Calcium dynamics and circadian rhythms in suprachiasmatic nucleus neurons

The hypothalamic suprachiasmatic nucleus (SCN) has a pivotal role in the mammalian circadian clock. SCN neurons generate circadian rhythms in action potential firing frequencies and neurotransmitter release, and the core oscillation is thought to be driven by "clock gene" transcription-translation feedback loops. Cytosolic Ca2+ mobilization followed by stimulation of various receptors has been shown to reset the gene transcription cycles in SCN neurons, whereas contribution of steady-state cytosolic Ca2+ levels to the rhythm generation is unclear. Recently, circadian rhythms in cytosolic Ca2+ levels have been demonstrated in cultured SCN neurons. The circadian Ca2+ rhythms are driven by the release of Ca2+ from ryanodine-sensitive internal stores and resistant to the blockade of action potentials. These results raise the possibility that gene translation/transcription loops may interact with autonomous Ca2+ oscillations in the production of circadian rhythms in SCN neurons

An Algebra of Pieces of Space -- Hermann Grassmann to Gian Carlo Rota

We sketch the outlines of Gian Carlo Rota's interaction with the ideas that Hermann Grassmann developed in his Ausdehnungslehre of 1844 and 1862, as adapted and explained by Giuseppe Peano in 1888. This leads us past what Rota variously called 'Grassmann-Cayley algebra', or 'Peano spaces', to the Whitney algebra of a matroid, and finally to a resolution of the question "What, really, was Grassmann's regressive product?". This final question is the subject of ongoing joint work with Andrea Brini, Francesco Regonati, and William Schmitt. The present paper was presented at the conference "The Digital Footprint of Gian-Carlo Rota: Marbles, Boxes and Philosophy" in Milano on 17 Feb 2009. It will appear in proceedings of that conference, to be published by Springer Verlag.Comment: 28 page

Minteos mesh protocol and SystemC simulator

This paper presents our industrial experience on the implementation of Minteos Mesh Protocol which is a memory, power and delay efficient mesh protocol; and Minteos SystemC Simulator for mesh networks. Experiments are carried out to validate the adequate use of Minteos Mesh Protocol. Also, simulation/test results are given to show the effectiveness and applicability of Minteos SystemC simulator for mesh networks

A novel mutation in isoform 3 of the plasma membrane Ca2+ pump impairs cellular Ca2+ homeostasis in a patient with cerebellar ataxia and laminin subunit 1\u3b1 mutations.

The particular importance of Ca2+ signaling to neurons demands its precise regulation within their cytoplasm. Isoform 3 of the plasma membrane Ca2+ ATPase (the PMCA3 pump), which is highly expressed in brain and cerebellum, plays an important role in the regulation of neuronal Ca2+. A genetic defect of the function of the PMCA3 pump has been described in one family with X-linked congenital cerebellar ataxia. Here we describe a novel mutation of the PMCA3 pump (ATP2B3) in a patient with global developmental delay, generalized hypotonia and cerebellar ataxia. The mutation (a R482H replacement) impairs the Ca2+ ejection function of the pump. It reduces the ability of the pump expressed in model cells to control Ca2+ transients generated by cell stimulation and impairs its Ca2+ extrusion function under conditions of low resting cytosolic Ca2+ as well. In silico analysis of the structural effect of the mutation suggests a reduced stabilization of the portion of the pump surrounding the mutated residue in the Ca2+-bound state. The patient also carries two missense mutations in LAMA1, encoding for laminin subunit 1\u3b1. On the basis of the family pedigree of the patient, the presence of both PMCA3 and LAMA1 mutations appears to be necessary for the development of the disease. Considering the observed defect in cellular Ca2+ homeostasis and the previous finding that PMCAs act as digenic modulators in Ca2+-linked pathologies, the PMCA3 dysfunction along with LAMA1 mutations could act synergistically to cause the neurological phenotype

PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER-Mitochondria Contacts in Parkinson's Disease

Endoplasmic reticulum (ER)-mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson's disease, are two of the best characterized mitophagy players. They accumulate at ER-mitochondria contact sites and modulate organelles crosstalk. Alterations in ER-mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson's disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER-mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy

Bilingualism Is Associated with a Delayed Onset of Dementia but Not with a Lower Risk of Developing it: a Systematic Review with Meta-Analyses.

Some studies have linked bilingualism with a later onset of dementia, Alzheimer's disease (AD), and mild cognitive impairment (MCI). Not all studies have observed such relationships, however. Differences in study outcomes may be due to methodological limitations and the presence of confounding factors within studies such as immigration status and level of education. We conducted the first systematic review with meta-analysis combining cross-sectional studies to explore if bilingualism might delay symptom onset and diagnosis of dementia, AD, and MCI. Primary outcomes included the age of symptom onset, the age at diagnosis of MCI or dementia, and the risk of developing MCI or dementia. A secondary outcome included the degree of disease severity at dementia diagnosis. There was no difference in the age of MCI diagnosis between monolinguals and bilinguals [mean difference: 3.2; 95% confidence intervals (CI): -3.4, 9.7]. Bilinguals vs. monolinguals reported experiencing AD symptoms 4.7 years (95% CI: 3.3, 6.1) later. Bilinguals vs. monolinguals were diagnosed with dementia 3.3 years (95% CI: 1.7, 4.9) later. Here, 95% prediction intervals showed a large dispersion of effect sizes (-1.9 to 8.5). We investigated this dispersion with a subgroup meta-analysis comparing studies that had recruited participants with dementia to studies that had recruited participants with AD on the age of dementia and AD diagnosis between mono- and bilinguals. Results showed that bilinguals vs. monolinguals were 1.9 years (95% CI: -0.9, 4.7) and 4.2 (95% CI: 2.0, 6.4) older than monolinguals at the time of dementia and AD diagnosis, respectively. The mean difference between the two subgroups was not significant. There was no significant risk reduction (odds ratio: 0.89; 95% CI: 0.68-1.16) in developing dementia among bilinguals vs. monolinguals. Also, there was no significant difference (Hedges' g = 0.05; 95% CI: -0.13, 0.24) in disease severity at dementia diagnosis between bilinguals and monolinguals, despite bilinguals being significantly older. The majority of studies had adjusted for level of education suggesting that education might not have played a role in the observed delay in dementia among bilinguals vs. monolinguals. Although findings indicated that bilingualism was on average related to a delayed onset of dementia, the magnitude of this relationship varied across different settings. This variation may be due to unexplained heterogeneity and different sources of bias in the included studies. Registration: PROSPERO CRD42015019100

On the log-local principle for the toric boundary

Let $X$ be a smooth projective complex variety and let $D=D_1+\cdots+D_l$ be a reduced normal crossing divisor on $X$ with each component $D_j$ smooth, irreducible, and nef. The log-local principle of van Garrel-Graber-Ruddat conjectures that the genus 0 log Gromov-Witten theory of maximal tangency of $(X,D)$ is equivalent to the genus 0 local Gromov-Witten theory of $X$ twisted by $\bigoplus_{j=1}^l\mathcal{O}(-D_j)$. We prove that an extension of the log-local principle holds for $X$ a (not necessarily smooth) $\mathbb{Q}$-factorial projective toric variety, $D$ the toric boundary, and descendent point insertions.Comment: 19 page

A split-GFP tool reveals differences in the sub-mitochondrial distribution of wt and mutant alpha-synuclein

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by dopaminergic neuronal loss that initiates in the substantia nigra pars compacta and by the formation of intracellular inclusions mainly constituted by aberrant \u3b1-synuclein (\u3b1-syn) deposits known as Lewy bodies. Most cases of PD are sporadic, but about 10% are familial, among them those caused by mutations in SNCA gene have an autosomal dominant transmission. SNCA encodes \u3b1-syn, a small 140-amino acids protein that, under physiological conditions, is mainly localized at the presynaptic terminals. It is prevalently cytosolic, but its presence has been reported in the nucleus, in the mitochondria and, more recently, in the mitochondria-associated ER membranes (MAMs). Whether different cellular localizations may reflect specific \u3b1-syn activities is presently unclear and its action at mitochondrial level is still a matter of debate. Mounting evidence supports a role for \u3b1-syn in several mitochondria-derived activities, among which maintenance of mitochondrial morphology and modulation of complex I and ATP synthase activity. \u3b1-syn has been proposed to localize at the outer membrane (OMM), in the intermembrane space (IMS), at the inner membrane (IMM) and in the mitochondrial matrix, but a clear and comparative analysis of the sub-mitochondrial localization of WT and mutant \u3b1-syn is missing. Furthermore, the reasons for this spread sub-mitochondrial localization under physiological and pathological circumstances remain elusive. In this context, we decided to selectively monitor the sub-mitochondrial distribution of the WT and PD-related \u3b1-syn mutants A53T and A30P by taking advantage from a bimolecular fluorescence complementation (BiFC) approach. We also investigated whether cell stress could trigger \u3b1-syn translocation within the different mitochondrial sub-compartments and whether PD-related mutations could impinge on it. Interestingly, the artificial targeting of \u3b1-syn WT (but not of the mutants) to the mitochondrial matrix impacts on ATP production, suggesting a potential role within this compartment