Cerebral small vessel disease and intracranial bleeding risk: prognostic and practical significance

Balancing the risks of recurrent ischaemia and antithrombotic-associated bleeding, particularly intracranial haemorrhage (ICH), is a key challenge in the secondary prevention of ischaemic stroke and transient ischaemic attack. In hyperacute ischaemic stroke, the use of acute reperfusion therapies is determined by the balance of anticipated benefit and the risk of ICH. Cerebral small vessel disease (CSVD) causes most spontaneous ICH. Here, we review the evidence linking neuroimaging markers of CSVD to antithrombotic and thrombolytic-associated ICH, with emphasis on cerebral microbleeds (CMB). We discuss their role in the prediction of ICH, and practical implications for clinical decision making. Although current observational data suggests CMB presence should not preclude antithrombotic therapy in patients with ischaemic stroke or TIA, they are useful for improving ICH risk prediction with potential relevance for determining the optimal secondary prevention strategy, including the use of left atrial appendage occlusion. Following ICH, recommencing antiplatelets is probably safe in most patients, while the inconclusive results of recent randomised controlled trials of anticoagulant use makes recruitment to ongoing trials (including those testing left atrial appendage occlusion) in this area a high priority. Concern regarding CSVD and ICH risk after hyperacute stroke treatment appears to be unjustified most patients, though some uncertainty remains regarding patients with very high CMB burden and other risk factors for ICH. We encourage careful phenotyping for underlying CSVD in future trials, with potential to enhance precision medicine in stroke

GAF: Mechanical Paint Line Test Stand

The roofing manufacturer GAF located in Shafter, CA is in pursuit of a mechanism with the ability to improve the quality of paint lining applied on a dynamic roll of roofing shingles. The mechanism must consist of an alignment system along which a paint line applicator can be adjusted in the vertical direction and operate at a certain range of speeds. Other requirements for the mechanism demand that it is feasibly portable, reasonably durable, capable of accurate alignment, mountable to the ground, and within a budget of $15,000. With the customer\u27s design requirements established and understood, a one-year project has been outlined with details on how the objectives assigned to the Cal Poly 2018 senior project team will be satisfied. The first quarter was spent researching, brainstorming ideas, drafting a Quality Functional Deployment chart and producing different design concepts from which a final design would be made. After finalizing the design concept, it was presented to GAF for evaluation where approval and feedback were provided. After evaluating the feedback from GAF, the team proceeded with the project doing an Interim Design review to finalize the design by deciding which parts of the design concept can remain in use, and identifying parts that needed to be changed or added to. Some of the original structural components were modified in an effort to help improve the quality of paint application. Additionally, the Pac-Man device is driven by a belt and pulley coupled to a motor while maintaining the use of a mill table and hydraulic scissor link table for horizontal and vertical position adjustability respectfully. Throughout the second quarter the team was tasked with conducting a critical design review which involved calculations needed for design verification. Also the majority of the quarter was spent on planning for the manufacturing and testing part of the following quarter. The third and final quarter was spent doing a final design review where the team concludes the project with the last round of design modifications, followed by a hardware and safety demo. From there the project was assembled and tested after all parts were ordered, manufactured, and assembled. This was then followed by the project exposition where it has been presented and shown to viewers what it was designed for and how it operates

Spatio-Temporal Patterning in Primary Motor Cortex at Movement Onset

Voluntary movement initiation involves the engagement of large populations of motor cortical neurons around movement onset. Despite knowledge of the temporal dynamics that lead to movement, the spatial structure of these dynamics across the cortical surface remains unknown. In data from 4 rhesus macaques, we show that the timing of attenuation of beta frequency local field potential oscillations, a correlate of locally activated cortex, forms a spatial gradient across primary motor cortex (MI). We show that these spatio-temporal dynamics are recapitulated in the engagement order of ensembles of MI neurons. We demonstrate that these patterns are unique to movement onset and suggest that movement initiation requires a precise spatio-temporal sequential activation of neurons in MI

Comparing Offline Decoding Performance in Physiologically Defined Neuronal Classes

Objective: Recently, several studies have documented the presence of a bimodal distribution of spike waveform widths in primary motor cortex. Although narrow and wide spiking neurons, corresponding to the two modes of the distribution, exhibit different response properties, it remains unknown if these differences give rise to differential decoding performance between these two classes of cells. Approach: We used a Gaussian mixture model to classify neurons into narrow and wide physiological classes. Using similar-size, random samples of neurons from these two physiological classes, we trained offline decoding models to predict a variety of movement features. We compared offline decoding performance between these two physiologically defined populations of cells. Main results: We found that narrow spiking neural ensembles decode motor parameters better than wide spiking neural ensembles including kinematics, kinetics, and muscle activity. Significance: These findings suggest that the utility of neural ensembles in brain machine interfaces may be predicted from their spike waveform widths

Synaptic depression and its relation to behavioral habituation within anterior piriform cortex.

The onset, time course, and extent of LOT synaptic depression during both in vitro electrical and in vivo odorant stimulation methods were similar. Similar to the odor specificity of cortical odor adaptation in vivo, there was no evidence of heterosynaptic depression between independent inputs in vitro. In vitro evidence suggests at least two mechanisms contribute to this activity-dependent synaptic depression: a rapidly recovering presynaptic depression during the initial 10--20 sec of the post-train recovery period and a longer lasting (120 sec) depression that can be blocked by the metabotropic glutamate receptor (mGluR) II/III antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) and by the beta-adrenergic receptor agonist isoproterenol. Importantly, in line with the in vitro findings, both adaptation of odor responses in the 15--35 Hz spectral range and the associated synaptic depression can also be blocked by intracortical infusion of CPPG in vivo. Additionally, blockade of group II/III mGluR activation in aPCX prevents habituation of the odor-evoked heart rate orienting response behavior in awake behaving rats.Short-term behavioral habituation is the response decrement observed in many behaviors that occurs during repeated presentation of non-reinforced stimuli. Within a number of invertebrate models of short-term behavioral habituation, depression of a defined synapse has been implicated as the mechanism. However, the synaptic mechanisms of short-term behavioral habituation have not been identified within mammals.Anterior piriform cortex (aPCX) neurons rapidly filter repetitive odor stimuli despite relatively maintained input from mitral/tufted cells. This cortical adaptation is correlated with short-term depression of afferent synapses, in vivo. The purpose of this study was to elucidate mechanisms underlying this non-associative neural plasticity using in vivo and in vitro preparations, determine its role in cortical odor adaptation and ultimately look at its relation to behavioral odor habituation. Lateral olfactory tract (LOT)-evoked responses were recorded in rat aPCX coronal slices. Extracellular and intracellular potentials were recorded before and after simulated odor stimulation of the LOT. Results were compared with in vivo intracellular recordings from aPCX layer II/III neurons and field recordings in urethane-anesthetized rats stimulated with odorants

Large-scale Spatiotemporal Spike Patterning Consistent with Wave Propagation in Motor Cortex

Aggregate signals in cortex are known to be spatiotemporally organized as propagating waves across the cortical surface, but it remains unclear whether the same is true for spiking activity in individual neurons. Furthermore, the functional interactions between cortical neurons are well documented but their spatial arrangement on the cortical surface has been largely ignored. Here we use a functional network analysis to demonstrate that a subset of motor cortical neurons in non-human primates spatially coordinate their spiking activity in a manner that closely matches wave propagation measured in the beta oscillatory band of the local field potential. We also demonstrate that sequential spiking of pairs of neuron contains task-relevant information that peaks when the neurons are spatially oriented along the wave axis. We hypothesize that the spatial anisotropy of spike patterning may reflect the underlying organization of motor cortex and may be a general property shared by other cortical areas

Identification and Analysis of Bacterial Genomic Metabolic Signatures

With continued rapid growth in the number and quality of fully sequenced and accurately annotated bacterial genomes, we have unprecedented opportunities to understand metabolic diversity. We selected 101 diverse and representative completely sequenced bacteria and implemented a manual curation effort to identify 846 unique metabolic variants present in these bacteria. The presence or absence of these variants act as a metabolic signature for each of the bacteria, which can then be used to understand similarities and differences between and across bacterial groups. We propose a novel and robust method of summarizing metabolic diversity using metabolic signatures and use this method to generate a metabolic tree, clustering metabolically similar organisms. Resulting analysis of the metabolic tree confirms strong associations with well-established biological results along with direct insight into particular metabolic variants which are most predictive of metabolic diversity. The positive results of this manual cu ration effort and novel method development suggest that future work is needed to further expand the set of bacteria to which this approach is applied and use the resulting tree to test broad questions about metabolic diversity and complexity across the bacterial tree of life

Toward the automated generation of genome-scale metabolic networks in the SEED

<p>Abstract</p> <p>Background</p> <p>Current methods for the automated generation of genome-scale metabolic networks focus on genome annotation and preliminary biochemical reaction network assembly, but do not adequately address the process of identifying and filling gaps in the reaction network, and verifying that the network is suitable for systems level analysis. Thus, current methods are only sufficient for generating draft-quality networks, and refinement of the reaction network is still largely a manual, labor-intensive process.</p> <p>Results</p> <p>We have developed a method for generating genome-scale metabolic networks that produces substantially complete reaction networks, suitable for systems level analysis. Our method partitions the reaction space of central and intermediary metabolism into discrete, interconnected components that can be assembled and verified in isolation from each other, and then integrated and verified at the level of their interconnectivity. We have developed a database of components that are common across organisms, and have created tools for automatically assembling appropriate components for a particular organism based on the metabolic pathways encoded in the organism's genome. This focuses manual efforts on that portion of an organism's metabolism that is not yet represented in the database. We have demonstrated the efficacy of our method by reverse-engineering and automatically regenerating the reaction network from a published genome-scale metabolic model for <it>Staphylococcus aureus</it>. Additionally, we have verified that our method capitalizes on the database of common reaction network components created for <it>S. aureus</it>, by using these components to generate substantially complete reconstructions of the reaction networks from three other published metabolic models (<it>Escherichia coli</it>, <it>Helicobacter pylori</it>, and <it>Lactococcus lactis</it>). We have implemented our tools and database within the SEED, an open-source software environment for comparative genome annotation and analysis.</p> <p>Conclusion</p> <p>Our method sets the stage for the automated generation of substantially complete metabolic networks for over 400 complete genome sequences currently in the SEED. With each genome that is processed using our tools, the database of common components grows to cover more of the diversity of metabolic pathways. This increases the likelihood that components of reaction networks for subsequently processed genomes can be retrieved from the database, rather than assembled and verified manually.</p

Evaluating the Consistency of Gene Sets Used in the Analysis of Bacterial Gene Expression Data

Background Statistical analyses of whole genome expression data require functional information about genes in order to yield meaningful biological conclusions. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) are common sources of functionally grouped gene sets. For bacteria, the SEED and MicrobesOnline provide alternative, complementary sources of gene sets. To date, no comprehensive evaluation of the data obtained from these resources has been performed. Results We define a series of gene set consistency metrics directly related to the most common classes of statistical analyses for gene expression data, and then perform a comprehensive analysis of 3581 Affymetrix gene expression arrays across 17 diverse bacteria. We find that gene sets obtained from GO and KEGG demonstrate lower consistency than those obtained from the SEED and MicrobesOnline, regardless of gene set size. Conclusions Despite the widespread use of GO and KEGG gene sets in bacterial gene expression data analysis, the SEED and MicrobesOnline provide more consistent sets for a wide variety of statistical analyses such data. Increased use of the SEED and MicrobesOnline gene sets in the analysis of bacterial gene expression data may improve statistical power and utility of expression data

Evolution of eukaryotic transcription : insights from the genome of Giardia lamblia

Author Posting. © Cold Spring Harbor Laboratory Press, 2004. This article is posted here by permission of Cold Spring Harbor Laboratory Press for personal use, not for redistribution. The definitive version was published in Genome Research 14 (2004): 1537-1547, doi:10.1101/gr.2256604.The Giardia lamblia genome sequencing project affords us a unique opportunity to conduct comparative analyses of core cellular systems between early and late-diverging eukaryotes on a genome-wide scale. We report a survey to identify canonical transcription components in Giardia, focusing on RNA polymerase (RNAP) subunits and transcription-initiation factors. Our survey revealed that Giardia contains homologs to 21 of the 28 polypeptides comprising eukaryal RNAPI, RNAPII, and RNAPIII; six of the seven RNAP subunits without giardial homologs are polymerase specific. Components of only four of the 12 general transcription initiation factors have giardial homologs. Surprisingly, giardial TATA-binding protein (TBP) is highly divergent with respect to archaeal and higher eukaryotic TBPs, and a giardial homolog of transcription factor IIB was not identified. We conclude that Giardia represents a transition during the evolution of eukaryal transcription systems, exhibiting a relatively complete set of RNAP subunits and a rudimentary basal initiation apparatus for each transcription system. Most class-specific RNAP subunits and basal initiation factors appear to have evolved after the divergence of Giardia from the main eukaryotic line of descent. Consequently, Giardia is predicted to be unique in many aspects of transcription initiation with respect to paradigms derived from studies in crown eukaryotes.This work was supported in part by NIH grant AI43273 to M.L.S., by NIH grant AI51089 to A.G.M, and DOE grant DE-FG02-01ER63201 to G.J.O. Additional support was provided by the G. Unger Vetlesen Foundation and LI-COR Biotechnology