The Primary Folding Defect and Rescue of ΔF508 CFTR Emerge during Translation of the Mutant Domain

In the vast majority of cystic fibrosis (CF) patients, deletion of residue F508 from CFTR is the cause of disease. F508 resides in the first nucleotide binding domain (NBD1) and its absence leads to CFTR misfolding and degradation. We show here that the primary folding defect arises during synthesis, as soon as NBD1 is translated. Introduction of either the I539T or G550E suppressor mutation in NBD1 partially rescues ΔF508 CFTR to the cell surface, but only I539T repaired ΔF508 NBD1. We demonstrated rescue of folding and stability of NBD1 from full-length ΔF508 CFTR expressed in cells to isolated purified domain. The co-translational rescue of ΔF508 NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis

Quantum Spacetime Phenomenology

I review the current status of phenomenological programs inspired by quantum-spacetime research. I stress in particular the significance of results establishing that certain data analyses provide sensitivity to effects introduced genuinely at the Planck scale. And my main focus is on phenomenological programs that managed to affect the directions taken by studies of quantum-spacetime theories.Comment: 125 pages, LaTex. This V2 is updated and more detailed than the V1, particularly for quantum-spacetime phenomenology. The main text of this V2 is about 25% more than the main text of the V1. Reference list roughly double

Water uptake of hydrophilic polymers determined by thermal gravimetric analyzer with a controlled humidity chamber

The moisture uptake of several water-soluble polymers at different humidities was investigated with a thermal gravimetric analyzer equipped with a controlled humidity chamber. The water sorption of poly(acrylic acid) sodium salt, poly(ethylene glycol) and silica, which are known as super absorbers, were examined. In addition, various hydrophilic polymeric materials were selected according to their structural features. These included hydroxyl functions on the side chains (e.g. poly(2-hydroxyethyl methacrylate)), as well as acidic or basic functionalities (e.g. poly (dimethylaminoethyl methacrylate) or poly(vinylimidazole)). In addition, poly(2-methyl-2-oxazoline) (P(MeOx)) and poly(2-ethyl-2-oxazoline) (P(EtOx)), which are well-known hydrophilic polymers, were also investigated in this context. More significant weight percent changes were obtained for P(MeOx) (60% at 90% relative humidity (RH)) in comparison to P(EtOx) (35% at 90% RH) as a result of the slight difference in hydrophilicity of the structures. The effect of the chain length on the ability for water uptake was also investigated for both poly(oxazolines). Finally, thermoresponsive polymers with a lower critical solution temperature (LCST) behavior (e.g. poly(N-isopropylacrylamide) and poly(dimethylaminoethyl methacrylate)) were also examined. The measurements for the latter polymers were performed below and above the LCST of each polymer whereby the humidities are varied from 0 to 90% with steps of 10%. Upon increasing humidity, the results revealed relatively high water uptake values (8% and 22% for P(NIPAM) and for P(DMAEMA), respectively) below the LCSTs of the polymers and, contrastingly, a small weight loss above their LCSTs. The present results allow a deeper insight into important structure–property relationships (e.g. the influence of the polymer backbone, functional groups, LCST behavior, etc. on the water-uptake properties), and will in subsequent steps permit the directed design of tailor-made polymers for selected applications

Trapezius Motor Evoked Potentials From Transcranial Electrical Stimulation and Transcranial Magnetic Stimulation: Reference Data, Characteristic Differences and Intradural Motor Velocities in Horses

Reason for Performing Study: So far, only transcranial motor evoked potentials (MEP) of the extensor carpi radialis and tibialis cranialis have been documented for diagnostic evaluation in horses. These allow for differentiating whether lesions are located in either the thoraco-lumbar region or in the cervical myelum and/or brain. Transcranial trapezius MEPs further enable to distinguish between spinal and supraspinal located lesions. No normative data are available. It is unclear whether transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) are interchangeable modalities. Objectives: To provide normative data for trapezius MEP parameters in horses for TES and TMS and to discern direct and indirect conduction routes by neurophysiological models that use anatomical geometric characteristics to relate latency times with peripheral (PCV) and central conduction velocities (CCV). Methods: Transcranial electrical stimulation-induced trapezius MEPs were obtained from twelve horses. TES and TMS-MEPs (subgroup 5 horses) were compared intra-individually. Trapezius MEPs were measured bilaterally twice at 5 intensity steps. Motoneurons were localized using nerve conduction models of the cervical and spinal accessory nerves (SAN). Predicted CCVs were verified by multifidus MEP data from two horses referred for neurophysiological assessment. Results: Mean MEP latencies revealed for TES: 13.5 (11.1-16.0)ms and TMS: 19.7 (12-29.5)ms, comprising ∼100% direct routes and for TMS mixed direct/indirect routes of L:23/50; R:14/50. Left/right latency decreases over 10 > 50 V for TES were: -1.4/-1.8 ms and over 10 > 50% for TMS: -1.7/-3.5 ms. Direct route TMS-TES latency differences were 1.88-4.30 ms. 95% MEP amplitudes ranges for TES were: L:0.26-22 mV; R:0.5-15 mV and TMS: L:0.9 - 9.1 mV; R:1.1-7.9 mV. Conclusion: This is the first study to report normative data characterizing TES and TMS induced- trapezius MEPs in horses. The complex trapezius innervation leaves TES as the only reliable stimulation modality. Differences in latency times along the SAN route permit for estimation of the location of active motoneurons, which is of importance for clinical diagnostic purpose. SAN route lengths and latency times are governed by anatomical locations of motoneurons across C2-C5 segments. TES intensity-dependent reductions of trapezius MEP latencies are similar to limb muscles while MEP amplitudes between sides and between TES and TMS are not different. CCVs may reach 180 m/s

alphaB-crystallin stimulates VEGF secretion and tumor cell migration and correlates with enhanced distant metastasis in head and neck squamous cell carcinoma

Contains fulltext : 111464.pdf (publisher's version ) (Open Access

Phylogeographic distribution of human and hare Francisella tularenses susp. holarctica strains in the Netherlands and its pathology in European brown hares (Lepus europaeus)

Sequence-based typing of Francisella tularensis has led to insights in the evolutionary developments of tularemia. In Europe, two major basal clades of F. tularensis subsp. holarctica exist, with a distinct geographical distribution. Basal clade B.6 is primarily found in Western Europe, while basal clade B.12 occurs predominantly in the central and eastern parts of Europe. There are indications that tularemia is geographically expanding and that strains from the two clades might differ in pathogenicity, with basal clade B.6 strains being potentially more virulent than basal clade B.12. This study provides information on genotypes detected in the Netherlands during 2011–2017. Data are presented for seven autochthonous human cases and for 29 European brown hares (Lepus europaeus) with laboratory confirmed tularemia. Associated disease patterns are described for 25 European brown hares which underwent post-mortem examination. The basal clades B.6 and B.12 are present both in humans and in European brown hares in the Netherlands, with a patchy geographical distribution. For both genotypes the main pathological findings in hares associated with tularemia were severe (sub)acute necrotizing hepatitis and splenitis as well as necrotizing lesions and hemorrhages in several other organs. Pneumonia was significantly more common in the B.6 than in the B.12 cases. In conclusion, the two major basal clades present in different parts in Europe are both present in the Netherlands. In hares found dead, both genotypes were associated with severe acute disease affecting multiple organs. Hepatitis and splenitis were common pathological findings in hares infected with either genotype, but pneumonia occurred significantly more frequently in hares infected with the B.6 genotype compared to hares infected with the B.12 genotype

Behavioural Economics in Unfair Contract Terms

Behavioural law and economics, Information disclosure, Consumer policy, Standard form contracts,