The RAB3-RIM Pathway Is Essential for the Release of Neuromodulators

Neurons secrete neuromodulators/neuropeptides from dense-core vesicles (DCVs) by a largely unknown mechanism. Persoon et al. identify RAB3 and RIM1/2 as essential factors. RAB3’s indispensable role is the first distinct feature of DCV secretion as compared to synaptic vesicle secretion

Effects of dorsolateral prefrontal cortex lesion on motor habit and performance assessed with manual grasping and control of force in macaque monkeys.

In the context of an autologous adult neural cell ecosystem (ANCE) transplantation study, four intact adult female macaque monkeys underwent a unilateral biopsy of the dorsolateral prefrontal cortex (dlPFC) to provide the cellular material needed to obtain the ANCE. Monkeys were previously trained to perform quantitative motor (manual dexterity) tasks, namely, the "modified-Brinkman board" task and the "reach and grasp drawer" task. The aim of the present study was to extend preliminary data on the role of the prefrontal cortex in motor habit and test the hypothesis that dlPFC contributes to predict the grip force required when a precise level of force to be generated is known beforehand. As expected for a small dlPFC biopsy, neither the motor performance (score) nor the spatiotemporal motor sequences were affected in the "modified-Brinkman board" task, whereas significant changes (mainly decreases) in the maximal grip force (force applied on the drawer knob) were observed in the "reach and grasp drawer" task. The present data in the macaque monkey related to the prediction of grip force are well in line with the previous fMRI data reported for human subjects. Moreover, the ANCE transplantation strategy (in the case of stroke or Parkinson's disease) based on biopsy in dlPFC does not generate unwanted motor consequences, at least as far as motor habit and motor performance are concerned in the context of a sequential grasping a small objects, which does not require the development of significant force levels

A new measurement of the neutron detection efficiency for the NaI Crystal Ball detector

We report on a measurement of the neutron detection efficiency in NaI crystals in the Crystal Ball detector obtained from a study of single p0 photoproduction on deuterium using the tagged photon beam at the Mainz Microtron. The results were obtained up to a neutron energy of 400 MeV. They are compared to previous measurements made more than 15 years ago at the pion beam at the BNL AGS

Measurements of double-polarized compton scattering asymmetries and extraction of the proton spin polarizabilities

The spin polarizabilities of the nucleon describe how the spin of the nucleon responds to an incident polarized photon. The most model-independent way to extract the nucleon spin polarizabilities is through polarized Compton scattering. Double-polarized Compton scattering asymmetries on the proton were measured in the Δ(1232) region using circularly polarized incident photons and a transversely polarized proton target at the Mainz Microtron. Fits to asymmetry data were performed using a dispersion model calculation and a baryon chiral perturbation theory calculation, and a separation of all four proton spin polarizabilities in the multipole basis was achieved. The analysis based on a dispersion model calculation yields γE1E1=−3.5±1.2, γM1M1=3.16±0.85, γE1M2=−0.7±1.2, and γM1E2=1.99±0.29, in units of 10−4  fm4

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.

p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate

Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Brain A beta deposition is a key early event in the pathogenesis of Alzheimer ' s disease (AD), but the long presymptomatic phase and poor correlation between A beta deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on A beta, we analyzed the trajectories of cerebral A beta accumulation, A beta seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in A beta-precursor protein transgenic mice. We find that A beta deposition increases linearly until it reaches an apparent plateau at a late age, while A beta seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of A beta generation in amyloid-laden mice reduced A beta deposition and associated glial changes, but failed to reduce A beta seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of A beta generation was started at pre-amyloid stages, CSF NfL did not increase despite some A beta deposition, microglial activation, and robust brain A beta seeding activity. A dissociation of A beta load and CSF NfL trajectories was also found in familial AD, consistent with the view that A beta aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when A beta seeding activity is saturated and before A beta deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease. The poor correlation between brain A beta deposition and clinical symptoms in Alzheimer ' s disease remains puzzling. Here, the authors show a temporal dissociation of A beta deposition and neurodegeneration