Secure Group Communication in Delay Tolerant Mobile Ad-Hoc Network

Delay-tolerant networks (DTNs) are well-known for delivering various types of information from different senders in a multicast manner, both in centralised and decentralised networks. Wireless mobile nodes form small networks in which one or more senders transmit data to one or more destinations through intermediate nodes. DTN routing protocols differ from traditional wireless routing protocols. There are security threats in DTNs, such as blackhole attackers dropping data, jamming attacks consuming bandwidth, and Vampire attacks depleting battery power and available bandwidth. This paper proposes a prevention scheme to detect and mitigate all three types of attackers in multicast communication. These attackers can impact performance by generating false replies, flooding with redundant information, and wasting communication power. The primary focus of this paper is on security issues related to DTN routing protocols. In order to counter malicious nodes, a blacklist is maintained, and if a neighbour identifies a node as malicious, it excludes packets from that node. Meanwhile, the neighbour continues sending packets to the malicious node, except for broadcast packets, which are dropped. If a node is found to forward no packets or only some packets by all its neighbours, any reply it gives to route requests is disregarded, and any request it initiates is ignored. Successful data reception at the destination indicates that hop-based data delivery maintains a record of successful transmissions. The proposed security scheme demonstrates improved performance

Virtual screening and molecular dynamics simulation studies to predict the binding of Sisymbrium irio L. derived phytochemicals against Staphylococcus aureus dihydrofolate reductase (DHFR)

The discovery of antibiotics initiated the era of drug innovation and implementation for human and animal health. Very soon, antibiotic resistance started evolving due to over-prescription and heavy usage of drugs leading to deleterious side effects. However, using plant extracts or medicinal plants has emerged as a new approach to dealing with the current problem. One such medicinal plant Sisymbrium irio L. is widely used in Unani therapy as an antimicrobial, analgesic, antipyretic, antioxidant, anti-inflammatory, hepatoprotective, bronchoprotective etc. The phytochemicals extracted from the aerial part of the plant have been used as a natural compound library and screened against a well-known anti-bacterial drug target Dihydrofolate reductase (DHFR)  enzyme of Staphylococcus aureus. The top two phytochemicals with lower docking score along with the positive control were subjected to molecular dynamics (MD) simulation studies to examine the stabilities of the complexes over 100 ns, followed by binding free energy estimation. The Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and Radius of Gyration (Rg) yielded established results throughout the MD run. Moreover, the derived phytochemicals exhibited lower binding free energy values than the positive control that can be tested for its in vitro efficacy, followed by further optimization to attain a potent therapeutic against S. aureus. Taken together, the present study suggests two promising phytochemicals derived from the aerial part of the plant S. irio with stable MD simulation results, strong binding affinity and no side effects

Applicability of Native L-Arginase produced by Streptomyces plicatus KAR73 as Antineoplastic Agent

Most of the cancer cells require high quantity of arginine for sustaining their fast-metabolic rates. Limiting supply of arginine to cancer cells using arginase may prove to be of great therapeutic value. The arginase produced by a micro organism isolated from soil has been used in industrial production of ornithine, however its use in anticancer activities is scarcely studied. This study optimized soybean meal supplemented basal media for Arginase production. Arginase was purified using ammonium sulphate precipitation, sephadex G-100 column chromatography and DEAE chromatography achieving 79.2% purification fold and 24.26% yield. It had 23 KD molecular weight as determined using Native PAGE and was active at considerably wide pH range of 6–10 and temperature 30–50℃. Whereas the maximum arginase activity was noticed with Mn²+ ions followed by polyvinyl pyrrolidine (PVP) at 70 mM substrate concentration, the maximum inhibition of activity was caused by CuC. Streptomyces plicatus KAR 73 produced arginase on mouse mammary cell line (CID 9) was not inhibited by the arginase upto 6.5 U/mL. Significant (p< 0.001) inhibition in Mouse mammary tumor (C1271) cell lines was observed with IC50 5.2 U/mL. The ornithine has been produced earlier with Mycoplasma and Clostridium by other researchers but production of native arginase from Streptomyces specifically for anticancer activities has not yet been reported. The present study infers that Arginase produced from native Streptomyces has shown promising results thereby enabling feasibility assessment towards cost effective industrial production of arginase

Applicability of Native L-Arginase produced by Streptomyces plicatus KAR73 as Antineoplastic Agent

841-849Most of the cancer cells require high quantity of arginine for sustaining their fast-metabolic rates. Limiting supply of arginine to cancer cells using arginase may prove to be of great therapeutic value. The arginase produced by a micro organism isolated from soil has been used in industrial production of ornithine, however its use in anticancer activities is scarcely studied. This study optimized soybean meal supplemented basal media for Arginase production. Arginase was purified using ammonium sulphate precipitation, sephadex G-100 column chromatography and DEAE chromatography achieving 79.2% purification fold and 24.26% yield. It had 23 KD molecular weight as determined using Native PAGE and was active at considerably wide pH range of 6–10 and temperature 30–50℃. Whereas the maximum arginase activity was noticed with Mn²+ ions followed by polyvinyl pyrrolidine (PVP) at 70 mM substrate concentration, the maximum inhibition of activity was caused by CuC. Streptomyces plicatus KAR 73 produced arginase on mouse mammary cell line (CID 9) was not inhibited by the arginase upto 6.5 U/mL. Significant (p50 5.2 U/mL. The ornithine has been produced earlier with Mycoplasma and Clostridium by other researchers but production of native arginase from Streptomyces specifically for anticancer activities has not yet been reported. The present study infers that Arginase produced from native Streptomyces has shown promising results thereby enabling feasibility assessment towards cost effective industrial production of arginase

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Ensuring the correctness of multithreaded programs is difficult, due to the potential for unexpected and nondeterministic interactions between threads. Researchers have developed tools for detecting race conditions, a situation where two threads simultaneously access the same data variable, and at least one of the accesses is a write. However, the absence of race conditions is neither necessary nor sufficient to ensure the absence of errors due to unexpected thread interactions. Race conditions, is a situation where two threads simultaneously access the same data variable, and at least one of the accesses is a write. Thus, there has to be a property to ensure the correctness of program at higher level of granularity. In my survey I have studied this noninterference property, namely the atomicity of code blocks. If a code block is atomic, we can safely reason about the program's behavior at a higher level of granularity, where the atomic block is executed ``in one step'', even though the scheduler is free to interleave threads at instruction level granularity. The notions of atomicity and race freedom are closely related, and both are often achieved in practice using synchronization mechanisms such as mutual exclusion locks, reader writer locks, or semaphores. So in this paper you will see a stronger noninterference property is required, namely th

Eight versus twelve weeks of sofosbuvir-velpatasvir in treatment-naïve non-cirrhotic patients with chronic hepatitis C virus infection: Study protocol for a multicentric, open labelled, randomized, non-inferiority trial (RESOLVE trial).

BackgroundHepatitis C virus (HCV) is a common cause of liver cirrhosis and hepatocellular carcinoma. Globally, nearly 71 million people have chronic HCV infection, and approximately 399,000 dies annually. In patients without cirrhosis, HCV infection is treated with 12 weeks of sofosbuvir/velpatasvir combination. Results from available small, single-centre observational studies suggest that the sofosbuvir/velpatasvir combination given for 8 weeks may be as effective as the standard 12 weeks of treatment. We propose to compare the treatment response of 12 weeks versus 8 weeks of sofosbuvir/velpatasvir in non-cirrhotic people with chronic HCV infection.MethodsThis multicentric, randomized, open-label, non-inferiority trial will include 880 (2 arms x 440) treatment naïve, viraemic (HCV RNA >10,000 IU/mL), non-cirrhotic adults (age >18 years) with chronic hepatitis C. People who are at high-risk for HCV reinfection such as haemophiliacs, people who inject drugs, those on maintenance hemodialysis or having HIV will be excluded. The presence or absence of cirrhosis will be determined with a combination of history, examination, ultrasound, liver stiffness measured with transient elastography, APRI, FIB-4, and esophagogastroduodenoscopy. Participants will be randomized to receive either 8- or 12-week sofosbuvir/velpatasvir treatment. A blood specimen will be collected before starting the treatment (to determine the HCV genotype), after 4 weeks of treatment (for early virological response), and at 12 weeks after treatment discontinuation for SVR12.DiscussionThe study will provide data on the efficacy of 8 weeks of treatment as compared to the standard of care (12 weeks) in non-cirrhotic patients with chronic HCV infection. Treatment for a shorter duration may improve treatment compliance, reduce the cost of treatment, and ease the treatment implementation from a public health perspective.Trial registrationRegistered with Clinical Trial Registry of India (http://ctri.nic.in) Registration No. CTRI/2022/03/041368 [Registered on: 24/03/2022]-Trial Registered Prospectively

Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties.

Germline mutations in mitochondrial DNA polymerase gamma (POLG1) induce mitochondrial DNA (mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human cancer. However, a role for germline variations in POLG1 in human cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human cancers. We analyzed the mutations, expression and copy number variation in POLG1 in several cancer databases and validated the analyses in primary breast tumors and breast cancer cell lines. We discovered 5-aza-2'-deoxycytidine led epigenetic regulation of POLG1, mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of POLG1 gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased glucose consumption, decreased ATP production and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human cancers and suggest a role for POLG1 germline variants in promoting tumorigenic properties

Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma

Abstract Background Colorectal adenocarcinomas are characterized by abnormal mitochondrial DNA (mtDNA) copy number and genomic instability, but a molecular interaction between mitochondrial and nuclear genome remains unknown. Here we report the discovery of increased copies of nuclear mtDNA (NUMT) in colorectal adenocarcinomas, which supports link between mtDNA and genomic instability in the nucleus. We name this phenomenon of nuclear occurrence of mitochondrial component as numtogenesis. We provide a description of NUMT abundance and distribution in tumor versus matched blood-derived normal genomes. Methods Whole-genome sequence data were obtained for colon adenocarcinoma and rectum adenocarcinoma patients participating in The Cancer Genome Atlas, via the Cancer Genomics Hub, using the GeneTorrent file acquisition tool. Data were analyzed to determine NUMT proportion and distribution on a genome-wide scale. A NUMT suppressor gene was identified by comparing numtogenesis in other organisms. Results Our study reveals that colorectal adenocarcinoma genomes, on average, contains up to 4.2-fold more somatic NUMTs than matched normal genomes. Women colorectal tumors contained more NUMT than men. NUMT abundance in tumor predicted parallel abundance in blood. NUMT abundance positively correlated with GC content and gene density. Increased numtogenesis was observed with higher mortality. We identified YME1L1, a human homolog of yeast YME1 (yeast mitochondrial DNA escape 1) to be frequently mutated in colorectal tumors. YME1L1 was also mutated in tumors derived from other tissues. We show that inactivation of YME1L1 results in increased transfer of mtDNA in the nuclear genome. Conclusions Our study demonstrates increased somatic transfer of mtDNA in colorectal tumors. Our study also reveals sex-based differences in frequency of NUMT occurrence and that NUMT in blood reflects NUMT in tumors, suggesting NUMT may be used as a biomarker for tumorigenesis. We identify YME1L1 as the first NUMT suppressor gene in human and demonstrate that inactivation of YME1L1 induces migration of mtDNA to the nuclear genome. Our study reveals that numtogenesis plays an important role in the development of cancer