Riemannian tangent space mapping and elastic net regularization for cost-effective EEG markers of brain atrophy in Alzheimer's disease

The diagnosis of Alzheimer's disease (AD) in routine clinical practice is most commonly based on subjective clinical interpretations. Quantitative electroencephalography (QEEG) measures have been shown to reflect neurodegenerative processes in AD and might qualify as affordable and thereby widely available markers to facilitate the objectivization of AD assessment. Here, we present a novel framework combining Riemannian tangent space mapping and elastic net regression for the development of brain atrophy markers. While most AD QEEG studies are based on small sample sizes and psychological test scores as outcome measures, here we train and test our models using data of one of the largest prospective EEG AD trials ever conducted, including MRI biomarkers of brain atrophy.Comment: Presented at NIPS 2017 Workshop on Machine Learning for Healt

The Expression of Epac2 and GluA3 in an Alzheimer's Disease Experimental Model and Postmortem Patient Samples

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by amyloid beta (Aβ) and hyperphosphorylated tau accumulation in the brain. Recent studies indicated that memory retrieval, rather than memory formation, was impaired in the early stage of AD. Our previous study reported that pharmacological activation of hippocampal Epac2 promoted memory retrieval in C57BL/6J mice. A recent study suggested that pharmacological inhibition of Epac2 prevented synaptic potentiation mediated by GluA3-containing AMPARs. In this study, we aimed to investigate proteins associated with Epac2-mediated memory in hippocampal postmortem samples of AD patients and healthy controls compared with the experimental AD model J20 and wild-type mice. Epac2 and phospho-Akt were downregulated in AD patients and J20 mice, while Epac1 and phospho-ERK1/2 were not altered. GluA3 was reduced in J20 mice and tended to decrease in AD patients. PSD95 tended to decrease in AD patients and J20. Interestingly, AKAP5 was increased in AD patients but not in J20 mice, implicating its role in tau phosphorylation. Our study points to the downregulation of hippocampal expression of proteins associated with Epac2 in AD. </p

The Adaptive Gain Integrating Pixel Detector at the European XFEL

The Adaptive Gain Integrating Pixel Detector (AGIPD) is an x-ray imager, custom designed for the European x-ray Free-Electron Laser (XFEL). It is a fast, low noise integrating detector, with an adaptive gain amplifier per pixel. This has an equivalent noise of less than 1 keV when detecting single photons and, when switched into another gain state, a dynamic range of more than 10$^4$ photons of 12 keV. In burst mode the system is able to store 352 images while running at up to 6.5 MHz, which is compatible with the 4.5 MHz frame rate at the European XFEL. The AGIPD system was installed and commissioned in August 2017, and successfully used for the first experiments at the Single Particles, Clusters and Biomolecules (SPB) experimental station at the European XFEL since September 2017. This paper describes the principal components and performance parameters of the system.Comment: revised version after peer revie

FELIX: an algorithm for indexing multiple crystallites in X-ray free-electron laser snapshot diffraction images

A novel algorithm for indexing multiple crystals in snapshot X-ray diffraction images, especially suited for serial crystallography data, is presented. The algorithm, FELIX, utilizes a generalized parametrization of the Rodrigues–Frank space, in which all crystal systems can be represented without singularities. The new algorithm is shown to be capable of indexing more than ten crystals per image in simulations of cubic, tetragonal and monoclinic crystal diffraction patterns. It is also used to index an experimental serial crystallography dataset from lysozyme microcrystals. The increased number of indexed crystals is shown to result in a better signal-to-noise ratio, and fewer images are needed to achieve the same data quality as when indexing one crystal per image. The relative orientations between the multiple crystals indexed in an image show a slight tendency of the lysozme microcrystals to adhere on $(\overline {1}10)$ facets

Quantum dot-based broadband optical antenna for efficient extraction of single photons in the telecom O-band

Long-distance fiber-based quantum communication relies on efficient non-classical light sources operating at telecommunication wavelengths. Semiconductor quantum dots are promising candidates for on-demand generation of single photons and entangled photon pairs for such applications. However, their brightness is strongly limited due to total internal reflection at the semiconductor/vacuum interface. Here we overcome this limitation using a dielectric antenna structure. The non-classical light source consists of a gallium phosphide solid immersion lens in combination with a quantum dot nanomembrane emitting single photons in the telecom O-band. With this device, the photon extraction is strongly increased in a broad spectral range. A brightness of 17% (numerical aperture of 0.6) is obtained experimentally, with a single photon purity of (2)(0)=0.049±0.02 at saturation power. This brings the practical implementation of quantum communication networks one step closer

Overcoming evasive resistance from vascular endothelial growth factor a inhibition in sarcomas by genetic or pharmacologic targeting of hypoxia-inducible factor 1α

Increased levels of hypoxia and hypoxia-inducible factor 1α (HIF-1α) in human sarcomas correlate with tumor progression and radiation resistance. Prolonged antiangiogenic therapy of tumors not only delays tumor growth but may also increase hypoxia and HIF-1α activity. In our recent clinical trial, treatment with the vascular endothelial growth factor A (VEGF-A) antibody, bevacizumab, followed by a combination of bevacizumab and radiation led to near complete necrosis in nearly half of sarcomas. Gene Set Enrichment Analysis of microarrays from pretreatment biopsies found that the Gene Ontology category “Response to hypoxia” was upregulated in poor responders and that the hierarchical clustering based on 140 hypoxia-responsive genes reliably separated poor responders from good responders. The most commonly used chemotherapeutic drug for sarcomas, doxorubicin (Dox), was recently found to block HIF-1α binding to DNA at low metronomic doses. In four sarcoma cell lines, HIF-1α shRNA or Dox at low concentrations blocked HIF-1α induction of VEGF-A by 84–97% and carbonic anhydrase 9 by 83–93%. HT1080 sarcoma xenografts had increased hypoxia and/or HIF-1α activity with increasing tumor size and with anti-VEGF receptor antibody (DC101) treatment. Combining DC101 with HIF-1α shRNA or metronomic Dox had a synergistic effect in suppressing growth of HT1080 xenografts, at least in part via induction of tumor endothelial cell apoptosis. In conclusion, sarcomas respond to increased hypoxia by expressing HIF-1α target genes that may promote resistance to antiangiogenic and other therapies. HIF-1α inhibition blocks this evasive resistance and augments destruction of the tumor vasculature. What’s new? Despite their initial promise, anti-angiogenic therapies have been a disappointment in the clinic. One reason is that solid tumors often become resistant to these drugs. Tumors that respond poorly to this type of therapy have increased activation of the hypoxia-induced transcription factor HIF-1α which can enhance tumor survival and progression. In this study, the authors report that this evasive resistance can be overcome by adding low-dose doxorubicin or shRNA to inhibit HIF-1α activity. They are thus developing a clinical trial combining the angiogenesis inhibitor bevacizumab with metronomic doxorubicin in sarcoma patients

FAK Mediates a Compensatory Survival Signal Parallel to PI3K-AKT in PTEN-Null T-ALL Cells

SummaryMutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) are observed in 15%–25% of cases of human T cell acute lymphoblastic leukemia (T-ALL). Pten deletion induces myeloproliferative disorders (MPDs), acute myeloid leukemia (AML), and/or T-ALL in mice. Previous studies attributed Pten-loss-related hematopoietic defects and leukemogenesis to excessive activation of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling. Although inhibition of this signal dramatically suppresses the growth of PTEN-null T-ALL cells in vitro, treatment with inhibitors of this pathway does not cause a complete remission in vivo. Here, we report that focal adhesion kinase (Fak), a protein substrate of Pten, also contributes to T-ALL development in Pten-null mice. Inactivation of the FAK signaling pathway by either genetic or pharmacologic methods significantly sensitizes both murine and human PTEN-null T-ALL cells to PI3K/AKT/mTOR inhibition when cultured in vitro on feeder layer cells or a matrix and in vivo

Regulation of polarised growth in fungi

Polarised growth in fungi occurs through the delivery of secretory vesicles along tracks formed by cytoskeletal elements to specific sites on the cell surface where they dock with a multiprotein structure called the exocyst before fusing with the plasmamembrane. The budding yeast, Saccharomyces cerevisiae has provided a useful model to investigate the mechanisms involved and their control. Cortical markers, provided by bud site selection pathways during budding, the septin ring during cytokinesis or the stimulation of the pheromone response receptors during mating, act through upstream signalling pathways to localise Cdc24, the GEF for the rho family GTPase, Cdc42. Cdc42 in its GTP-bound activates a multiprotein protein complex called the polarisome which nucleates actin cables along which the secretory vesicles are transported to the cell surface. Hyphae can elongate at a rate orders of magnitude faster than the extension of a yeast bud, so understanding hyphal growth will require substantial modification of the yeast paradigm. The rapid rate of hyphal growth is driven by a structure called the Spitzenkörper, located just behind the growing tip and which is rich in secretory vesicles. It is thought that secretory vesicles are delivered to the apical region where they accumulate in the Spitzenkörper. The Spitzenkörper then acts as vesicle supply centre in which vesicles exit the Spitzenkörper in all directions, but because of its proximity, the tip receives a greater concentration of vesicles per unit area than subapical regions. There are no obvious equivalents to the bud site selection pathway to provide a spatial landmark for polarised growth in hyphae. However, an emerging model is the way that the site of polarised growth in the fission yeast, Schizosaccharomyces pombe, is marked by delivery of the kelch repeat protein, Tea1, along microtubules. The relationship of the Spitzenkörper to the polarisome and the mechanisms that promote its formation are key questions that form the focus of current research

Population density, water supply, and the risk of dengue fever in Vietnam: cohort study and spatial analysis.

BACKGROUND: Aedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas. We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk. METHODS AND FINDINGS: We conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013). We applied space-time scan statistics and mathematical models to confirm the findings. We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks. In the study area, this population density was typical of villages and some peri-urban areas. Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks. The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range. Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks. CONCLUSIONS: Rural areas may contribute at least as much to the dissemination of dengue fever as cities. Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts. Please see later in the article for the Editors' Summary