Direct Measurement of the Pseudoscalar Decay Constant fD+

The absolute branching fraction of $D^+ \to \mu^+ \nu$ has been directly measured by an analysis of a data sample of about 33 ${\rm pb^{-1}}$ collected around $\sqrt{s}=3.773$ GeV with the BES-II at the BEPC. At these energies, $D^-$ meson is produced in pair as $e^+e^-\to D^{+} D^{-}$. A total of $5321 \pm 149 \pm 160$ $D^-$ mesons are reconstructed from this data set. In the recoil side of the tagged $D^-$ mesons, $2.67\pm1.74$ purely leptonic decay events of $D^+ \to \mu^+ \nu$ are observed. This yields a branching fraction of $BF(D^+ \to \mu^+ \nu_{\mu}) = (0.122^{+0.111}_{-0.053}\pm 0.010)$, and a corresponding pseudoscalar decay constant $f_{D^+}=(371^{+129}_{-119}\pm 25)$ MeV.Comment: 7 pages, 8 figures, Submitted to Physics Letters B in October, 200

GSK3β Impairs KIF1A Transport in a Cellular Model of Alzheimer’s Disease but Does Not Regulate Motor Motility at S402

Impairment of axonal transport is an early pathologic event that precedes neurotoxicity in Alzheimer’s disease (AD). Soluble amyloid-β oligomers (AβOs), a causative agent of AD, activate intracellular signaling cascades that trigger phosphorylation of many target proteins, including tau, resulting in microtubule destabilization and transport impairment. Here, we investigated how KIF1A, a kinesin-3 family motor protein required for the transport of neurotrophic factors, is impaired in mouse hippocampal neurons treated with AβOs. By live cell imaging, we observed that AβOs inhibit transport of KIF1A-GFP similarly in wild-type and tau knock-out neurons, indicating that tau is not required for this effect. Pharmacological inhibition of glycogen synthase kinase 3β (GSK3β), a kinase overactivated in AD, prevented the transport defects. By mass spectrometry on KIF1A immunoprecipitated from transgenic AD mouse brain, we detected phosphorylation at S402, which conforms to a highly conserved GSK3β consensus site. We confirmed that this site is phosphorylated by GSK3β in vitro. Finally, we tested whether a phosphomimic of S402 could modulate KIF1A motility in control and AβO-treated mouse neurons and in a Golgi dispersion assay devoid of endogenous KIF1A. In both systems, transport driven by mutant motors was similar to that of WT motors. In conclusion, GSK3β impairs KIF1A transport but does not regulate motor motility at S402. Further studies are required to determine the specific phosphorylation sites on KIF1A that regulate its cargo binding and/or motility in physiological and disease states

Usual and unusual causes of extrahepatic cholestasis: Assessment with magnetic resonance cholangiography and fast MRI

Cholestasis may result from hepatocellular (intrahepatic) disease or biliary tract (extrahepatic) abnormalities. Etiologies causing extrahepatic cholestasis are extremely diverse and invasive procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC), were previously required to establish the diagnosis. Due to refinements of magnetic resonance imaging (MRI) techniques, the patient with extrahepatic cholestasis currently can be evaluated noninvasively, and the information revealed frequently exceeds the findings obtained by ERCP and PTC. In this essay, we illustrate the classic MR cholangiographic (MRC) and MRI features of a variety of disorders causing extrahepatic cholestasis, including non-neoplastic disorders of the biliary tract (congenital abnormalities, infectious processes, iatrogenic disorders, and postsurgical complications) and neoplastic conditions (e.g., tumors of the pancreas, biliary tree, liver, ampulla, and regional lymph nodes). In most cases, familiarity with the key MRC features in addition to information obtained via cross-sectional MR images provide sufficient information for adequate lesion characterization

A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations

Many patients with chronic pulmonary disease similar to that seen in cystic fibrosis have normal (or nondiagnostic) sweat chloride values. It has been difficult to make the diagnosis of cystic fibrosis in these patients because no associated mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been identified. We evaluated 23 patients with pulmonary disease characteristic of cystic fibrosis but with sweat chloride concentrations in the normal range. Mutations in the CFTR gene were sought by direct sequencing of polymerase chain reaction-amplified nasal epithelial messenger RNA and by testing the functioning of affected epithelium. A cytidine phosphate guanosine dinucleotide C-to-T point mutation in intron 19 of the CFTR gene, termed 3849+10 kb C to T, was identified in 13 patients from eight unrelated families. This mutation was found in patients from three different ethnic groups with three different extended haplotypes. The mutation leads to the creation of a partially active splice site in intron 19 and to the insertion into most CFTR transcripts of a new 84-base-pair “exon,” containing an in-frame stop codon, between exons 19 and 20. Normally spliced transcripts were also detected at a level approximately 8 percent of that found in normal subjects. This mutation is associated with abnormal nasal epithelial and sweat acinar epithelial function. We have identified a point mutation in intron 19 of CFTR and abnormal epithelial function in patients who have cystic fibrosis-like lung disease but normal sweat chloride values. The identification of this mutation indicates that this syndrome is a form of cystic fibrosis. Screening for the mutation should prove diagnostically useful in this population of patients