Enhanced end-to-end security through symmetric-key cryptography in wearable medical sensor networks

Computer Science

Communication and security trade-offs for battery-powered devices: a case study on wearable medical sensor systems

Computer Science

In-depth energy analysis of security algorithms and protocols for the Internet of Things

Computer Science

TORC1 Determines Fab1 Lipid Kinase Function at Signaling Endosomes and Vacuoles

Organelles of the endomembrane system maintain their identity and integrity during growth or stress conditions by homeostatic mechanisms that regulate membrane flux and biogenesis. At lysosomes and endosomes, the Fab1 lipid kinase complex and the nutrient-regulated target of rapamycin complex 1 (TORC1) control the integrity of the endolysosomal homeostasis and cellular metabolism. Both complexes are functionally connected as Fab1-dependent generation of PI(3,5)P2 supports TORC1 activity. Here, we identify Fab1 as a target of TORC1 on signaling endosomes, which are distinct from multivesicular bodies, and provide mechanistic insight into their crosstalk. Accordingly, TORC1 can phosphorylate Fab1 proximal to its PI3P-interacting FYVE domain, which causes Fab1 to shift to signaling endosomes, where it generates PI(3,5)P2. This, in turn, regulates (1) vacuole morphology, (2) recruitment of TORC1 and the TORC1-regulatory Rag GTPase-containing EGO complex to signaling endosomes, and (3) TORC1 activity. Thus, our study unravels a regulatory feedback loop between TORC1 and the Fab1 complex that controls signaling at endolysosomes

Lentiviral delivery of the human wild-type tau protein mediates a slow and progressive neurodegenerative tau pathology in the rat brain.

Most models for tauopathy use a mutated form of the Tau gene, MAPT, that is found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and that leads to rapid neurofibrillary degeneration (NFD). Use of a wild-type (WT) form of human Tau protein to model the aggregation and associated neurodegenerative processes of Tau in the mouse brain has thus far been unsuccessful. In the present study, we generated an original "sporadic tauopathy-like" model in the rat hippocampus, encoding six Tau isoforms as found in humans, using lentiviral vectors (LVs) for the delivery of a human WT Tau. The overexpression of human WT Tau in pyramidal neurons resulted in NFD, the morphological characteristics and kinetics of which reflected the slow and sporadic neurodegenerative processes observed in sporadic tauopathies, unlike the rapid neurodegenerative processes leading to cell death and ghost tangles triggered by the FTDP-17 mutant Tau P301L. This new model highlights differences in the molecular and cellular mechanisms underlying the pathological processes induced by WT and mutant Tau and suggests that preference should be given to animal models using WT Tau in the quest to understand sporadic tauopathies

Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies.

BACKGROUND: In sporadic Tauopathies, neurofibrillary degeneration (NFD) is characterised by the intraneuronal aggregation of wild-type Tau proteins. In the human brain, the hierarchical pathways of this neurodegeneration have been well established in Alzheimer's disease (AD) and other sporadic tauopathies such as argyrophilic grain disorder and progressive supranuclear palsy but the molecular and cellular mechanisms supporting this progression are yet not known. These pathways appear to be associated with the intercellular transmission of pathology, as recently suggested in Tau transgenic mice. However, these conclusions remain ill-defined due to a lack of toxicity data and difficulties associated with the use of mutant Tau. RESULTS: Using a lentiviral-mediated rat model of hippocampal NFD, we demonstrated that wild-type human Tau protein is axonally transferred from ventral hippocampus neurons to connected secondary neurons even at distant brain areas such as olfactory and limbic systems indicating a trans-synaptic protein transfer. Using different immunological tools to follow phospho-Tau species, it was clear that Tau pathology generated using mutated Tau remains near the IS whereas it spreads much further using the wild-type one. CONCLUSION: Taken together, these results support a novel mechanism for Tau protein transfer compared to previous reports based on transgenic models with mutant cDNA. It also demonstrates that mutant Tau proteins are not suitable for the development of experimental models helpful to validate therapeutic intervention interfering with Tau spreading

The yeast protein kinase Sch9 adjusts V-ATPase assembly/disassembly to control pH homeostasis and longevity in response to glucose availability

The evolutionary conserved TOR complex 1 controls growth in response to the quality and quantity of nutrients such as carbon and amino acids. The protein kinase Sch9 is the main TORC1 effector in yeast. However, only few of its direct targets are known. In this study, we performed a genome-wide screening looking for mutants which require Sch9 function for their survival and growth. In this way, we identified multiple components of the highly conserved vacuolar proton pump (V-ATPase) which mediates the luminal acidification of multiple biosynthetic and endocytic organelles. Besides a genetic interaction, we found Sch9 also physically interacts with the V- ATPase to regulate its assembly state in response to glucose availability and TORC1 activity. Moreover, the interaction with the V-ATPase has consequences for ageing as it allowed Sch9 to control vacuolar pH and thereby trigger either lifespan extension or lifespan shortening. Hence, our results provide insights into the signaling mechanism coupling glucose availability, TORC1 signaling, pH homeostasis and longevity. As both Sch9 and the V-ATPase are highly conserved and implicated in various pathologies, these results offer fertile ground for further research in higher eukaryotes

TORC1 determines Fab1 lipid kinase function at signaling endosomes and vacuoles

Acknowledgments: We thank Lars Langemeyer for feedback, all members from the Ungermann lab for discussions, and Kathrin Auffarth, Angela Perz, and Malika Jaquenoud for expert technical assistance. This work was supported by the DFG (UN111/10-1 to C.U.), the Canton of Fribourg (to J.D. and C.D.V.), and the Swiss National Science Foundation (310030_166474/184671 to C.D.V. and 310030_184781 and 316030_177088 to J.D.). Z.C. received support from a travel stipend of the Boehringer Ingelheim Fonds. P.C.M. received additional support from the graduate program of the Collaborative Research Center 944 (SFB 944) and Department of Biology/Chemistry Osnabrück. E.E. received a fellowship of FWO Vlaanderen, Belgium (SB-FWO 1S06419N). Author Contributions: Z.C. and P.C.M. conducted all experiments on Fab1 localization and function; R.H. conducted experiments on development and analysis of the Sch91–183 probe; R.N., Z.H., M.-P.P.-G., and J.D. did the phosphorylation assays and analyses; and E.E. and J.W. conceived and performed the initial Sch9 mapping. T.N. and C.J.S. did the lipid analysis of the mutant alleles. J.G. analyzed microcopy data with Z.C. C.D.V. and C.U. conceived the study and wrote the manuscript with support of J.W.Peer reviewedPublisher PD

The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?

Insights into tau molecular structures have advanced significantly in recent years. This field has been the subject of recent breakthroughs, including the first cryo-electron microscopy structures of tau filaments from Alzheimer’s and Pick’s disease inclusions, as well as the structure of the repeat regions of tau bound to microtubules. Tau structure covers various species as the tau protein itself takes many forms. We will here address a range of studies that help to define the many facets of tau protein structures and how they translate into pathogenic forms. New results shed light on previous data that need now to be revisited in order to up-date our knowledge of tau molecular structure. Finally, we explore how these data can contribute the important medical aspects of this research - diagnosis and therapeutics