498 research outputs found
Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.
Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus
callosum (TCC) is a common and clinically distinct form of familial spastic
paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected
families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval
and identified ten mutations in a previously unidentified gene expressed
ubiquitously in the nervous system but most prominently in the cerebellum,
cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense
or insertions and deletions leading to a frameshift, suggesting a
loss-of-function mechanism. The identification of the function of the gene will
provide insight into the mechanisms leading to the degeneration of the
corticospinal tract and other brain structures in this frequent form of ARHSP
The Anti-Apoptotic Bcl-xL Protein, a New Piece in the Puzzle of Cytochrome C Interactome
A structural model of the adduct between human cytochrome c and the human
anti-apoptotic protein Bcl-xL, which defines the protein-protein
interaction surface, was obtained from solution NMR chemical shift perturbation
data. The atomic level information reveals key intermolecular contacts
identifying new potentially druggable areas on cytochrome c and
Bcl-xL. Involvement of residues on cytochrome c other than those
in its complexes with electron transfer partners is apparent. Key differences in
the contact area also exist between the Bcl-xL adduct with the Bak
peptide and that with cytochrome c. The present model provides insights to the
mechanism by which cytochrome c translocated to cytosol can be intercepted, so
that the apoptosome is not assembled
Age and baseline values predict 12 and 24-month functional changes in type 2 SMA
The aim of this retrospective study was to establish the range of functional changes at 12 and 24-month in 267 type 2 Spinal Muscular Atrophy (SMA) patients with multiple assessments. We included 652 Hammersmith Functional Motor Scale Expanded (HFMSE) assessments at 12 month- and 305 at 24 month- intervals. The cohort was subdivided by functional level, Survival of Motor Neuron copy number and age. Stable scores (± 2 points) were found in 68% at 12 months and in 55% at 24 months. A decrease ≥2 points was found in 21% at 12 months and in 35% at 24 months. An increase ≥2 points was found in 11% at 12 months and 9.5% at 24 months. The risk of losing ≥2 points increased with age and HFMSE score at baseline both at 12 and 24-month. For each additional HFMSE point at baseline, the relative risk of a >2 point decline at 12 months increases by 5% before age 5 years (p = 0.023), by 8% between 5 and 13 (p<0.001) and by 26% after 13 years (p = 0.003). The combination of age and HFMSE scores at baseline increased the ability to predict progression in type 2 SMA
High-resolution structure determination of the CylR2 homodimer using paramagnetic relaxation enhancement and structure-based prediction of molecular alignment
Structure determination of homooligomeric proteins by NMR spectroscopy is difficult due to the lack of chemical shift perturbation data, which is very effective in restricting the binding interface in heterooligomeric systems, and the difficulty of obtaining a sufficient number of intermonomer distance restraints. Here we solved the high-resolution solution structure of the 15.4 kDa homodimer CylR2, the regulator of cytolysin production from Enterococcus faecalis, which deviates by 1.1 Å from the previously determined X-ray structure. We studied the influence of different experimental information such as long-range distances derived from paramagnetic relaxation enhancement, residual dipolar couplings, symmetry restraints and intermonomer Nuclear Overhauser Effect restraints on the accuracy of the derived structure. In addition, we show that it is useful to combine experimental information with methods of ab initio docking when the available experimental data are not sufficient to obtain convergence to the correct homodimeric structure. In particular, intermonomer distances may not be required when residual dipolar couplings are compared to values predicted on the basis of the charge distribution and the shape of ab initio docking solutions
Neonatal jaundice and stool production in breast- or formula-fed term infants
It has remained unclear whether the amount of fecal fat excreted in the stool and stool production influences the severity of neonatal jaundice. We determined the relationship between stool production, fecal fat excretion and jaundice in healthy breast-fed (BF) or formula-fed (FF) (near-)term neonates. From postnatal day 1–4, we quantitatively collected stools from 27 FF and 33 BF infants in daily fractions. Stool production and fecal fat contents were related to unconjugated bilirubin (UCB) levels, as determined by transcutaneous bilirubinometry (TcB). Bilirubin concentrations and stool production did not differ between FF and BF neonates during the study period. Neonatal bilirubin levels were not inversely correlated with stool production. FF and BF infants had similar fecal fat excretion rates. The stool production of FF infants was profoundly lower in the present study than in a 1985 study by De Carvalho et al. [J Pediatr (1985) 107:786–790]. We conclude that increased jaundice during the first postnatal days in healthy term neonates can no longer be attributed to breast-feeding and speculate that improved absorbability of formulas since 1985 has contributed to similar fat excretion and stool production in FF and BF neonates in 2007
Muscle magnetic resonance imaging of a large cohort of distal hereditary motor neuropathies reveals characteristic features useful for diagnosis
Protein–protein HADDocking using exclusively pseudocontact shifts
In order to enhance the structure determination process of macromolecular assemblies by NMR, we have implemented long-range pseudocontact shift (PCS) restraints into the data-driven protein docking package HADDOCK. We demonstrate the efficiency of the method on a synthetic, yet realistic case based on the lanthanide-labeled N-terminal ε domain of the E. coli DNA polymerase III (ε186) in complex with the HOT domain. Docking from the bound form of the two partners is swiftly executed (interface RMSDs < 1 Å) even with addition of very large amount of noise, while the conformational changes of the free form still present some challenges (interface RMSDs in a 3.1–3.9 Å range for the ten lowest energy complexes). Finally, using exclusively PCS as experimental information, we determine the structure of ε186 in complex with the HOT-homologue θ subunit of the E. coli DNA polymerase III
Neutrophils in cancer: neutral no more
Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets
Observation of a J^PC = 1-+ exotic resonance in diffractive dissociation of 190 GeV/c pi- into pi- pi- pi+
The COMPASS experiment at the CERN SPS has studied the diffractive
dissociation of negative pions into the pi- pi- pi+ final state using a 190
GeV/c pion beam hitting a lead target. A partial wave analysis has been
performed on a sample of 420000 events taken at values of the squared
4-momentum transfer t' between 0.1 and 1 GeV^2/c^2. The well-known resonances
a1(1260), a2(1320), and pi2(1670) are clearly observed. In addition, the data
show a significant natural parity exchange production of a resonance with
spin-exotic quantum numbers J^PC = 1-+ at 1.66 GeV/c^2 decaying to rho pi. The
resonant nature of this wave is evident from the mass-dependent phase
differences to the J^PC = 2-+ and 1++ waves. From a mass-dependent fit a
resonance mass of 1660 +- 10+0-64 MeV/c^2 and a width of 269+-21+42-64 MeV/c^2
is deduced.Comment: 7 page, 3 figures; version 2 gives some more details, data unchanged;
version 3 updated authors, text shortened, data unchange
Structure of a Wbl protein and implications for NO sensing by M. tuberculosis
Mycobacterium tuberculosis causes pulmonary tuberculosis (TB) and claims ~1.8 million human lives per annum. Host nitric oxide (NO) is important in controlling TB infection. M. tuberculosis WhiB1 is a NO-responsive Wbl protein (actinobacterial iron-sulfur proteins first identified in the 1970s). Until now, the structure of a Wbl protein has not been available. Here a NMR structural model of WhiB1 reveals that Wbl proteins are four-helix bundles with a core of three α-helices held together by a [4Fe-4S] cluster. The iron-sulfur cluster is required for formation of a complex with the major sigma factor (σA) and reaction with NO disassembles this complex. The WhiB1 structure suggests that loss of the iron-sulfur cluster (by nitrosylation) permits positively charged residues in the C-terminal helix to engage in DNA binding, triggering a major reprogramming of gene expression that includes components of the virulence-critical ESX-1 secretion system
- …