Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by deficiency of the mitochondrial protein frataxin. Lack of frataxin causes neuronal loss in various areas of the CNS and PNS. In particular, cerebellar neuropathology in FRDA patients includes loss of large principal neurons and synaptic terminals in the dentate nucleus (DN), and previous studies have demonstrated early synaptic deficits in the Knockin-Knockout mouse model of FRDA. However, the exact correlation of frataxin deficiency with cerebellar neuropathology remains unclear. Here we report that doxycycline-induced frataxin knockdown in a mouse model of FRDA (FRDAkd) leads to synaptic cerebellar degeneration that can be partially reversed by AAV8-mediated frataxin restoration. Loss of cerebellar Purkinje neurons and large DN principal neurons are observed in the FRDAkd mouse cerebellum. Levels of the climbing fiber-specific glutamatergic synaptic marker VGLUT2 decline starting at 4 weeks after dox induction, whereas levels of the parallel fiber-specific synaptic marker VGLUT1 are reduced by 18-weeks. These findings suggest initial selective degeneration of climbing fiber synapses followed by loss of parallel fiber synapses. The GABAergic synaptic marker GAD65 progressively declined during dox induction in FRDAkd mice, while GAD67 levels remained unaltered, suggesting specific roles for frataxin in maintaining cerebellar synaptic integrity and function during adulthood. Expression of frataxin following AAV8-mediated gene transfer partially restored VGLUT1/2 levels. Taken together, our findings show that frataxin knockdown leads to cerebellar degeneration in the FRDAkd mouse model, suggesting that frataxin helps maintain cerebellar structure and function

Ultrafast optical generation of coherent phonons in CdTe1-xSex quantum dots

We report on the impulsive generation of coherent optical phonons in CdTe0.68Se0.32 nanocrystallites embedded in a glass matrix. Pump probe experiments using femtosecond laser pulses were performed by tuning the laser central energy to resonate with the absorption edge of the nanocrystals. We identify two longitudinal optical phonons, one longitudinal acoustic phonon and a fourth mode of a mixed longitudinal-transverse nature. The amplitude of the optical phonons as a function of the laser central energy exhibits a resonance that is well described by a model based on impulsive stimulated Raman scattering. The phases of the coherent phonons reveal coupling between different modes. At low power density excitations, the frequency of the optical coherent phonons deviates from values obtained from spontaneous Raman scattering. This behavior is ascribed to the presence of electronic impurity states which modify the nanocrystal dielectric function and, thereby, the frequency of the infrared-active phonons

Decentralization and regional government size in Spain

The aim of this paper is to investigate the impact of fiscal decen- tralization on the size of regional governments in Spain, by controlling for economies of scale, interregional heterogeneity and institutional framework. We study it over 1985 to 2004 using a panel dataset of seventeen spanish regions. The results can be easily summarized. Firstly, it supports the classic public goods theory of a trade-off-between the economic benefits of size and the costs of heterogeneity. Secondly, it doesn’t reject the “Leviathan” hypoth- esis and neither does the “common pool” hypothesis. Thirdly, by contrast, the paper partly rejects the “Wallis”’ hypothesis. It argues that government size is mediated by financial resources obtained through intergovernmental grants, consistent with welfare economics and positive economic policies. We conclude that later advances in the decentralisation process must be compatible with the goal of reducing fiscal imbalances that emanate from the vertical structure of fiscal power.info:eu-repo/semantics/publishedVersio

Cinema-going trajectories in the digital age

The activity of cinema-going constantly evolves and gradually integrates the use of digital data and platforms to become more engaging for the audiences. Combining methods from the fields of Human Computer Interaction and Film Studies, we conducted two workshops seeking to understand cinema audiences’ digital practices and explore how the contemporary cinema-going experience is shaped in the digital age. Our findings suggest that going to the movies constitutes a trajectory during which cinemagoers interact with multiple digital platforms. At the same time, depending on their choices, they construct unique digital identities that represent a set of online behaviours and rituals that cinemagoers adopt before, while and after cinema-going. To inform the design of new, engaging cinemagoing experiences, this research establishes a preliminary map of contemporary cinema-going including digital data and platforms. We then discuss how audiences perceive the potential improvement of the experience and how that would lead to the construction of digital identities

Perspectives on privacy in the use of online systems

Human-Computer Interaction looks to better understand the relationship between people and computers. Our work considers this relationship in the context of privacy and the privacy expectations users have when using online systems. While many surveys suggest the public care about this subject, users often act in a manner perceived contrary to their claims; a notion termed the ‘Privacy Paradox’. However, research suggests privacy is inherently subjective and contextual, leading us to question: do users actually define ‘private online behaviour’ in the same manner as those who study the topic? Although our exploratory survey found a general intersection between participants’ perceptions and those in existing literature, opinions differed in several key areas. For example, we found users often conceptualise protection in less-technical terms and are prone to conflating privacy and security. We believe that when we expand our analyses to the general public, we will see an even greater disparity between privacy perceptions. Through this research we look to inform the development of systems and privacy-protective tools that users can actually appreciate

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease