Refine
Year of publication
- 2016 (730) (remove)
Document Type
- Article (730) (remove)
Language
- English (730) (remove)
Has Fulltext
- yes (730)
Is part of the Bibliography
- no (730)
Keywords
- Mitochondria (7)
- crystal structure (7)
- invasion (5)
- Cortex (4)
- Gender (4)
- Invasive species (4)
- apoptosis (4)
- cancer (4)
- management (4)
- Apoptosis (3)
Institute
- Medizin (283)
- Biowissenschaften (70)
- Physik (69)
- Geowissenschaften (61)
- Frankfurt Institute for Advanced Studies (FIAS) (58)
- Biochemie und Chemie (46)
- Informatik (38)
- Biodiversität und Klima Forschungszentrum (BiK-F) (34)
- Institut für Ökologie, Evolution und Diversität (27)
- Senckenbergische Naturforschende Gesellschaft (27)
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The paper titled "Cure of Chronic Viral Infection and Virus-Induced Type 1 Diabetes by Neutralizing Antibodies" has been retracted as it was found that the paper was unintentionally published twice by the journal’s former publisher.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.