Yeast Mitochondrial Biogenesis: A Role for the PUF RNA-Binding Protein Puf3p in mRNA Localization

The asymmetric localization of mRNA plays an important role in coordinating posttranscriptional events in eukaryotic cells. We investigated the peripheral mitochondrial localization of nuclear-encoded mRNAs (MLR) in various conditions in which the mRNA binding protein context and the translation efficiency were altered. We identified Puf3p, a Pumilio family RNA-binding protein, as the first trans-acting factor controlling the MLR phenomenon. This allowed the characterization of two classes of genes whose mRNAs are translated to the vicinity of mitochondria. Class I mRNAs (256 genes) have a Puf3p binding motif in their 3'UTR region and many of them have their MLR properties deeply affected by PUF3 deletion. Conversely, mutations in the Puf3p binding motif alter the mitochondrial localization of BCS1 mRNA. Class II mRNAs (224 genes) have no Puf3p binding site and their asymmetric localization is not affected by the absence of PUF3. In agreement with a co-translational import process, we observed that the presence of puromycin loosens the interactions between most of the MLR-mRNAs and mitochondria. Unexpectedly, cycloheximide, supposed to solidify translational complexes, turned out to destabilize a class of mRNA-mitochondria interactions. Classes I and II mRNAs, which are therefore transported to the mitochondria through different pathways, correlated with different functional modules. Indeed, Class I genes code principally for the assembly factors of respiratory chain complexes and the mitochondrial translation machinery (ribosomes and translation regulators). Class II genes encode proteins of the respiratory chain or proteins involved in metabolic pathways. Thus, MLR, which is intimately linked to translation control, and the activity of mRNA-binding proteins like Puf3p, may provide the conditions for a fine spatiotemporal control of mitochondrial protein import and mitochondrial protein complex assembly. This work therefore provides new openings for the global study of mitochondria biogenesis

Neurobehavioral Mechanisms of Temporal Processing Deficits in Parkinson's Disease

Parkinson's disease (PD) disrupts temporal processing, but the neuronal sources of deficits and their response to dopamine (DA) therapy are not understood. Though the striatum and DA transmission are thought to be essential for timekeeping, potential working memory (WM) and executive problems could also disrupt timing.The present study addressed these issues by testing controls and PD volunteers 'on' and 'off' DA therapy as they underwent fMRI while performing a time-perception task. To distinguish systems associated with abnormalities in temporal and non-temporal processes, we separated brain activity during encoding and decision-making phases of a trial. Whereas both phases involved timekeeping, the encoding and decision phases emphasized WM and executive processes, respectively. The methods enabled exploration of both the amplitude and temporal dynamics of neural activity. First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction. Unlike studies of timed movement, our results could not be attributed to traditional roles of the striatum and cerebellum in movement. Second, for the first time we identified temporal and non-temporal sources of impaired time perception. Striatal dysfunction was found during both phases consistent with its role in timekeeping. Activation was also abnormal in a WM network (middle-frontal and parietal cortex, lateral cerebellum) during encoding and a network that modulates executive and memory functions (parahippocampus, posterior cingulate) during decision making. Third, hypoactivation typified neuronal dysfunction in PD, but was sometimes characterized by abnormal temporal dynamics (e.g., lagged, prolonged) that were not due to longer response times. Finally, DA therapy did not alleviate timing deficits.Our findings indicate that impaired timing in PD arises from nigrostriatal and mesocortical dysfunction in systems that mediate temporal and non-temporal control-processes. However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity

GRANDMA and HXMT Observations of GRB 221009A -- the Standard-Luminosity Afterglow of a Hyper-Luminous Gamma-Ray Burst

GRB 221009A is the brightest Gamma-Ray Burst (GRB) detected in more than 50 years of study. In this paper, we present observations in the X-ray and optical domains after the GRB obtained by the GRANDMA Collaboration (which includes observations from more than 30 professional and amateur telescopes) and the Insight-HXMT Collaboration. We study the optical afterglow with empirical fitting from GRANDMA+HXMT data, augmented with data from the literature up to 60 days. We then model numerically, using a Bayesian approach, the GRANDMA and HXMT-LE afterglow observations, that we augment with Swift-XRT and additional optical/NIR observations reported in the literature. We find that the GRB afterglow, extinguished by a large dust column, is most likely behind a combination of a large Milky-Way dust column combined with moderate low-metallicity dust in the host galaxy. Using the GRANDMA+HXMT-LE+XRT dataset, we find that the simplest model, where the observed afterglow is produced by synchrotron radiation at the forward external shock during the deceleration of a top-hat relativistic jet by a uniform medium, fits the multi-wavelength observations only moderately well, with a tension between the observed temporal and spectral evolution. This tension is confirmed when using the extended dataset. We find that the consideration of a jet structure (Gaussian or power-law), the inclusion of synchrotron self-Compton emission, or the presence of an underlying supernova do not improve the predictions, showing that the modelling of GRB22109A will require going beyond the most standard GRB afterglow model. Placed in the global context of GRB optical afterglows, we find the afterglow of GRB 221009A is luminous but not extraordinarily so, highlighting that some aspects of this GRB do not deviate from the global known sample despite its extreme energetics and the peculiar afterglow evolution.Comment: Accepted to ApJL for the special issue, 37 pages, 23 pages main text, 6 tables, 13 figure