Mitigating Reversing Vulnerabilities in .NET Applications Using Virtualized Software Protection

Protecting intellectual property contained in application source code and preventing tampering with application binaries are both major concerns for software developers. Simply by possessing an application binary, any user is able to attempt to reverse engineer valuable information or produce unanticipated execution results through tampering. As reverse engineering tools become more prevalent, and as the knowledge required to effectively use those tools decreases, applications come under increased attack from malicious users. Emerging development tools such as Microsoft\u27s .NET Application Framework allow diverse source code composed of multiple programming languages to be integrated into a single application binary, but the potential for theft of intellectual property increases due to the metadata-rich construction of compiled .NET binaries. Microsoft\u27s new Software Licensing and Protection Services (SLPS) application is designed to mitigate trivial reversing of .NET applications through the use of virtualization. This research investigates the viability of the SLPS software protection utility Code Protector as a means of mitigating the inherent vulnerabilities of .NET applications. The results of the research show that Code Protector does indeed protect compiled .NET applications from reversing attempts using commonly-available tools. While the performance of protected applications can suffer if the protections are applied to sections of the code that are used repeatedly, it is clear that low-use .NET application code can be protected by Code Protector with little performance impact

Rapid Quantification of Biofouling With an Inexpensive, Underwater Camera and Image Analysis

To reduce the transport of potentially invasive species on ships\u27 submerged surfaces, rapid-and accurate-estimates of biofouling are needed so shipowners and regulators can effectively assess and manage biofouling. This pilot study developed a model approach for that task. First, photographic images were collected in situ with a submersible, inexpensive pocket camera. These images were used to develop image processing algorithms and train machine learning models to classify images containing natural assemblages of fouling organisms. All of the algorithms and models were implemented in a widely available software package (MATLAB©). Initially, an unsupervised clustering model was used, and three types of fouling were delineated. Using a supervised classification approach, however, seven types of fouling could be identified. In this manner, fouling was successfully quantified over time on experimental panels immersed in seawater. This work provides a model for the easy, quick, and cost-effective classification of biofouling

Unbiased Characterization of Anopheles Mosquito Blood Meals by Targeted High-Throughput Sequencing

Understanding mosquito host choice is important for assessing vector competence or identifying disease reservoirs. Unfortunately, the availability of an unbiased method for comprehensively evaluating the composition of insect blood meals is very limited, as most current molecular assays only test for the presence of a few pre-selected species. These approaches also have limited ability to identify the presence of multiple mammalian hosts in a single blood meal. Here, we describe a novel high-throughput sequencing method that enables analysis of 96 mosquitoes simultaneously and provides a comprehensive and quantitative perspective on the composition of each blood meal. We validated in silico that universal primers targeting the mammalian mitochondrial 16S ribosomal RNA genes (16S rRNA) should amplify more than 95% of the mammalian 16S rRNA sequences present in the NCBI nucleotide database. We applied this method to 442 female Anopheles punctulatus s. l. mosquitoes collected in Papua New Guinea (PNG). While human (52.9%), dog (15.8%) and pig (29.2%) were the most common hosts identified in our study, we also detected DNA from mice, one marsupial species and two bat species. Our analyses also revealed that 16.3% of the mosquitoes fed on more than one host. Analysis of the human mitochondrial hypervariable region I in 102 human blood meals showed that 5 (4.9%) of the mosquitoes unambiguously fed on more than one person. Overall, analysis of PNG mosquitoes illustrates the potential of this approach to identify unsuspected hosts and characterize mixed blood meals, and shows how this approach can be adapted to evaluate inter-individual variations among human blood meals. Furthermore, this approach can be applied to any disease-transmitting arthropod and can be easily customized to investigate non-mammalian host sources

Proline dehydrogenase is essential for proline protection against hydrogen peroxide induced cell death

Proline metabolism has an underlying role in apoptotic signaling that impacts tumorigenesis. Proline is oxidized to glutamate in the mitochondria with the rate limiting step catalyzed by proline dehydrogenase (PRODH). PRODH expression is inducible by p53 leading to increased proline oxidation, reactive oxygen species (ROS) formation, and induction of apoptosis. Paradoxical to its role in apoptosis, proline also protects cells against oxidative stress. Here we explore the mechanism of proline protection against hydrogen peroxide stress in melanoma WM35 cells. Treatment of WM35 cells with proline significantly increased cell viability, diminished oxidative damage of cellular lipids and proteins, and retained ATP and NADPH levels after exposure to hydrogen peroxide. Inhibition or siRNA-mediated knockdown of PRODH abolished proline protection against oxidative stress whereas knockdown of Δ1-pyrroline-5- carboxylate reductase, a key enzyme in proline biosynthesis, had no impact on proline protection. Potential linkages between proline metabolism and signaling pathways were explored. The combined inhibition of the mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 eliminated proline protection. A significant increase in Akt activation was observed in proline treated cells after hydrogen peroxide stress along with a corresponding increase in the phosphorylation of the fork head transcription factor class O3a (FoxO3a). The role of PRODH in proline mediated protection was validated in the prostate carcinoma cell line, PC3. Knockdown of PRODH in PC3 cells attenuated phosphorylated levels of Akt and FoxO3a and decreased cell survival during hydrogen peroxide stress. The results provide evidence that PRODH is essential in proline protection against hydrogen peroxide mediated cell death and that proline/PRODH helps activate Akt in cancer cells

Proline dehydrogenase is essential for proline protection against hydrogen peroxide induced cell death

Proline metabolism has an underlying role in apoptotic signaling that impacts tumorigenesis. Proline is oxidized to glutamate in the mitochondria with the rate limiting step catalyzed by proline dehydrogenase (PRODH). PRODH expression is inducible by p53 leading to increased proline oxidation, reactive oxygen species (ROS) formation, and induction of apoptosis. Paradoxical to its role in apoptosis, proline also protects cells against oxidative stress. Here we explore the mechanism of proline protection against hydrogen peroxide stress in melanoma WM35 cells. Treatment of WM35 cells with proline significantly increased cell viability, diminished oxidative damage of cellular lipids and proteins, and retained ATP and NADPH levels after exposure to hydrogen peroxide. Inhibition or siRNA-mediated knockdown of PRODH abolished proline protection against oxidative stress whereas knockdown of Δ1-pyrroline-5- carboxylate reductase, a key enzyme in proline biosynthesis, had no impact on proline protection. Potential linkages between proline metabolism and signaling pathways were explored. The combined inhibition of the mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 eliminated proline protection. A significant increase in Akt activation was observed in proline treated cells after hydrogen peroxide stress along with a corresponding increase in the phosphorylation of the fork head transcription factor class O3a (FoxO3a). The role of PRODH in proline mediated protection was validated in the prostate carcinoma cell line, PC3. Knockdown of PRODH in PC3 cells attenuated phosphorylated levels of Akt and FoxO3a and decreased cell survival during hydrogen peroxide stress. The results provide evidence that PRODH is essential in proline protection against hydrogen peroxide mediated cell death and that proline/PRODH helps activate Akt in cancer cells

Discovery of a Faint Companion to Alcor Using MMT/AO 5 μ\mum Imaging

We report the detection of a faint stellar companion to the famous nearby A5V star Alcor (80 UMa). The companion has M-band ($\lambda$ = 4.8 $\mu$m) magnitude 8.8 and projected separation 1".11 (28 AU) from Alcor. The companion is most likely a low-mass ($\sim$0.3 \msun) active star which is responsible for Alcor's X-ray emission detected by ROSAT (L$_{\rm X}$ $\simeq$ 10$^{28.3}$ erg/s). Alcor is a nuclear member of the Ursa Major star cluster (UMa; d $\simeq$ 25 pc, age $\simeq$ 0.5 Gyr), and has been occasionally mentioned as a possible distant (709") companion of the stellar quadruple Mizar ($\zeta$ UMa). Comparing the revised Hipparcos proper motion for Alcor with the mean motion for other UMa nuclear members shows that Alcor has a peculiar velocity of 1.1 km/s, which is comparable to the predicted velocity amplitude induced by the newly-discovered companion ($\sim$1 km/s). Using a precise dynamical parallax for Mizar and the revised Hipparcos parallax for Alcor, we find that Mizar and Alcor are physically separated by 0.36 $\pm$ 0.19 pc (74 $\pm$ 39 kAU; minimum 18 kAU), and their velocity vectors are marginally consistent ($\chi^2$ probability 6%). Given their close proximity and concordant motions we suggest that the Mizar quadruple and the Alcor binary be together considered the 2nd closest stellar sextuplet. The addition of Mizar-Alcor to the census of stellar multiples with six or more components effectively doubles the local density of such systems within the local volume (d $<$ 40 pc).Comment: 28 pages, 2 figures, AJ, in press; emulateapj short version at http://www.pas.rochester.edu/~emamajek/alcor.pd

Conjugates of Superoxide Dismutase 1 with Amphiphilic Poly(2-oxazoline) Block Copolymers for Enhanced Brain Delivery: Synthesis, Characterization and Evaluation in Vitro and in Vivo

Superoxide dismutase 1 (SOD1) efficiently catalyzes dismutation of superoxide but its poor delivery to the target sites in the body, such as brain, hinders its use as a therapeutic agent for superoxide-associated disorders. Here to enhance the delivery of SOD1 across the blood brain barrier (BBB) and in neurons the enzyme was conjugated with poly(2-oxazoline) (POx) block copolymers, P(MeOx-b-BuOx) or P(EtOx-b-BuOx), comprised of 1) hydrophilic 2-methyl-2-oxazoline (MeOx) or 2-ethyl-2-oxazoline (EtOx) and 2) hydrophobic 2-butyl-2-oxazoline (BuOx) repeating units. The conjugates contained from 2 to 3 POx chains joining the protein amino groups via cleavable -(ss)- or non-cleavable –(cc)- linkers at the BuOx block terminus. They retained 30% to 50% of initial SOD1 activity, were conformationally and thermally stable and assembled in 8 or 20 nm aggregates in aqueous solution. They had little if any toxicity to CATH.a neurons and displayed enhanced uptake in these neurons as compared to native or PEGylated SOD1. Of the two conjugates, SOD1-(cc)-P(MeOx-b-BuOx) and SOD1-(cc)-P(EtOx-b-BuOx) compared, the latter was entering cells 4 to 7 times faster and at 6 h colocalized predominantly with endoplasmic reticulum (41 ± 3%) and mitochondria (21 ± 2%). Colocalization with endocytosis markers and pathway inhibition assays suggested that it was internalized through lipid raft/caveolae, also employed by the P(EtOx-b-BuOx) copolymer. The SOD activity in cell lysates and ability to attenuate angiotensin II (Ang II)-induced superoxide in live cells were increased for this conjugate compared to SOD1 and PEG-SOD1. Studies in mice showed that SOD1-POx had ca. 1.75 times longer half-life in blood than native SOD1 (28.4 vs 15.9 min) and after i.v. administration penetrated the BBB significantly faster than albumin to accumulate in brain parenchyma. The conjugate maintained high stability both in serum and in brain (77% vs. 84% at 1 h post injection). Its amount taken up by the brain reached a maximum value of 0.08%ID/g (percent of the injected dose taken up per gram of brain) 4 h post injection. The entry of SOD1-(cc)-P(EtOx-b-BuOx) to the brain was mediated by a non-saturable mechanism. Altogether, SOD1-POx conjugates are promising candidates as macromolecular antioxidant therapies for superoxide-associated diseases such as Ang II induced neuro-cardiovascular diseases

Nanoformulation of the Superoxide Dismutase Mimic, MnTnBuOE-2-PyP5+, Prevents its Acute Hypotensive Response

Scavenging superoxide (O2•-) via overexpression of superoxide dismutase (SOD) or administration of SOD mimics improves outcomes in multiple experimental models of human disease including cardiovascular disease, neurodegeneration, and cancer. While few SOD mimics have transitioned to clinical trials, MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin SOD mimic, is currently in clinical trials as a radioprotector for cancer patients; thus, providing hope for the use of SOD mimics in the clinical setting. However, BuOE transiently alters cardiovascular function including a significant and precipitous decrease in blood pressure. To limit BuOE\u27s acute hypotensive action, we developed a mesoporous silica nanoparticle and lipid bilayer nanoformulation of BuOE (nanoBuOE) that allows for slow and sustained release of the drug. Herein, we tested the hypothesis that unlike native BuOE, nanoBuOE does not induce an acute hypotensive response, as the nanoformulation prevents BuOE from scavenging O2•- while the drug is still encapsulated in the formulation. We report that intact nanoBuOE does not effectively scavenge O2•-, whereas BuOE released from the nanoformulation does retain SOD-like activity. Further, in mice, native BuOE, but not nanoBuOE, rapidly, acutely, and significantly decreases blood pressure, as measured by radiotelemetry. To begin exploring the physiological mechanism by which native BuOE acutely decreases blood pressure, we recorded renal sympathetic nerve activity (RSNA) in rats. RSNA significantly decreased immediately following intravenous injection of BuOE, but not nanoBuOE. These data indicate that nanoformulation of BuOE, a SOD mimic currently in clinical trials in cancer patients, prevents BuOE\u27s negative side effects on blood pressure homeostasis

Inhibition of fatty acid oxidation promotes macrophage control of Mycobacterium tuberculosis

Macrophage activation involves metabolic reprogramming to support antimicrobial cellular functions. How these metabolic shifts influence the outcome of infection by intracellular pathogens remains incompletely understood