Algorithm Selection Framework for Cyber Attack Detection

The number of cyber threats against both wired and wireless computer systems and other components of the Internet of Things continues to increase annually. In this work, an algorithm selection framework is employed on the NSL-KDD data set and a novel paradigm of machine learning taxonomy is presented. The framework uses a combination of user input and meta-features to select the best algorithm to detect cyber attacks on a network. Performance is compared between a rule-of-thumb strategy and a meta-learning strategy. The framework removes the conjecture of the common trial-and-error algorithm selection method. The framework recommends five algorithms from the taxonomy. Both strategies recommend a high-performing algorithm, though not the best performing. The work demonstrates the close connectedness between algorithm selection and the taxonomy for which it is premised.Comment: 6 pages, 7 figures, 1 table, accepted to WiseML '2

Recombinant factor VIIa analog NN1731 (V158D/E296V/M298Q-FVIIa) enhances fibrin formation, structure and stability in lipidated hemophilic plasma

Introduction—The bypassing agent recombinant factor VIIa (rFVIIa) is efficacious in treating bleeding in hemophilia patients with inhibitors. Efforts have focused on the rational engineering of rFVIIa variants with increased hemostatic potential. One rFVIIa analog (V158D/E296V/M298QFVIIa, NN1731) improves thrombin generation and clotting in purified systems, whole blood from hemophilic patients and factor VIII-deficient mice. Methods—We used calibrated automated thrombography and plasma clotting assays to compare effects of bypassing agents (rFVIIa, NN1731) on hemophilic clot formation, structure, and ability to resist fibrinolysis. Results—Both rFVIIa and NN1731 shortened the clotting onset and increased the maximum rate of fibrin formation and fibrin network density in hemophilic plasma clots. In the presence of tissue plasminogen activator, both rFVIIa and NN1731 shortened the time to peak turbidity (TTPeaktPA) and increased the area under the clot formation curve (AUCtPA). Phospholipids increased both rFVIIa and NN1731 activity in a lipid concentration-dependent manner. Estimated geometric mean concentrations of rFVIIa and NN1731 producing similar onset, rate, TTPeaktPA, and AUCtPA as seen with 100% factors VIII and IX were: 24.5, 74.3, 29.7, and 37.1 nM rFVIIa, and 8.6, 31.2, 9.0, and 11.3 nM NN1731, respectively. In each case, the NN1731 concentration was significantly lower than rFVIIa. Conclusions—These findings suggest that like rFVIIa, NN1731 improves the formation, structure, and stability of hemophilic clots. Higher lipid concentrations may facilitate assessment of both rFVIIa and NN1731 activity. NN1731 appears likely to support rapid clot formation in tissues with high endogenous fibrinolytic activity

Plasma-based assays distinguish hyperfibrinolysis and shutdown subgroups in trauma-induced coagulopathy

BACKGROUND Trauma patients with abnormal fibrinolysis have increased morbidity and mortality. Knowledge of mechanisms differentiating fibrinolytic phenotypes is important to optimize treatment. We hypothesized that subjects with abnormal fibrinolysis identified by whole blood viscoelastometry can also be distinguished by plasma thrombin generation, clot structure, fibrin formation, and plasmin generation measurements. METHODS Platelet-poor plasma (PPP) from an observational cross-sectional trauma cohort with fibrinolysis shutdown (% lysis at 30 minutes [LY30] \u3c 0.9, n = 11) or hyperfibrinolysis (LY30 \u3e 3%, n = 9) defined by whole blood thromboelastography were studied. Noninjured control subjects provided comparative samples. Thrombin generation, fibrin structure and formation, and plasmin generation were measured by fluorescence, confocal microscopy, turbidity, and a fluorescence-calibrated plasmin assay, respectively, in the absence/presence of tissue factor or tissue plasminogen activator (tPA). RESULTS Whereas spontaneous thrombin generation was not detected in PPP from control subjects, PPP from hyperfibrinolysis or shutdown patients demonstrated spontaneous thrombin generation, and the lag time was shorter in hyperfibrinolysis versus shutdown. Addition of tissue factor masked this difference but revealed increased thrombin generation in hyperfibrinolysis samples. Compared with shutdown, hyperfibrinolysis PPP formed denser fibrin networks. In the absence of tPA, the fibrin formation rate was faster in shutdown than hyperfibrinolysis, but hyperfibrinolysis clots lysed spontaneously; these differences were masked by addition of tPA. Tissue plasminogen activator–stimulated plasmin generation was similar in hyperfibrinolysis and shutdown samples. Differences in LY30, fibrin structure, and lysis correlated with pH. CONCLUSION This exploratory study using PPP-based assays identified differences in thrombin generation, fibrin formation and structure, and lysis in hyperfibrinolysis and shutdown subgroups. These groups did not differ in their ability to promote tPA-triggered plasmin generation. The ability to characterize these activities in PPP facilitates studies to identify mechanisms that promote adverse outcomes in trauma

Chemoenzymatische Synthese optisch aktiver β,δ\beta,\delta-Dihydroxyester

A new access to optically active $\beta, \delta$-dihydroxy esters and $\delta$-hydroxy-$\beta$-keto esters is presented. These compunds are valuable intermediates for the synthesis of important natural products and pharmaceuticals, e. g. HMG-CoA reductase inhibitors of the mevinic acid type. The synthesis strategy is based on an unprecedented highly regio- and enantioselective biocatalytic reduction of achiral $\beta, \delta$-diketo esters. In a screening, two enantiocomplementary biocatalysts were found to be particularly suitable for this purpose. Thus, the $\beta, \delta$-diketo ester $\textit{tert}$-butyl 6-chloro-3,5-dioxohexanoate was reduced by NADP(H)-dependent alcohol dehydrogenase of $\textit{Lactobacillus brevis}$ to afford enantiomerically pure $\delta$-hydroxy-$\beta$-keto ester $\textit{tert}$-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate in a 72-84 % isolated yield (>99.5% ee). The enzyme is readily available in the form of a crude cell extract from a recombinant $\textit{E. coli}$ strain (recLBADH). A scale-up of the one-step substrate synthesis (140 g scale) and of the enzymatic reduction (70 g scale, substrate-coupled NADPH-regeneration) was established. The enantiomeric $\delta$-hydroxy-$\beta$-keto ester $\textit{tert}$-butyl (R)-6-chloro-5-hydroxy-3-oxohexanoate was obtained by reduction of $\textit{tert}$-butyl 6-chloro-3,5-dioxohexanoate with baker's yeast ($\textit{Saccharomyces cerevisiae}$). A detailed investigation of the reaction parameters of this whole-cell transformation led to the application of a biphasic system by which the enantiomeric excess could be raised from 48% ee to 94% ee (50% isolated yield). The $\beta$-keto group of both enantiomers thus obtained was reduced by $\textit{syn}$- and $\textit{anti}$-selective borohydride reductions. Combination of the reduction methods afforded all four stereoisomers of the crystalline $\beta, \delta$-dihydroxy ester $\textit{tert}$-butyl 6-chloro-3,5-dihydroxyhexanoate (>99% ee and $\textit{dr}$ > 200:1 each, 52-70% isolated yield). Alternatively, the $\textit{syn}$- (3R,5S)-isomer of this known building block was obtained in one step and with high stereoisomeric purity by reduction of $\textit{tert}$-butyl 6-chloro-3,5-dioxohexanoate with whole cells of $\textit{Lactobacillus kefir}$. An iodide and an epoxide suitable for C-C-bond formation at C-6 were derived from $\textit{tert}$-butyl $\textit{syn}$-(3R,5S)-6-chloro-3,5-dihydroxyhexanoate. recLBADH accepts a variety of $\beta, \delta$-diketo esters as was determined in a photometric assay. The $\beta, \delta$-diketo esters $\textit{tert}$-butyl 3,5-dioxohexanoate and $\textit{tert}$-butyl 3,5-dioxoheptanoate were reduced an a 1-10 mmol scale to afford the corresponding (R)-$\delta$-hydroxy-$beta$-keto esters with 99.4% ee and 98.1% ee, respectively (61-77 % isolated yield). The reduction ofthe branched $\beta, \delta$-diketo ester $\textit{tert}$-butyl $\textit{rac}$-4-methyl-3,5-dioxohexanoate proceeds via a dynamic kinetic resolution which resulted in a 66% isolated yield of the corresponding $\textit{syn}$-(4S,5R)-$\delta$-hydroxy-$beta$-keto ester (99.2% ee, dr = 35:1). To underline the applicability of the virtually enantiopure enzymatic products, they were used as starting materials for several new natural product syntheses. Furthermore, a convenient process for the large-scale separation of noncrystallising diastereomeric $\textit{syn}$- and $\textit{anti}$- 1,3-diols was developed. The crucial step of this new method is a diastereomer-differentiating hydrolysis of the respective acetonides

Multifunctional beta-NaGdF4:Ln(3+) (Ln = Yb, Er, Dy) nanoparticles with NIR to visible upconversion and high transverse relaxivity: a potential bimodal contrast agent for high-field MRI and optical imaging

© 2016 The Royal Society of Chemistry. A novel series of active-core/active-shell upconverting nanoparticles (AC/AS-UCNPs) based on NaGdF4doped with Yb3+/Er3+in the core and Yb3+/Dy3+in the shell having average particle size between 29.2 and 32.9 nm were synthesized. The UCNPs exhibit favorable properties for bimodal magnetic resonance imaging (MRI) and optical imaging (OI). Excitation of the UCNPs at 980 nm dispersed in water at room temperature resulted in intense green upconversion emission of Er3+. The proton nuclear magnetic relaxation dispersion (1H-NMRD) studies show very low longitudinal relaxivity (r1) values, which decreases with an increase of magnetic field. On the other hand, the transverse relaxivity (r2) values show an increasing trend with both increase in doping of Dy3+as well as the increase in magnetic field reaching a maximum value of r2= 70.07 s-1mM-1(per Ln3+ion) for NaGdF4:Yb3+/Er3+# NaYbF4:38.06% Dy3+at 500 MHz and 310 K. Exhibiting such a high r2value at high magnetic field and intense upconversion luminescence under 980 nm excitation makes these NPs exceptional candidates towards bioimaging applications.status: publishe

Physical Determinants of Fibrinolysis in Single Fibrin Fibers

Fibrin fibers form the structural backbone of blood clots; fibrinolysis is the process in which plasmin digests fibrin fibers, effectively regulating the size and duration of a clot. To understand blood clot dissolution, the influence of clot structure and fiber properties must be separated from the effects of enzyme kinetics and perfusion rates into clots. Using an inverted optical microscope and fluorescently-labeled fibers suspended between micropatterned ridges, we have directly measured the lysis of individual fibrin fibers. We found that during lysis 64 ± 6% of fibers were transected at one point, but 29 ± 3% of fibers increase in length rather than dissolving or being transected. Thrombin and plasmin dose-response experiments showed that the elongation behavior was independent of plasmin concentration, but was instead dependent on the concentration of thrombin used during fiber polymerization, which correlated inversely with fiber diameter. Thinner fibers were more likely to lyse, while fibers greater than 200 ± 30 nm in diameter were more likely to elongate. Because lysis rates were greatly reduced in elongated fibers, we hypothesize that plasmin activity depends on fiber strain. Using polymer physics- and continuum mechanics-based mathematical models, we show that fibers polymerize in a strained state and that thicker fibers lose their prestrain more rapidly than thinner fibers during lysis, which may explain why thick fibers elongate and thin fibers lyse. These results highlight how subtle differences in the diameter and prestrain of fibers could lead to dramatically different lytic susceptibilities