse.
Methods: From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan–Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use.
Results: Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [n = 21,154] vs 20.9 % [i.v. ibandronate; n = 20,472] and 24.8 % [i.v. zoledronic acid; n = 3966] and 16.7–17.5 % [oral bisphosphonates; n = 114,401]; all P < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96–2.02, respectively; all P < 0.0001).
Conclusions: Two-year persistence with denosumab was 1.5–2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab than with bisphosphonates. A more detailed understanding of factors affecting medication-taking behavior may improve persistence and thereby reduce rates of fracture.
More than 30% of the world's population are anemic with serious economic consequences including reduced work capacity and other obstacles to national welfare and development. Red blood cell transfusion is the mainstay to correct anemia, but it is also 1 of the top 5 overused procedures. Patient blood management (PBM) is a proactive, patient-centered, and multidisciplinary approach to manage anemia, optimize hemostasis, minimize iatrogenic blood loss, and harness tolerance to anemia. Although the World Health Organization has endorsed PBM in 2010, many hospitals still seek guidance with the implementation of PBM in clinical routine. Given the use of proven change management principles, we propose simple, cost-effective measures enabling any hospital to reduce both anemia and red blood cell transfusions in surgical and medical patients. This article provides comprehensive bundles of PBM components encompassing 107 different PBM measures, divided into 6 bundle blocks acting as a working template to develop institutions' individual PBM practices for hospitals beginning a program or trying to improve an already existing program. A stepwise selection of the most feasible measures will facilitate the implementation of PBM. In this manner, PBM represents a new quality and safety standard.
The abiotic and biotic drivers of rapid diversification in Andean bellflowers (Campanulaceae)
(2016)
The tropical Andes of South America, the world's richest biodiversity hotspot, are home to many rapid radiations. While geological, climatic, and ecological processes collectively explain such radiations, their relative contributions are seldom examined within a single clade. We explore the contribution of these factors by applying a series of diversification models that incorporate mountain building, climate change, and trait evolution to the first dated phylogeny of Andean bellflowers (Campanulaceae: Lobelioideae). Our framework is novel for its direct incorporation of geological data on Andean uplift into a macroevolutionary model. We show that speciation and extinction are differentially influenced by abiotic factors: speciation rates rose concurrently with Andean elevation, while extinction rates decreased during global cooling. Pollination syndrome and fruit type, both biotic traits known to facilitate mutualisms, played an additional role in driving diversification. These abiotic and biotic factors resulted in one of the fastest radiations reported to date: the centropogonids, whose 550 species arose in the last 5 million yr. Our study represents a significant advance in our understanding of plant evolution in Andean cloud forests. It further highlights the power of combining phylogenetic and Earth science models to explore the interplay of geology, climate, and ecology in generating the world's biodiversity.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients.
Purpose: Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols.
Design: Of 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy.
Results: In MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis.
Conclusion: The MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases.
Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. Notably, 69% of ara-C-resistant samples show a good to fair response to BV6. Furthermore, combination treatment with ara-C and BV6 exerts additive effects in most samples. Whole-genome gene expression profiling identifies cell death, TNFR1 and NF-κB signaling among the top pathways that are activated by BV6 in BV6-sensitive, but not in BV6-resistant cases. Furthermore, sensitivity of primary AML blasts to BV6 correlates with significantly elevated expression levels of TNF and lower levels of XIAP in diagnostic samples, as well as with NPM1 mutation. In a large set of primary AML samples, these data provide novel insights into factors regulating Smac mimetic response in AML and have important implications for the development of Smac mimetic-based therapies and related diagnostics in AML.
The use of phylogenies in ecology is increasingly common and has broadened our understanding of biological diversity. Ecological sub-disciplines, particularly conservation, community ecology and macroecology, all recognize the value of evolutionary relationships but the resulting development of phylogenetic approaches has led to a proliferation of phylogenetic diversity metrics. The use of many metrics across the sub-disciplines hampers potential meta-analyses, syntheses, and generalizations of existing results. Further, there is no guide for selecting the appropriate metric for a given question, and different metrics are frequently used to address similar questions. To improve the choice, application, and interpretation of phylo-diversity metrics, we organize existing metrics by expanding on a unifying framework for phylogenetic information.
Generally, questions about phylogenetic relationships within or between assemblages tend to ask three types of question: how much; how different; or how regular? We show that these questions reflect three dimensions of a phylogenetic tree: richness, divergence, and regularity. We classify 70 existing phylo-diversity metrics based on their mathematical form within these three dimensions and identify ‘anchor’ representatives: for α-diversity metrics these are PD (Faith's phylogenetic diversity), MPD (mean pairwise distance), and VPD (variation of pairwise distances). By analysing mathematical formulae and using simulations, we use this framework to identify metrics that mix dimensions, and we provide a guide to choosing and using the most appropriate metrics. We show that metric choice requires connecting the research question with the correct dimension of the framework and that there are logical approaches to selecting and interpreting metrics. The guide outlined herein will help researchers navigate the current jungle of indices.
The multifunctional protein p21Cip1/CDKN1A (p21) is an important and universal Cdk-interacting protein. Recently, we have reported that p21 is involved in the regulation of the mitotic kinase Cdk1/cyclin B1 and critical for successful mitosis and cytokinesis. In the present work we show that S130 of p21 is phosphorylated by Cdk1/cyclin B1 during mitosis, which reduces p21’s stability and binding affinity to Cdk1/cyclin B1. Interfering with this phosphorylation results in extended mitotic duration and defective chromosome segregation, indicating that this regulation ensures proper mitotic progression. Given that p53, the major transcriptional activator of p21, is the most frequently mutated gene in human cancer and that deregulated Cdk1 associates with the development of different types of cancer, this work provides new insight into the understanding of how deregulated p21 contributes to chromosomal instability and oncogenesis.
Impact of Polo-like kinase 1 inhibitors on human adipose tissue-derived mesenchymal stem cells
(2016)
Polo-like kinase 1 (Plk1) has been established as one of the most promising targets for molecular anticancer intervention. In fact, various Plk1 inhibitors have been identified and characterized. While the data derived from the bench are prospective, the clinical outcomes are less encouraging by showing modest efficacy. One of the explanations for this discrepancy could be unintendedly targeting of non-malignant cells by Plk1 inhibitors. In this work, we have addressed the effect of Plk1 inhibition in adipose tissue-derived mesenchymal stem cells (ASCs). We show that both visceral and subcutaneous ASCs display monopolar spindles, reduced viability and strong apoptosis induction upon treatment with BI 2536 and BI 6727, the Plk1 kinase domain inhibitors, and with Poloxin, the regulatory Polo-box domain inhibitor. While Poloxin triggers quickly apoptosis, BI 2536 and BI 6727 result in mitotic arrest in ASCs. Importantly, survived ASCs exhibit DNA damage and a pronounced senescent phenotype. In addition, Plk1 inhibition impairs ASCs’ motility and homing ability. These results show that Plk1 inhibitors target slowly proliferating ASCs, an important population of anti-inflammation and immune modulation. The toxic effects on primary cells like ASCs could be partially responsible for the reported moderate antitumor activity in patients treated with Plk1 inhibitors.
Although the mechanistic target of rapamycin (mTOR) inhibitor, everolimus, has improved the outcome of patients with renal cell carcinoma (RCC), improvement is temporary due to the development of drug resistance. Since many patients encountering resistance turn to alternative/complementary treatment options, an investigation was initiated to evaluate whether the natural compound, sulforaphane (SFN), influences growth and invasive activity of everolimus-resistant (RCCres) compared to everolimus-sensitive (RCCpar) RCC cell lines in vitro. RCC cells were exposed to different concentrations of SFN and cell growth, cell proliferation, apoptosis, cell cycle, cell cycle regulating proteins, the mTOR-akt signaling axis, adhesion to human vascular endothelium and immobilized collagen, chemotactic activity, and influence on surface integrin receptor expression were investigated. SFN caused a significant reduction in both RCCres and RCCpar cell growth and proliferation, which correlated with an elevation in G2/M- and S-phase cells. SFN induced a marked decrease in the cell cycle activating proteins cdk1 and cyclin B and siRNA knock-down of cdk1 and cyclin B resulted in significantly diminished RCC cell growth. SFN also modulated adhesion and chemotaxis, which was associated with reduced expression of the integrin subtypes α5, α6, and β4. Distinct differences were seen in RCCres adhesion and chemotaxis (diminished by SFN) and RCCpar adhesion (enhanced by SFN) and chemotaxis (not influenced by SFN). Functional blocking of integrin subtypes demonstrated divergent action on RCC binding and invasion, depending on RCC cell sensitivity to everolimus. Therefore, SFN administration could hold potential for treating RCC patients with established resistance towards everolimus.
EUSOBI and 30 national breast radiology bodies support mammography for population-based screening, demonstrated to reduce breast cancer (BC) mortality and treatment impact. According to the International Agency for Research on Cancer, the reduction in mortality is 40 % for women aged 50–69 years taking up the invitation while the probability of false-positive needle biopsy is <1 % per round and overdiagnosis is only 1–10 % for a 20-year screening. Mortality reduction was also observed for the age groups 40–49 years and 70–74 years, although with “limited evidence”. Thus, we firstly recommend biennial screening mammography for average-risk women aged 50–69 years; extension up to 73 or 75 years, biennially, is a second priority, from 40–45 to 49 years, annually, a third priority. Screening with thermography or other optical tools as alternatives to mammography is discouraged. Preference should be given to population screening programmes on a territorial basis, with double reading. Adoption of digital mammography (not film-screen or phosphor-plate computer radiography) is a priority, which also improves sensitivity in dense breasts. Radiologists qualified as screening readers should be involved in programmes. Digital breast tomosynthesis is also set to become “routine mammography” in the screening setting in the next future. Dedicated pathways for high-risk women offering breast MRI according to national or international guidelines and recommendations are encouraged.
We assessed the prognostic value of hypoxia (carbonic anhydrase 9; CA9), vessel density (CD31), with macrophages (CD68) and B cells (CD20) that can interact and lead to immune suppression and disease progression using scanning and histological mapping of whole-mount FFPE pancreatectomy tissue sections from 141 primarily resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with surgery and adjuvant chemotherapy. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin). The median OS was 21 months after a mean follow-up of 20 months (range, 2–69 months). The median tumor surface area positive for CA9 and CD31 was 7.8% and 8.1%, respectively. Although total expression of these markers lacked prognostic value in the entire cohort, nevertheless, high tumor compartment CD68 expression correlated with worse PFS (p = 0.033) and DMFS (p = 0.047). Also, high CD31 expression predicted for worse OS (p = 0.004), PFS (p = 0.008), LPFS (p = 0.014) and DMFS (p = 0.004) in patients with moderate density stroma. High stromal and peripheral compartment CD68 expression predicted for significantly worse outcome in patients with loose and moderate stroma density, respectively. Altogether, in contrast to the current notion, hypoxia levels in PDAC appear to be comparable to other malignancies. CD31 and CD68 constitute prognostic markers in patient subgroups that vary according to tumor compartment and stromal density. Our study provides important insight on the pathophysiology of PDAC and should be exploited for future treatments.
Background: Few studies have evaluated the impact of pre-treatment drug resistance (PDR) on response to combination antiretroviral treatment (cART) in children. The objective of this joint EuroCoord-CHAIN-EPPICC/PENTA project was to assess the prevalence of PDR mutations and their association with virological outcome in the first year of cART in children.
Methods: HIV-infected children <18 years initiating cART between 1998 and 2008 were included if having at least one genotypic resistance test prior to cART initiation. We used the World Health Organization 2009 resistance mutation list and Stanford algorithm to infer resistance to prescribed drugs. Time to virological failure (VF) was defined as the first of two consecutive HIV-RNA > 500 copies/mL after 6 months cART and was assessed by Cox proportional hazards models. All models were adjusted for baseline demographic, clinical, immunology and virology characteristics and calendar period of cART start and initial cART regimen.
Results: Of 476 children, 88 % were vertically infected. At cART initiation, median (interquartile range) age was 6.6 years (2.1–10.1), CD4 cell count 297 cells/mm3 (98–639), and HIV-RNA 5.2 log10copies/mL (4.7–5.7). Of 37 children (7.8 %, 95 % confidence interval (CI), 5.5–10.6) harboring a virus with ≥1 PDR mutations, 30 children had a virus resistant to ≥1 of the prescribed drugs. Overall, the cumulative Kaplan-Meier estimate for virological failure was 19.8 % (95 %CI, 16.4–23.9). Cumulative risk for VF tended to be higher among children harboring a virus with PDR and resistant to ≥1 drug prescribed than among those receiving fully active cART: 32.1 % (17.2–54.8) versus 19.4 % (15.9–23.6) (P = 0.095). In multivariable analysis, age was associated with a higher risk of VF with a 12 % reduced risk per additional year (HR 0.88; 95 %CI, 0.82–0.95; P < 0.001).
Conclusions: PDR was not significantly associated with a higher risk of VF in children in the first year of cART. The risk of VF decreased by 12 % per additional year at treatment initiation which may be due to fading of PDR mutations over time. Lack of appropriate formulations, in particular for the younger age group, may be an important determinant of virological failure.
Influence of the sFlt-1/PlGF ratio on clinical decision-making in women with suspected preeclampsia
(2016)
Objective: To evaluate the influence of the soluble fms-like tyrosine kinase 1/placental growth factor ratio in physicians’ decision making in pregnant women with signs and symptoms of preeclampsia in routine clinical practice.
Methods: A multicenter, prospective, open, non-interventional study enrolled pregnant women presenting with preeclampsia signs and symptoms in several European perinatal care centers. Before the soluble fms-like tyrosine kinase 1/placental growth factor ratio result was known, physicians documented intended clinical procedures using an iPad® application (data locked/time stamped). After the result was available, clinical decisions were confirmed or revised and documented. An independent adjudication committee evaluated the appropriateness of decisions based on maternal/fetal outcomes. Clinician decision making with regard to hospitalization was the primary outcome.
Results: In 16.9% of mothers (20/118) the hospitalization decision was changed after knowledge of the ratio. In 13 women (11.0%), the initial decision to hospitalize was changed to no hospitalization. In seven women (5.9%) the revised decision was hospitalization. All revised decisions were considered appropriate by the panel of adjudicators (McNemar test; p < 0.0001).
Conclusions: The use of the soluble fms-like tyrosine kinase 1/placental growth factor test influenced clinical decision making towards appropriate hospitalization in a considerable proportion of women with suspected preeclampsia. This is the first study to demonstrate the impact of angiogenic biomarkers on decision making in a routine clinical practice.
Background: Hemodynamic instability is frequent and outcome-relevant in critical illness. The understanding of complex hemodynamic disturbances and their monitoring and management plays an important role in treatment of intensive care patients. An increasing number of treatment recommendations and guidelines in intensive care medicine emphasize hemodynamic goals, which go beyond the measurement of blood pressures. Yet, it is not known to which extent the infrastructural prerequisites for extended hemodynamic monitoring are given in intensive care units (ICUs) and how hemodynamic management is performed in clinical practice. Further, it is still unclear which factors trigger the use of extended hemodynamic monitoring.
Methods: In this multicenter, 1-day (November 7, 2013, and the preceding 24 h) cross-sectional study, we retrieved data on patient monitoring from ICUs in Germany, Austria, and Switzerland by means of a web-based case report form. One hundred and sixty-one intensive care units contributed detailed information on availability of hemodynamic monitoring. In addition, detailed information on hemodynamic monitoring of 1789 patients that were treated on due date was collected, and independent factors triggering the use of extended hemodynamic monitoring were identified by multivariate analysis.
Results: Besides basic monitoring with electrocardiography (ECG), pulse oximetry, and blood pressure monitoring, the majority of patients received invasive arterial (77.9 %) and central venous catheterization (55.2 %). All over, additional extended hemodynamic monitoring for assessment of cardiac output was only performed in 12.3 % of patients, while echocardiographic examination was used in only 1.9 %. The strongest independent predictors for the use of extended hemodynamic monitoring of any kind were mechanical ventilation, the need for catecholamine therapy, and treatment backed by protocols. In 71.6 % of patients in whom extended hemodynamic monitoring was added during the study period, this extension led to changes in treatment.
Conclusions: Extended hemodynamic monitoring, which goes beyond the measurement of blood pressures, to date plays a minor role in the surveillance of critically ill patients in German, Austrian, and Swiss ICUs. This includes also consensus-based recommended diagnostic and monitoring applications, such as echocardiography and cardiac output monitoring. Mechanical ventilation, the use of catecholamines, and treatment backed by protocol could be identified as factors independently associated with higher use of extended hemodynamic monitoring.
Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug’s mechanism of action.
Background: Community acquired viruses (CRVs) may cause severe disease in cancer patients. Thus, efforts should be made to diagnose CRV rapidly and manage CRV infections accordingly.
Methods: A panel of 18 clinicians from the Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology have convened to assess the available literature and provide recommendations on the management of CRV infections including influenza, respiratory syncytial virus, parainfluenza virus, human metapneumovirus and adenovirus.
Results: CRV infections in cancer patients may lead to pneumonia in approximately 30% of the cases, with an associated mortality of around 25%. For diagnosis of a CRV infection, combined nasal/throat swabs or washes/aspirates give the best results and nucleic acid amplification based-techniques (NAT) should be used to detect the pathogen. Hand hygiene, contact isolation and face masks have been shown to be of benefit as general infection management. Causal treatment can be given for influenza, using a neuraminidase inhibitor, and respiratory syncytial virus, using ribavirin in addition to intravenous immunoglobulins. Ribavirin has also been used to treat parainfluenza virus and human metapneumovirus, but data are inconclusive in this setting. Cidofovir is used to treat adenovirus pneumonitis.
Conclusions: CRV infections may pose a vital threat to patients with underlying malignancy. This guideline provides information on diagnosis and treatment to improve the outcome.
Background: Shortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12.
Methods: In this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0–F2 fibrosis, patients with HCV-RNA <25 IU/mL (detectable/undetectable) at Week 2, and undetectable HCV-RNA at Weeks 4 and 8, stopped all treatment at Week 12. All other patients continued PR for a further 12 weeks. Baseline factors significantly associated with SVR12 were identified through logistic regression.
Results: Of 163 patients who participated in the study, 123 (75%) qualified for 12-week treatment; of these, 81 (66%) achieved SVR12. Baseline factors positively associated with SVR12 rates in patients receiving the 12-week regimen were: IL28B CC genotype: (94% SVR12); HCV RNA ≤800,000 IU/mL (82%); F0–F1 fibrosis (74%). Among all 163 patients, 94% experienced ≥1 adverse event (AE), 4% a serious AE, and 2.5% discontinued due to an AE. Reduced impairment in patient-reported outcomes was observed in the 12-week vs >12-week regimen.
Conclusions: Overall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen.
Trial Registration: ClinicalTrials.gov NCT01846832
Core Facilities (CF) for advanced light microscopy (ALM) have become indispensable support units for research in the life sciences. Their organizational structure and technical characteristics are quite diverse, although the tasks they pursue and the services they offer are similar. Therefore, throughout Europe, scientists from ALM‐CFs are forming networks to promote interactions and discuss best practice models. Here, we present recommendations for ALM‐CF operations elaborated by the workgroups of the German network of ALM‐CFs, German Bio‐Imaging (GerBI). We address technical aspects of CF planning and instrument maintainance, give advice on the organization and management of an ALM‐CF, propose a scheme for the training of CF users, and provide an overview of current resources for image processing and analysis. Further, we elaborate on the new challenges and opportunities for professional development and careers created by CFs. While some information specifically refers to the German academic system, most of the content of this article is of general interest for CFs in the life sciences.
In modern welfare states, family policies may resolve the tension between employment and care-focused demands. However these policies sometimes have adverse consequences for distinct social groups. This study examined gender and educational differences in working parents’ perceived work–family conflict and used a comparative approach to test whether family policies, in particular support for child care and leave from paid work, are capable of reducing work–family conflict as well as the gender and educational gaps in work–family conflict. We use data from the European Social Survey 2010 for 20 countries and 5296 respondents (parents), extended with information on national policies for maternity and parental leave and child care support from the OECD Family Database. Employing multilevel analysis, we find that mothers and the higher educated report most work–family conflict. Policies supporting child care reduce the level of experienced work–family conflict; family leave policy appears to have no alleviating impact on working parents’ work–family conflict. Our findings indicate that family policies appear to be unable to reduce the gender gap in conflict perception and even widen the educational gap in work–family conflict.
Background: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Growing evidence indicates that tumor-initiating cells (TICs) are responsible for tumor growth and progression. Conventional chemotherapeutics do not sufficiently eliminate TICs, leading to tumor relapse. We aimed to gain insight into TIC biology by comparing the transcriptome of primary TIC cultures and their normal stem cell counterparts to uncover expression differences.
Methods: We established colonosphere cultures derived from the resection of paired specimens of primary tumor and normal mucosa in patients with CRC. These colonospheres, enriched for TICs, were used for differential transcriptome analyses to detect new targets for a TIC-directed therapy. Effects of target inhibition on CRC cells were studied in vitro and in vivo.
Results: Pathway analysis of the regulated genes showed enrichment of genes central to PI3K/AKT and Wnt-signaling. We identified CD133 as a marker for a more aggressive CRC subpopulation enriched with TICs in SW480 CRC cells in an in vivo cancer model. Treatment of CRC cells with the selective AKT inhibitor MK-2206 caused a decrease in cell proliferation, particularly in the TIC fraction, resulting in a significant reduction of the stemness capacity to form colonospheres in vitro and to initiate tumor formation in vivo. Consequently, MK-2206 treatment of mice with established xenograft tumors exhibited a significant deceleration of tumor progression. Primary patient-derived tumorsphere growth was significantly inhibited by MK-2206.
Conclusion: This study reveals that AKT signaling is critical for TIC proliferation and can be efficiently targeted by MK-2206 representing a preclinical therapeutic strategy to repress colorectal TICs.
Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69 ± .06 for the cohort without IT and .69 ± .10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21 ± .05, 3-year CITRM, .10 ± .04; IT patients: 3-year CIR, .18 ± .09, 3-year CITRM .13 ± .07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL.
Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.