NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration

The correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome

<p>Abstract</p> <p>Background</p> <p>To evaluate the relationship between endometrial thickness on day of human chorionic gonadotrophin administration (hCG) and pregnancy outcome in a large number of consecutive in vitro fertilization and embryo transfer (IVF-ET) cycles.</p> <p>Methods</p> <p>A retrospective cohort study including all patients who had IVF-ET from January 2003–December 2005 conducted at a tertiary center.</p> <p>Results</p> <p>A total of 2464 cycles were analysed. Pregnancy rate (PR) was 35.8%. PR increased linearly (r = 0.864) from 29.4% among patients with a lining of less than or equal to 6 mm, to 44.4% among patients with a lining of greater than or equal to 17 mm. ROC showed that endometrial thickness is not a good predictor of PR, so a definite cut-off value could not be established (AUC = 0.55).</p> <p>Conclusion</p> <p>There is a positive linear relationship between the endometrial thickness measured on the day of hCG injection and PR, and is independent of other variables. Hence aiming for a thicker endometrium should be considered.</p

Effects of Alcohol on the Acquisition and Expression of Fear Potentiated Startle in Mouse Lines Selectively Bred for High and Low Alcohol Preference

Rationale: Anxiety disorders and alcohol-use disorders frequently co-occur in humans perhaps because alcohol relieves anxiety. Studies in humans and rats indicate that alcohol may have greater anxiolytic effects in organisms with increased genetic propensity for high alcohol consumption. Objectives and Methods: The purpose of this study was to investigate the effects of moderate doses of alcohol (0.5, 1.0, 1.5 g/kg) on the acquisition and expression of anxiety-related behavior using a fear-potentiated startle (FPS) procedure. Experiments were conducted in two replicate pairs of mouse lines selectively bred for high- (HAP1 and HAP2) and low- (LAP1 and LAP2) alcohol preference; these lines have previously shown a genetic correlation between alcohol preference and FPS (HAP\u3eLAP; Barrenha and Chester 2007). In a control experiment, the effect of diazepam (4.0 mg/kg) on the expression of FPS was tested in HAP2 and LAP2 mice. Results: The 1.5 g/kg alcohol dose moderately decreased the expression of FPS in both HAP lines but not LAP lines. Alcohol had no effect on the acquisition of FPS in any line. Diazepam reduced FPS to a similar extent in both HAP2 and LAP2 mice. Conclusions: HAP mice may be more sensitive to the anxiolytic effects of alcohol than LAP mice when alcohol is given prior to the expression of FPS. These data collected in two pairs of HAP/LAP mouse lines suggest that the anxiolytic response to alcohol in HAP mice may be genetically correlated with their propensity toward high alcohol preference and robust FPS

Measurement of single π0 production by coherent neutral-current ν Fe interactions in the MINOS Near Detector

Forward single π0 production by coherent neutral-current interactions, νA→νAπ0, is investigated using a 2.8×1020 protons-on-target exposure of the MINOS Near Detector. For single-shower topologies, the event distribution in production angle exhibits a clear excess above the estimated background at very forward angles for visible energy in the range 1-8 GeV. Cross sections are obtained for the detector medium comprised of 80% iron and 20% carbon nuclei with =48, the highest- target used to date in the study of this coherent reaction. The total cross section for coherent neutral-current single π0 production initiated by the νμ flux of the NuMI low-energy beam with mean (mode) Eν of 4.9 GeV (3.0 GeV), is 77.6±5.0(stat)-16.8+15.0(syst)×10-40 cm2 pernucleus. The results are in good agreement with predictions of the Berger-Sehgal model

Search for Sterile Neutrinos Mixing with Muon Neutrinos in MINOS

We report results of a search for oscillations involving a light sterile neutrino over distances of 1.04 and 735 km in a νμ-dominated beam with a peak energy of 3 GeV. The data, from an exposure of 10.56 × 10^20 protons on target, are analyzed using a phenomenological model with one sterile neutrino. We constrain the mixing parameters θ24 and Δm41^2 and set limits on parameters of the four-dimensional Pontecorvo-Maki- Nakagawa-Sakata matrix, |Uμ4|2 and |Uτ4|2, under the assumption that mixing between νe and νs is negligible (|Ue4|^2 = 0). No evidence for νμ → νs transitions is found and we set a world-leading limit on θ24 for values of Δm41^2 ≲ 1 eV^2

Search for flavor-changing nonstandard neutrino interactions using nu(e) appearance in MINOS

We report new constraints on flavor-changing nonstandard neutrino interactions from the MINOS long-baseline experiment using νe and ¯νe appearance candidate events from predominantly νμ and ¯νμ beams. We used a statistical selection algorithm to separate νe candidates from background events, enabling an analysis of the combined MINOS neutrino and antineutrino data. We observe no deviations from standard neutrino mixing, and thus place constraints on the nonstandard interaction matter effect, |ϵeτ|, and phase, (δCP+δeτ), using a 30-bin likelihood fit

Measurement of Neutrino and Antineutrino Oscillations Using Beam and Atmospheric Data in MINOS

We report measurements of oscillation parameters from νμ and ν̅ μ disappearance using beam and atmospheric data from MINOS. The data comprise exposures of 10.71×1020 protons on target in the νμ-dominated beam, 3.36×1020 protons on target in the ν̅ μ-enhanced beam, and 37.88 kton yr of atmospheric neutrinos. Assuming identical ν and ν̅ oscillation parameters, we measure |Δm2|=(2.41-0.10+0.09)×10-3  eV2 and sin⁡2(2θ)=0.950-0.036+0.035. Allowing independent ν and ν̅ oscillations, we measure antineutrino parameters of |Δm̅ 2|=(2.50-0.25+0.23)×10-3  eV2 and sin⁡2(2θ̅ )=0.97-0.08+0.03, with minimal change to the neutrino parameters

Differential Role of Human Choline Kinase α and β Enzymes in Lipid Metabolism: Implications in Cancer Onset and Treatment

11 pages, 6 figures, 1 table.Background The Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK) is the first enzyme of the Kennedy branch of synthesis of 1phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKβ in carcinogenesis has been reported. Methodology/Principal Findings Here we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKβ display an ethanolamine kinase role, ChoKα1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKα1 than ChoKβ. Conclusion/Significance This study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ isoforms, suggesting different physiological roles and implications in human carcinogenesis. These findings constitute a step forward in the design of an antitumoral strategy based on ChoK inhibition.This work has been supported by grants to JCL from Comunidad de Madrid (GR-SAL-0821-2004), Ministerio de Ciencia e Innovación (SAF2008-03750, RD06/0020/0016), Fundación Mutua Madrileña, and by a grant to ARM from Fundación Mutua Madrileña.Peer reviewe

Precision measurement of the speed of propagation of neutrinos using the MINOS detectors

We report a two-detector measurement of the propagation speed of neutrinos over a baseline of 734 km. The measurement was made with the NuMI beam at Fermilab between the near and far MINOS detectors. The fractional difference between the neutrino speed and the speed of light is determined to be (v/c−1)=(1.0±1.1)×10−6, consistent with relativistic neutrinos