Migalastat HCl reduces globotriaosylsphingosine (Lyso- Gb3) in Fabry transgenic mice and in the plasma of Fabry patients

Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme a-galactosidase A (a-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of a-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD

A Nearly Four-Year Longitudinal Study of Search-Engine Poisoning

We investigate the evolution of search-engine poisoning using data on over 5 million search results collected over nearly 4 years. We build on prior work investigating search-redirection attacks, where criminals compromise high-ranking websites and direct search traf-fic to the websites of paying customers, such as unlicensed phar-macies who lack access to traditional search-based advertisements. We overcome several obstacles to longitudinal studies by amalga-mating different resources and adapting our measurement infras-tructure to changes brought by adaptations by both legitimate op-erators and attackers. Our goal is to empirically characterize how strategies for carrying out and combating search poisoning have evolved over a relatively long time period. We investigate how the composition of search results themselves has changed. For in-stance, we find that search-redirection attacks have steadily grown to take over a larger share of results (rising from around 30 % in late 2010 to a peak of nearly 60 % in late 2012), despite efforts by search engines and browsers to combat their effectiveness. We also study the efforts of hosts to remedy search-redirection attacks. We find that the median time to clean up source infections has fallen from around 30 days in 2010 to around 15 days by late 2013, yet the number of distinct infections has increased considerably over the same period. Finally, we show that the concentration of traffic to the most successful brokers has persisted over time. Further, these brokers have been mostly hosted on a few autonomous systems, which indicates a possible intervention strategy. Categories and Subject Descriptors K.4.1 [Public Policy Issues]: Abuse and crime involving comput-er

Adversarial Matching of Dark Net Market Vendor Accounts

Many datasets feature seemingly disparate entries that actually refer to the same entity. Reconciling these entries, or matching, is challenging, especially in situations where there are errors in the data. In certain contexts, the situation is even more complicated: an active adversary may have a vested interest in having the matching process fail. By leveraging eight years of data, we investigate one such adversarial context: matching different online anonymous marketplace vendor handles to unique sellers. Using a combination of random forest classifiers and hierarchical clustering on a set of features that would be hard for an adversary to forge or mimic, we manage to obtain reasonable performance (over 75% precision and recall on labels generated using heuristics), despite generally lacking any ground truth for training. Our algorithm performs particularly well for the top 30% of accounts by sales volume, and hints that 22,163 accounts with at least one confirmed sale map to 15,652 distinct sellers---of which 12,155 operate only one account, and the remainder between 2 and 11 different accounts. Case study analysis further confirms that our algorithm manages to identify non-trivial matches, as well as impersonation attempts

Booting the booters: Evaluating the effects of police interventions in the market for Denial-of-Service attacks

Illegal booter services offer denial of service (DoS) attacks for a fee of a few tens of dollars a month. Internationally, police have implemented a range of different types of intervention aimed at those using and offering booter services, including arrests and website takedown. In order to measure the impact of these interventions we look at the usage reports that booters themselves provide and at measurements of reflected UDP DoS attacks, leveraging a five year measurement dataset that has been statistically demonstrated to have very high coverage. We analysed time series data (using a negative binomial regression model) to show that several interventions have had a statistically significant impact on the number of attacks. We show that, while there is no consistent effect of highly-publicised court cases, takedowns of individual booters precede significant, but short-lived, reductions in recorded attack numbers. However, more wide-ranging disruptions have much longer effects. The closure of HackForums' booter market reduced attacks for 13 weeks globally (and for longer in particular countries) and the FBI's coordinated operation in December 2018, which involved both takedowns and arrests, reduced attacks by a third for at least 10 weeks and resulted in lasting change to the structure of the booter market.This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) [grant number EP/M020320/1]

Migalastat HCl Reduces Globotriaosylsphingosine (Lyso-Gb(3)) in Fabry Transgenic Mice and in the Plasma of Fabry Patients

Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of α-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD

Towards the reconstruction of the genome-scale metabolic model of Lactobacillus acidophilus La-14

Lactobacillus acidophilus is a probiotic lactic acid bacterium used in food and dietary supplements for many years. However, despite its importance for industrial development and recognized health-promoting effects, no genome-scale metabolic model has been reported. A GSM model for L. acidophilus La-14 was developed, accounting 494 genes and 783 reactions. A genome annotation was performed to identify the metabolic potential of the bacterium. The biomass composition was determined based on information available in literature and previously published models. The model was validated by comparing in silico simulations with experimental data, regarding the aerobic and anaerobic growth. The reconstruction of the metabolic model has confirmed the fastidious requirements of L. acidophilus for amino acids, fatty acids, and vitamins. This model can be used for a better understanding of the metabolism of this bacterium and identification of industrially desirable compounds.This study was performed under the scope of the project “BIODATA.PT – Portuguese Biological Data Network” (ref. LISBOA-01-0145-FEDER-022231), funded by FCT/MCTES, through national funds of PIDDAC, Fundo Europeu de Desenvolvimento Regional (FEDER), Programa Operacional de Competitividade e Internacionalização (POCI) and Programa Operacional Regional de Lisboa (Lisboa 2020).info:eu-repo/semantics/publishedVersio

Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice

Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase α-galactosidase A (α-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human α-Gal A (rhα-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rhα-Gal A has low physical stability, a short circulating half-life, and variable uptake into different disease-relevant tissues. We hypothesized that coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1-deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rhα-Gal A via binding and stabilization. AT1001 prevented rhα-Gal A denaturation and activity loss in vitro at neutral pH and 37 °C. Coincubation of Fabry fibroblasts with rhα-Gal A and AT1001 resulted in up to fourfold higher cellular α-Gal A and ~30% greater GL-3 reduction compared to rhα-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rhα-Gal A by >2.5-fold, and in GLA knockout mice resulted in up to fivefold higher α-Gal A levels and fourfold greater GL-3 reduction than rhα-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rhα-Gal A, thus warranting clinical investigation

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

4-(4-nitrobenzyl)pyridine tests for alkylating agents following chemical oxidative activation

A chemical activation system (CAS) designed to mimic the mammalian mixed-function oxidase enzymes was found to activate target compounds to reactive electrophiles. Activated compounds were assayed by reaction with 4-(4-nitrobenzyl)pyridine (NBP). A model nucleophile of 7-alkylguanine of nucleic acids, NBP produces a violet color following alkylation. Twenty compounds from several chemical classes were tested. The test generally gave positive and negative responses where expected. Two compounds, trichloroethylene and diethylnitrosamine, exhibited a linear Beer's law relationship in the concentration range tested. A high degree of linear correlation (r>0.97) was obtained for these compounds. Other compounds showed varying degrees of linear correlation from high correlation (r=0.94) to weak correlation (r=0.44). The CAS-NBP assay results were compared to bacterial mutagenicity and animal carcinogenicity test results when information was available. A good correlation (r=0.80) existed between direct alkylating activity and direct mutagenicity. Similar correlations existed between NBP alkylation following activation and mutagenicity following microsomal activation (r=0.73). Also, different correlations were observed between carcinogenicity and NBP alkylation following activation (r=0.69) and without activation (r=0.38).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48076/1/244_2004_Article_BF00213289.pd

A blockchain-based Trust System for the Internet of Things

Comunicació presentada a la SACMAT '18: The 23rd ACM Symposium on Access Control Models and Technologies, celebrada a Indianapolis (Estats Units d'Amèrica) del 13 al 15 de juny de 2018.One of the biggest challenges for the Internet of Things (IoT) is to bridge the currently fragmented trust domains. The traditional PKI model relies on a common root of trust and does not fit well with the heterogeneous IoT ecosystem where constrained devices belong to independent administrative domains. In this work we describe a distributed trust model for the IoT that leverages the existing trust domains and bridges them to create end-to-end trust between IoT devices without relying on any common root of trust. Furthermore we define a new cryptographic primitive, denoted as obligation chain designed as a credit-based Blockchain with a built-in reputation mechanism. Its innovative design enables a wide range of use cases and business models that are simply not possible with current Blockchain-based solutions while not experiencing traditional blockchain delays. We provide a security analysis for both the obligation chain and the overall architecture and provide experimental tests that show its viability and quality