Glioblastoma Extracellular Vesicle-Specific Peptides Inhibit EV-Induced Neuronal Cytotoxicity

WHO Grade 4 IDH-wild type astrocytoma (GBM) is the deadliest brain tumor with a poor prognosis. Meningioma (MMA) is a more common “benign” central nervous system tumor but with significant recurrence rates. There is an urgent need for brain tumor biomarkers for early diagnosis and effective treatment options. Extracellular vesicles (EVs) are tiny membrane-enclosed vesicles that play essential functions in cell-to-cell communications among tumor cells. We aimed to identify epitopes of brain tumor EVs by phage peptide libraries. EVs from GBM plasma, MMA plasma, or brain tumor cell lines were used to screen phage-displayed random peptide libraries to identify high-affinity peptides. We purified EVs from three GBM plasma pools (23 patients), one MMA pool (10 patients), and four brain tumor cell lines. We identified a total of 21 high-affinity phage peptides (12 unique) specific to brain tumor EVs. The peptides shared high sequence homologies among those selected by the same EVs. Dose–response ELISA demonstrated that phage peptides were specific to brain tumor EVs compared to controls. Peptide affinity purification identified unique brain tumor EV subpopulations. Significantly, GBM EV peptides inhibit brain tumor EV-induced complement-dependent cytotoxicity (necrosis) in neurons. We conclude that phage display technology could identify specific peptides to isolate and characterize tumor EVs.     

Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects

The voltage-dependent L-type calcium channel isoform Ca_V1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the Ca_V1.2 α₁-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified Ca_V1.2^L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.     

DOT1L Methyltransferase Regulates Calcium Influx in Erythroid Progenitor Cells in Response to Erythropoietin

Erythropoietin (EPO) signaling plays a vital role in erythropoiesis by regulating proliferation and lineage-specific differentiation of murine hematopoietic progenitor cells (HPCs). An important downstream response of EPO signaling is calcium (Ca²⁺) influx, which is regulated by transient receptor potential channel (TRPC) proteins, particularly TRPC2 and TRPC6. While EPO induces Ca²⁺ influx through TRPC2, TRPC6 inhibits the function of TRPC2. Thus, interactions between TRPC2 and TRPC6 regulate the rate of Ca²⁺ influx in EPO-induced erythropoiesis. In this study, we observed that the expression of TRPC6 in KIT-positive erythroid progenitor cells was regulated by DOT1L. DOT1L is a methyltransferase that plays an important role in many biological processes during embryonic development including early erythropoiesis. We previously reported that Dot1l knockout (Dot1l^KO) HPCs in the yolk sac failed to develop properly, which resulted in lethal anemia. In this study, we detected a marked downregulation of Trpc6 gene expression in Dot1l^KO progenitor cells in the yolk sac compared to the wild type (WT). The promoter and the proximal regions of the Trpc6 gene locus exhibited an enrichment of H3K79 methylation, which is mediated solely by DOT1L. However, the expression of Trpc2, the positive regulator of Ca²⁺ influx, remained unchanged, resulting in an increased TRPC2/TRPC6 ratio. As the loss of DOT1L decreased TRPC6, which inhibited Ca²⁺ influx by TRPC2, Dot1l^KO HPCs in the yolk sac exhibited accelerated and sustained elevated levels of Ca²⁺ influx. Such heightened Ca²⁺ levels might have detrimental effects on the growth and proliferation of HPCs in response to EPO.     

Electromagnetically assisted sheet metal stamping

A new approach, electromagnetically assisted sheet metal stamping, has been developed to alter strain distribution and improve formability in sheet metal stamping. In this study, this new approach was applied to form a non-symmetric panel from Al 6111-T4. The results show that this new approach greatly increased the draw depth of the formed panel, compared with conventional stamping. A detailed analysis of strain distribution, stretching and draw-in shows that both a more homogeneous strain distribution and enhanced draw-in contribute to producing deeper pans in a single press operation. This work demonstrates the feasibility of electromagnetically assisted sheet metal stamping, which offers a much improved ability to make complex components in a single press stroke as compared to conventional stamping.     

Cooperative detection and protection for Interest flooding attacks in named data networking

Named data networking (NDN) is a new emerging architecture for future network, which may be a substitute of the current TCP/IP‐based network, for the content‐oriented data request mode becoming the future trend of development. The security of NDN has attracted much attention, as an implementation of next‐generation Internet architecture. Although NDN is immune to most current attack, it cannot resist the distributed denial of service like attack – Interest flooding attack (IFA) – effectively. IFA takes advantages of the forwarding mechanism of NDN, flooding a large number of malicious Interest packets at quite a high rate, and exploits the network resources, which may cause the paralysis of the network. Taking into account the severity of the destruction, we propose an algorithm to counter such new type of attack. We analyze three properties of IFA, and use them to judge and filter Interest packets. Vector space model and Markov model are used in our method to realize a cooperative detection. Meanwhile, we present the retransmission forwarding mechanism to ensure legitimate user request. The ndnSIM module of ns3 is used for the corresponding simulation, and results of the simulation will be given to show the effectiveness of our algorithm. Copyright © 2014 John Wiley & Sons, Ltd.     

Finite element simulation of package stress in transfer molded MEMS pressure sensors

The goal of this paper is to investigate the effect of residual packaging stress resulting from transfer molding of a micro electro mechanical system pressure sensor. A model of a silicon diaphragm micro electro mechanical system pressure sensor geometry was used to simulate the stresses developed during the molding process. The analyses were carried out with an assumption that the epoxy molding compound was a temperature dependent elastic material. Finite element analysis was used to calculate the residual packaging stress. The stress values were used to obtain the electrical output signal and sensitivity of the packaged sensor. In this way, a direct link was established between package stress and device performance.The calculated output signal and sensitivity were compared with experimental data to verify the simulated stress and hence determine the effect of the packaging process on the pressure sensor. Four different service temperatures were considered to examine the temperature effects on the output signal and the sensitivity for the packaged sensor.     

变化中的SoC设计流程

身处市场领先地位的SoC（系统单芯片）设计团队认为,“惯常的业务”已不复重现,强大的技术与商务力量（似乎独立于EDA供应商的路线图）,都在将SoC设计方法重新塑造为新的形式,并与仅仅几年前的最佳实践有非常大的差异。     

Noise reduction in rhythmic and multitrial biosignals with applications to event-related potentials

A new noise reduction algorithm is presented for signals displaying repeated patterns or multiple trials. Each pattern is stored in a matrix, forming a set of events, which is termed multievent signal. Each event is considered as an affine transform of a basic template signal that allows for time scaling and shifting. Wavelet transforms, decimated and undecimated, are applied to each event. Noise reduction on the set of coefficients of the transformed events is applied using either wavelet de- noising or principal component analysis (PCA) noise reduction methodologies. The method does not require any manual selection of coefficients. Nonstationary multievent synthetic signals are employed to demonstrate the performance of the method using normalized mean square error against classical wavelet and PCA based algorithms. The new method shows a significant improvement in low SNRs (typically <0 dB). On the experimental side, evoked potentials in a visual oddball paradigm are used. The reduced-noise visual oddball event-related potentials reveal gradual changes in morphology from trial to trial (especially for N1-P2 and N2-P3 waves at Fz), which can be hypothetically linked to attention or decision processes. The new noise reduction method is, thus, shown to be particularly suited for recovering single-event features in non- stationary low SNR multievent contexts.     

Minimizing Average Schedule Length under Memory Constraints by Optimal Partitioning and Prefetching

Over the last 20 years, the performance gap between CPU and memory has been steadily increasing. As a result, a variety of techniques has been devised to hide that performance gap, from intermediate fast memories (caches) to various prefetching and memory management techniques for manipulating the data present in these caches. In this paper we propose a new memory management technique that takes advantage of access pattern information that is available at compile time by prefetching certain data elements before explicitly being requested by the CPU, as well as maintaining certain data in the local memory over a number of iterations. In order to better take advantage of the locality of reference present in loop structures, our technique also uses a new approach to memory by partitioning it and reducing execution to each partition, so that information is reused at much smaller time intervals than if execution followed the usual pattern. These combined approaches—using a new set of memory instructions as well as partitioning the memory—lead to improvements in total execution time of approximately 25% over existing methods.