MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity.

Presynaptic homeostatic plasticity (PHP) controls synaptic transmission in organisms from Drosophila to human and is hypothesized to be relevant to the cause of human disease. However, the underlying molecular mechanisms of PHP are just emerging and direct disease associations remain obscure. In a forward genetic screen for mutations that block PHP we identified mctp (Multiple C2 Domain Proteins with Two Transmembrane Regions). Here we show that MCTP localizes to the membranes of the endoplasmic reticulum (ER) that elaborate throughout the soma, dendrites, axon and presynaptic terminal. Then, we demonstrate that MCTP functions downstream of presynaptic calcium influx with separable activities to stabilize baseline transmission, short-term release dynamics and PHP. Notably, PHP specifically requires the calcium coordinating residues in each of the three C2 domains of MCTP. Thus, we propose MCTP as a novel, ER-localized calcium sensor and a source of calcium-dependent feedback for the homeostatic stabilization of neurotransmission

Laser powder bed fusion of NdFeB and influence of powder bed heating on density and magnetic properties

Laser powder bed fusion (L-PBF) is an additive manufacturing technique that provides an opportunity to create complex NdFeB magnets, potentially enhancing their performance. L-PBF possesses its own processing challenges, such as porosity/cracks and thermal stresses due to rapid cooling. This study focused on optimizing the parameters and the use of elevated temperature (300–550 °C) powder bed heating to reduce defect generation. This paper includes a detailed process parameter investigation, which revealed samples with a maximum energy product, (BH)max, of 81 kJ/m3 (remanence, Br 0.72 T; coercivity, Hci 891 kA/m) without post/pretreatment, which are the highest (BH)max and Br for L-PBF-processed NdFeB commercial powder. It was observed that all the high-magnetism samples possessed high density, but not all the high-density samples possessed high magnetism. The SEM images and discussions are academically valuable since they clearly illustrate grain formation and morphology in the melt pool, areas where the literature provides limited discussion. Furthermore, this paper incorporates quantitative phase analyses, revealing that the magnetic properties increase with increasing volume fraction of the strong magnetic phase Nd2Fe14B. Another significant contribution of this paper is that it is the first study to investigate the effect of heated bed on L-PBF-NdFeB alloys. The density of the samples and Br can be improved with the use of elevated powder bed heating, while the Hc decreases. The (BH)max can also be improved from 55 to 84 kJ/m3 through elevated powder bed heating. The maximum magnetic properties obtained with the heated bed (400 °C) were as follows: Br, 0.76 T; Hci, 750 kA/m; and (BH)max, 84 kJ/m3

NoCry: No More Secure Encryption Keys for Cryptographic Ransomware

Since the appearance of ransomware in the cyber crime scene, researchers and anti-malware companies have been offering solutions to mitigate the threat. Anti-malware solutions differ on the specific strategy they implement, and all have pros and cons. However, three requirements concern them all: their implementation must be secure, be effective, and be efficient. Recently, Genç et al. proposed to stop a specific class of ransomware, the cryptographically strong one, by blocking unauthorized calls to cryptographically secure pseudo-random number generators, which are required to build strong encryption keys. Here, in adherence to the requirements, we discuss an implementation of that solution that is more secure (with components that are not vulnerable to known attacks), more effective (with less false negatives in the class of ransomware addressed) and more efficient (with minimal false positive rate and negligible overhead) than the original, bringing its security and technological readiness to a higher level

On Deception-Based Protection Against Cryptographic Ransomware

In order to detect malicious file system activity, some commercial and academic anti-ransomware solutions implement deception-based techniques, specifically by placing decoy files among user files. While this approach raises the bar against current ransomware, as any access to a decoy file is a sign of malicious activity, the robustness of decoy strategies has not been formally analyzed and fully tested. In this paper, we analyze existing decoy strategies and discuss how they are effective in countering current ransomware by defining a set of metrics to measure their robustness. To demonstrate how ransomware can identify existing deception-based detection strategies, we have implemented a proof-of-concept anti-decoy ransomware that successfully bypasses decoys by using a decision engine with few rules. Finally, we discuss existing issues in decoy-based strategies and propose practical solutions to mitigate them

The role of ITO resistivity on current spreading and leakage in InGaN/GaN light emitting diodes

The effect of a transparent ITO current spreading layer on electrical and light output properties of blue InGaN/GaN light emitting diodes (LEDs) is discussed. When finite conductivity of ITO is taken into account, unlike in previous models, the topology of LED die and contacts are shown to significantly affect current spreading and light output characteristics in top emitting devices. We propose an approach for calculating the current transfer length describing current spreading. We show that an inter-digitated electrode configuration with distance between the contact pad and the edge of p-n junction equal to transfer length in the current spreading ITO layer allows one to increase the optical area of LED chip, as compared to the physical area of the die, light output power, and therefore, the LED efficiency for a given current density. A detailed study of unpassivated LEDs also shows that current transfer lengths longer than the distance between the contact pad and the edge of p-n junction leads to increasing surface leakage that can only be remedied with proper passivation. © 2017 Elsevier Lt

Next Generation Cryptographic Ransomware

We are assisting at an evolution in the ecosystem of cryptoware - the malware that encrypts files and makes them unavailable unless the victim pays up. New variants are taking the place once dominated by older versions; incident reports suggest that forthcoming ransomware will be more sophisticated, disruptive, and targeted. Can we anticipate how such future generations of ransomware will work in order to start planning on how to stop them? We argue that among them there will be some which will try to defeat current anti-ransomware; thus, we can speculate over their working principle by studying the weak points in the strategies that seven of the most advanced anti-ransomware are currently implementing. We support our speculations with experiments, proving at the same time that those weak points are in fact vulnerabilities and that the future ransomware that we have imagined can be effective

Activated Human CD4+CD45RO+ Memory T-Cells Indirectly Inhibit NLRP3 Inflammasome Activation through Downregulation of P2X7R Signalling

Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1β. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ suppresses NLRP3 inflammasome activation through an indirect mechanism involving decreased P2X7R signaling. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society