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NEK family kinases are serine/threonine kinases that have been functionally implicated in the regulation of the disjunction of the centrosome, the assembly of the mitotic spindle, the function of the primary cilium and the DNA damage response. NEK1 shows pleiotropic functions and has been found to be mutated in cancer cells, ciliopathies such as the polycystic kidney disease, as well as in the genetic diseases short-rib thoracic dysplasia, Mohr-syndrome and amyotrophic lateral sclerosis. NEK1 is essential for the ionizing radiation DNA damage response and priming of the ATR kinase and of Rad54 through phosphorylation. Here we report on the structure of the kinase domain of human NEK1 in its apo- and ATP-mimetic inhibitor bound forms. The inhibitor bound structure may allow the design of NEK specific chemo-sensitizing agents to act in conjunction with chemo- or radiation therapy of cancer cells. Furthermore, we characterized the dynamic protein interactome of NEK1 after DNA damage challenge with cisplatin. Our data suggest that NEK1 and its interaction partners trigger the DNA damage pathways responsible for correcting DNA crosslinks.
CryoEM structures of membrane pore and prepore complex reveal cytolytic mechanism of Pneumolysin
(2017)
Many pathogenic bacteria produce pore-forming toxins to attack and kill human cells. We have determined the 4.5 Å structure of the ~2.2 MDa pore complex of pneumolysin, the main virulence factor of Streptococcus pneumoniae, by cryoEM. The pneumolysin pore is a 400 Å ring of 42 membrane-inserted monomers. Domain 3 of the soluble toxin refolds into two ~85 Å β-hairpins that traverse the lipid bilayer and assemble into a 168-strand β-barrel. The pore complex is stabilized by salt bridges between β-hairpins of adjacent subunits and an internal α-barrel. The apolar outer barrel surface with large sidechains is immersed in the lipid bilayer, while the inner barrel surface is highly charged. Comparison of the cryoEM pore complex to the prepore structure obtained by electron cryo-tomography and the x-ray structure of the soluble form reveals the detailed mechanisms by which the toxin monomers insert into the lipid bilayer to perforate the target membrane.
Background: Recurrent airway infections are common in patients with Down’s syndrome (DS). Hence, ruling out Cystic Fibrosis (CF) in these patients is often required. In the past, the value of sweat testing – the gold standard to diagnose CF – has been questioned in DS as false positive results have been reported. However, these reports are based on measurements of sweat osmolality or sodium concentrations, not chloride concentrations. This study analyses sweat secretion rate and chloride concentration in sweat samples of patients with DS in comparison to healthy controls.
Methods: We assessed sweat samples in 16 patients with DS and 16 healthy controls regarding sweat secretion rate (SSR) and sweat chloride concentration.
Results: All measured chloride concentrations were within the normal range. The chloride concentrations were slightly, but not significantly lower in patients with DS (15,54 mmol/l (±4,47)) compared to healthy controls (18,31 mmol/l (±10,12)). While no gender gap in chloride concentration could be found, chloride concentration increased with age in both groups.
Insufficient sweat was collected in 2 females with DS (12.5% of the study group) but not in an individual of the control group. A significant lower sweat secretion rate was found in the DS group (27,6 μl/30 min (± 12,18)) compared to the control group (42,7 μl/30 min (± 21,22)). In a sub-analysis, female patients produced significantly less sweat (20,8 ± 10,6 μl/30 min) than male patients with DS (36,4 ± 7,8 μl/30 min), which accounts for the difference between patients and controls. Furthermore, while the sweating secretion rate increased with age in the control group, it did not do so in the DS group. Once again this was due to female patients with DS, who did not show a significant increase of sweat secretion rate with age.
Conclusions: Sweat chloride concentrations were within the normal range in patients with DS and therefore seem to be a reliable tool for testing for CF in these patients. Interestingly, we found a reduced sweat secretion rate in the DS group. Whether the last one has a functional and clinical counterpart, possibly due to a disturbed thermoregulation in DS patients, requires further investigation.
Membrane proteins frequently assemble into higher order homo- or hetero-oligomers within their natural lipid environment. This complex formation can modulate their folding, activity as well as substrate selectivity. Non-disruptive methods avoiding critical steps, such as membrane disintegration, transfer into artificial environments or chemical modifications are therefore essential to analyze molecular mechanisms of native membrane protein assemblies. The combination of cell-free synthetic biology, nanodisc-technology and non-covalent mass spectrometry provides excellent synergies for the analysis of membrane protein oligomerization within defined membranes. We exemplify our strategy by oligomeric state characterization of various membrane proteins including ion channels, transporters and membrane-integrated enzymes assembling up to hexameric complexes. We further indicate a lipid-dependent dimer formation of MraY translocase correlating with the enzymatic activity. The detergent-free synthesis of membrane protein/nanodisc samples and the analysis by LILBID mass spectrometry provide a versatile platform for the analysis of membrane proteins in a native environment.
A primordial state of matter consisting of free quarks and gluons that existed in the early universe a few microseconds after the Big Bang is also expected to form in high-energy heavy-ion collisions. Determining the equation of state (EoS) of such a primordial matter is the ultimate goal of high-energy heavy-ion experiments. Here we use supervised learning with a deep convolutional neural network to identify the EoS employed in the relativistic hydrodynamic simulations of heavy ion collisions. High-level correlations of particle spectra in transverse momentum and azimuthal angle learned by the network act as an effective EoS-meter in deciphering the nature of the phase transition in quantum chromodynamics. Such EoS-meter is model-independent and insensitive to other simulation inputs including the initial conditions for hydrodynamic simulations.
Background: Agrocybe aegerita is an agaricomycete fungus with typical mushroom features, which is commercially cultivated for its culinary use. In nature, it is a saprotrophic or facultative pathogenic fungus causing a white-rot of hardwood in forests of warm and mild climate. The ease of cultivation and fructification on solidified media as well as its archetypal mushroom fruit body morphology render A. aegerita a well-suited model for investigating mushroom developmental biology.
Results: Here, the genome of the species is reported and analysed with respect to carbohydrate active genes and genes known to play a role during fruit body formation. In terms of fruit body development, our analyses revealed a conserved repertoire of fruiting-related genes, which corresponds well to the archetypal fruit body morphology of this mushroom. For some genes involved in fruit body formation, paralogisation was observed, but not all fruit body maturation-associated genes known from other agaricomycetes seem to be conserved in the genome sequence of A. aegerita. In terms of lytic enzymes, our analyses suggest a versatile arsenal of biopolymer-degrading enzymes that likely account for the flexible life style of this species. Regarding the amount of genes encoding CAZymes relevant for lignin degradation, A. aegerita shows more similarity to white-rot fungi than to litter decomposers, including 18 genes coding for unspecific peroxygenases and three dye-decolourising peroxidase genes expanding its lignocellulolytic machinery.
Conclusions: The genome resource will be useful for developing strategies towards genetic manipulation of A. aegerita, which will subsequently allow functional genetics approaches to elucidate fundamentals of fruiting and vegetative growth including lignocellulolysis.
Summary: Persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium found that persistence with denosumab remains consistently high after 24 months in patients at high risk of fracture.
Purpose: Continued persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of clinical practice evaluated medication-taking behavior of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium and factors influencing persistence.
Methods: Subcutaneous denosumab (60 mg every 6 months) was assigned according to prescribing information and local guidelines before and independently of enrollment; outcomes were recorded during routine practice for up to 24 months. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection and adherence as administration of subsequent injections within 6 months ± 4 weeks of the previous injection. Medication coverage ratio (MCR) was calculated as the proportion of time a patient was covered by denosumab. Associations between pre-specified baseline covariates and 24-month persistence were assessed using multivariable logistic regression.
Results: The 24-month analyses included 1479 women (mean age 66.3–72.5 years) from 140 sites; persistence with denosumab was 75.1–86.0%, adherence 62.9–70.1%, and mean MCR 87.4–92.4%. No covariate had a significant effect on persistence across all four countries. For three countries, a recent fall decreased persistence; patients were generally older with chronic medical conditions. In some countries, other covariates (e.g., older age, comorbidity, immobility, and prescribing reasons) decreased persistence. Adverse drug reactions were reported in 2.3–6.9% patients.
Conclusions: Twenty-four-month persistence with denosumab is consistently high among postmenopausal women in Europe and may be influenced by patient characteristics. Further studies are needed to identify determinants of low persistence.
Activation of Mitochondrial complex II-dependent respiration is beneficial for α-Synucleinopathies
(2015)
Parkinson’s disease and dementia with Lewy bodies are major challenges in research and clinical medicine world-wide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APP-transgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synuclein-transgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNAArg genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.
NMR spectroscopy is a powerful technique to study ribonucleic acids (RNAs) which are key players in a plethora of cellular processes. Although the NMR toolbox for structural studies of RNAs expanded during the last decades, they often remain challenging. Here, we show that solvent paramagnetic relaxation enhancements (sPRE) induced by the soluble, paramagnetic compound Gd(DTPA-BMA) provide a quantitative measure for RNA solvent accessibility and encode distance-to-surface information that correlates well with RNA structure and improves accuracy and convergence of RNA structure determination. Moreover, we show that sPRE data can be easily obtained for RNAs with any isotope labeling scheme and is advantageous regarding sample preparation, stability and recovery. sPRE data show a large dynamic range and reflect the global fold of the RNA suggesting that they are well suited to identify interaction surfaces, to score structural models and as restraints in RNA structure determination.
UICC classification accurately predicts overall survival but not recurrence-risk. We report here data of overall and first site-specific recurrence following curative surgery useful for the development of recurrence-oriented preventive target therapies. Patients who underwent resection for gastric cancer were stratified according to curability of surgery [curative (R0) vs non-curative resection], extent of surgery [limited (D1) vs extended (D2) node dissection] and pathological nodal/serosal status. The intent-to-treat principle, log-rank test and Cox regression analysis were used for statistical analysis of time-to-event (recurrence, death) endpoints. Curative resection only produced a chance of cure whereas survival was very poor following non-curative resection (P < 0.0001). For D2 R0 subgroup of patients, a pathological serosa and a node state-based classification into three groups, proved to be of clinical implication. Risk of recurrence after a median follow-up of 92 months was low among patients with both serosa and node-negative cancer (first group; 11%), moderate among those with either serosa or node-positive cancer (second group; 53%) and very high among those with both serosa and node-positive cancer (third group; 83%). In multivariate analysis, the relative risks of recurrence and death from gastric cancer among patients in the second and third groups, as compared to those in the first, were 7.07 (95% CI, 2.36–21.17; P = 0.0002) and 16.19 (95% CI, 5.76–45.54; P < 0.0001) respectively. First site-specific recurrence analysis revealed: low rate of loco-regional recurrence alone (12%), serosa state determinant factor of the site-recurrence (peritoneal for serosa-positive and haematogenous for serosa-negative cancers) and dramatic increase of all types of recurrence by the presence of nodal metastases. Our findings demonstrate that a pathological serosa- and node-based classification is very simple and predicts accurately site-specific recurrence-risks. Furthermore they reveal that risk of recurrence following curative D2 surgery alone is low for serosa- and node-negative cancers, but very high in serosa- and node-positive cancers suggesting the need for new therapeutic strategies in this subgroup of patients.