In this webinar for education institutions we will consider: - contract principles - early questions to consider: • what is the purpose of collaboration? • what IP may be generated? • who owns background IP? ...

Richard Cupitt is a Senior Fellow and Director of the Partnerships in Proliferation Prevention program at Stimson. His areas of expertise include WMD nonproliferation, export controls, and foreign policy.

The post COVID-19 Pandemic Vulnerable to Exploitation by Proliferators, Terrorists & Criminals appeared first on Inter Press Service.

There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor–targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1–targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic "class" effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC₅₀ and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1–targeted combination therapy for Ewing sarcoma.

Lipid rafts, solid regions of the plasma membrane enriched in cholesterol and glycosphingolipids, are essential parts of a cell. Functionally, lipid rafts present a platform that facilitates interaction of cells with the outside world. However, the unique properties of lipid rafts required to fulfill this function at the same time make them susceptible to exploitation by pathogens. Many steps of pathogen interaction with host cells, and sometimes all steps within the entire lifecycle of various pathogens, rely on host lipid rafts. Such steps as binding of pathogens to the host cells, invasion of intracellular parasites into the cell, the intracellular dwelling of parasites, microbial assembly and exit from the host cell, and microbe transfer from one cell to another all involve lipid rafts. Interaction also includes modification of lipid rafts in host cells, inflicted by pathogens from both inside and outside the cell, through contact or remotely, to advance pathogen replication, to utilize cellular resources, and/or to mitigate immune response. Here, we provide a systematic overview of how and why pathogens interact with and exploit host lipid rafts, as well as the consequences of this interaction for the host, locally and systemically, and for the microbe. We also raise the possibility of modulation of lipid rafts as a therapeutic approach against a variety of infectious agents.

ABSTRACT

One of the primary functions of the mucosal barrier, found lining epithelial cells, is to serve as a first-line of defense against microbial pathogens. The major structural components of mucus are heavily glycosylated proteins called mucins. Mucins are key components of the innate immune system as they aid in the clearance of pathogens and can decrease pathogen virulence. It has also been recently reported that individual mucins and derived glycans can attenuate the virulence of the human pathogen Pseudomonas aeruginosa. Here, we show data indicating that mucins not only play a role in host defense but that they can also be subverted by P. aeruginosa to cause disease. We found that the mucin MUL-1 and mucin-derived monosaccharides N-acetyl-galactosamine and N-acetylglucosamine are required for P. aeruginosa killing of Caenorhabditis elegans. We also found that the defective adhesion of P. aeruginosa to human lung alveolar epithelial cells, deficient in the mucin MUC1, can be reversed by the addition of individual monosaccharides. The monosaccharides identified in this study are found in a wide range of organisms where they act as host factors required for bacterial pathogenesis. While mucins in C. elegans lack sialic acid caps, which makes their monosaccharides readily available, they are capped in other species. Pathogens such as P. aeruginosa that lack sialidases may rely on enzymes from other bacteria to utilize mucin-derived monosaccharides.

IMPORTANCE One of the first lines of defense present at mucosal epithelial tissues is mucus, which is a highly viscous material formed by mucin glycoproteins. Mucins serve various functions, but importantly they aid in the clearance of pathogens and debris from epithelial barriers and serve as innate immune factors. In this study, we describe a requirement of host monosaccharides, likely derived from host mucins, for the ability of Pseudomonas aeruginosa to colonize the intestine and ultimately cause death in Caenorhabditis elegans. We also demonstrate that monosaccharides alter the ability of bacteria to bind to both Caenorhabditis elegans intestinal cells and human lung alveolar epithelial cells, suggesting that there are conserved mechanisms underlying host-pathogen interactions in a range of organisms. By gaining a better understanding of pathogen-mucin interactions, we can develop better approaches to protect against pathogen infection.

ABSTRACT

Selectable markers are indispensable for genetic engineering, yet their number and variety are limited. Most selection procedures for prototrophic cells rely on the introduction of antibiotic resistance genes. New minimally invasive tools are needed to facilitate sophisticated genetic manipulations. Here, we characterized three endogenous genes in the human fungal pathogen Aspergillus fumigatus for their potential as markers for targeted genomic insertions of DNAs of interest (DOIs). Since these genes are involved in uptake and metabolization of pyrimidines, resistance to the toxic effects of prodrugs 5-fluorocytosine and 5-fluorouracil can be used to select successfully integrated DOIs. We show that DOI integration, resulting in the inactivation of these genes, caused no adverse effects with respect to nutrient requirements, stress resistance, or virulence. Beside the individual use of markers for site-directed integration of reporter cassettes, including the 17-kb penicillin biosynthetic cluster, we demonstrate their sequential use by inserting three genes encoding fluorescent proteins into a single strain for simultaneous multicolor localization microscopy. In addition to A. fumigatus, we validated the applicability of this novel toolbox in Penicillium chrysogenum and Fusarium oxysporum. Enabling multiple targeted insertions of DOIs without the necessity for exogenous markers, this technology has the potential to significantly advance genetic engineering.

IMPORTANCE This work reports the discovery of a novel genetic toolbox comprising multiple, endogenous selectable markers for targeted genomic insertions of DNAs of interest (DOIs). Marker genes encode proteins involved in 5-fluorocytosine uptake and pyrimidine salvage activities mediating 5-fluorocytosine deamination as well as 5-fluorouracil phosphoribosylation. The requirement for their genomic replacement by DOIs to confer 5-fluorocytosine or 5-fluorouracil resistance for transformation selection enforces site-specific integrations. Due to the fact that the described markers are endogenously encoded, there is no necessity for the exogenous introduction of commonly employed markers such as auxotrophy-complementing genes or antibiotic resistance cassettes. Importantly, inactivation of the described marker genes had no adverse effects on nutrient requirements, growth, or virulence of the human pathogen Aspergillus fumigatus. Given the limited number and distinct types of selectable markers available for the genetic manipulation of prototrophic strains such as wild-type strains, we anticipate that the proposed methodology will significantly advance genetic as well as metabolic engineering of fungal species.

Pseudomonas aeruginosa exploits intrinsic and acquired resistance mechanisms to resist almost every antibiotic used in chemotherapy. Antimicrobial resistance in P. aeruginosa isolates recovered from cystic fibrosis (CF) patients is further enhanced by the occurrence of hypermutator strains, a hallmark of chronic infections in CF patients. However, the within-patient genetic diversity of P. aeruginosa populations related to antibiotic resistance remains unexplored. Here, we show the evolution of the mutational resistome profile of a P. aeruginosa hypermutator lineage by performing longitudinal and transversal analyses of isolates collected from a CF patient throughout 20 years of chronic infection. Our results show the accumulation of thousands of mutations, with an overall evolutionary history characterized by purifying selection. However, mutations in antibiotic resistance genes appear to have been positively selected, driven by antibiotic treatment. Antibiotic resistance increased as infection progressed toward the establishment of a population constituted by genotypically diversified coexisting sublineages, all of which converged to multidrug resistance. These sublineages emerged by parallel evolution through distinct evolutionary pathways, which affected genes of the same functional categories. Interestingly, ampC and ftsI, encoding the β-lactamase and penicillin-binding protein 3, respectively, were found to be among the most frequently mutated genes. In fact, both genes were targeted by multiple independent mutational events, which led to a wide diversity of coexisting alleles underlying β-lactam resistance. Our findings indicate that hypermutators, apart from boosting antibiotic resistance evolution by simultaneously targeting several genes, favor the emergence of adaptive innovative alleles by clustering beneficial/compensatory mutations in the same gene, hence expanding P. aeruginosa strategies for persistence.

Mr White also took issue with the duchess's allegation that the publisher "acted dishonestly" when deciding which parts of her letter to her father to publish.

Yep, in-the-wild SQL injection exploits in 2020 are still a thing.

'Good Morning Britain' host has previously criticised Lord Sugar for his attitude towards the government's handling of the pandemic

Singer imprisoned for nine years for getting teenagers to send him explicit pictures

A former star of The X Factor has been jailed for nine years for sexually exploiting seven teenage boys.

Danny Tetley, from Bradford, was described as “a despicable creature with very few redeeming features” for encouraging the youngsters to send him explicit pictures in exchange for money.

Five U.S. defendants convicted for their activity in a global child pornography trafficking enterprise were sentenced today in the Northern District of Florida. The defendants had pled to multiple charges, including engaging in a child exploitation enterprise; conspiracy to advertise, transport, ship, receive and possess child pornography; advertising child pornography; transporting child pornography; and receiving child pornography.

WASHINGTON and PENSACOLA, Fla. – Six U.S. defendants convicted for their activity in a global child pornography trafficking enterprise were sentenced today in the Northern District of Florida, Acting Assistant Attorney General of the Criminal Division Rita M. Glavin, U.S. Attorney for the Northern District of Florida Thomas F. Kirwin and FBI Executive Assistant Director J. Stephen Tidwell announced.

James Freeman of Santa Rosa Beach, Fla., was sentenced to life in prison today for his activity in a global child pornography trafficking enterprise. Freeman, a registered sex offender, was found guilty following a six-day trial in January 2009 of six counts relating to his criminal activities as a member of the child exploitation enterprise.

Warren Mumpower of Spokane, Wash., was sentenced to life in prison today for his activity in a global child pornography trafficking enterprise.

The Justice Department announced the indictment of Alec Souphone Sou and Mike Mankone Sou, owners of Aloun Farm in Hawaii, and Thai labor recruiter William Khoo late yesterday for engaging in a conspiracy to commit forced labor and visa fraud.

A federal grand jury in Atlanta has indicted an Ellenwood, Ga., husband and wife, Juna Gwendolyn Babb, 54, and Michael J. Babb, 53, on charges of conspiracy, forced labor, document servitude, which is confiscating someone’s passport and visa, and harboring an alien for financial gain, the Justice Department announced.

The national coordinator is charged with formulating and implementing a national strategy to combat child exploitation, and with submitting the strategy and relevant reports to Congress.

Two individuals pleaded guilty for their participation in an international group of child pornography collectors who used a social networking site to share thousands of sexually explicit images.

Attorney General Eric Holder today announced that the Department of Justice released its first-ever National Strategy for Child Exploitation Prevention and Interdiction.

"As the Justice Department brings its fight against child exploitation to a new level today, I am honored to stand with so many incredible colleagues and public servants who have made it their life’s work to protect exploited children and seek justice for the most vulnerable members of our society," said Acting Deputy Attorney General Grindler.

"Today marks an important step forward in meeting these responsibilities and taking our fight against child exploitation and sexual abuse to the next level," said Attorney General Holder.

A federal grand jury in Honolulu indicted Mordechai Orian, an Israeli national; Pranee Tubchumpol, Shane Germann and Sam Wongsesanit of Global Horizons Manpower Inc., located in Los Angeles; and Thai labor recruiters Ratawan Chunharutai and Podjanee Sinchai for engaging in a conspiracy to commit forced labor and document servitude.

Paul Edward Pavulak, 66, of New Castle, Del., was convicted today by a federal jury in Wilmington of child exploitation offenses.

Sophia Manuel and Alfonso Baldonado Jr., owners of Quality Staffing Services Corporation, a labor contracting service, were sentenced for conspiring to hold approximately 39 Filipino nationals in forced service to work in country clubs and hotels in Southeast Florida.

A Rochester, Ill., firefighter pleaded guilty today to one count of production of child pornography, one count of possession of child pornography and one count of destruction of evidence.

Stephen Sims was sentenced today by Senior U.S. District Court Judge Gustave Diamond in the Western District of Pennsylvania to 17 years in prison for engaging in a child exploitation enterprise.

Ryan Chiles of Hampton, Va., was sentenced today in the Western District of Pennsylvania to 102 months in prison and a lifetime of supervised release for engaging in a child exploitation enterprise.

Fred Woolum of Lexington, Va., was sentenced today in the Western District of Pennsylvania to 15 years in prison and a lifetime of supervised release for engaging in a child exploitation enterprise.

Patrick Carney of Manchester, N.H., was sentenced today in the Western District of Pennsylvania to 15 years in prison and a lifetime of supervised release for engaging in a child exploitation enterprise.

Today a grand jury in the Eastern District of Wisconsin returned a one-count indictment against U.S. citizen Roland J. Flath for traveling in foreign commerce and engaging in and attempting to engage in illicit sexual conduct with a minor less than 18 years of age.

Brandon Miller, 23, of Omaha, Neb., was sentenced today to 102 months in prison and a lifetime of supervised release after pleading guilty to engaging in a child exploitation enterprise.

David R. Bostic, of Bloomington, Ind., pleaded guilty today to multiple charges of sexual exploitation of children relating to his participation in an international conspiracy to sexually exploit children through the trading of child pornography.

Bruce Schwartz, 53, Sam Wongsesanit, 40, and Shane Germann, 42, have pleaded guilty to human trafficking violations involving the Los Angeles based recruiting company Global Horizons.

Attorney General Holder and Department of Homeland Security (DHS) Secretary Napolitano announced today the unsealing of three indictments and one complaint charging a total of 72 individuals for their participation in an international criminal network dedicated to the sexual abuse of children and the creation and dissemination of graphic images and videos of child sexual abuse throughout the world.

A former Rochester, Ill., firefighter was sentenced today to 30 years in prison and lifetime supervised release for child exploitation charges, announced Assistant Attorney General Lanny A. Breuer of the Criminal Division and U.S. Attorney for the Central District of Illinois James A. Lewis.

Paul Edward Pavulak, 67, of New Castle, Del., was sentenced by U.S. District Judge Sue L. Robinson in Wilmington, Del.

Attorney General Eric Holder today convened a panel of experts from Facebook, Microsoft and the National Center for Missing and Exploited Children to discuss concrete ways to prevent and deter child sexual exploitation at a national summit entitled, “A Call to Action: Protecting Children from Sexual Exploitation.”

"To more effectively prevent and combat child exploitation and abuse, we need greater engagement – and not just from our traditional law enforcement, advocacy and government partners," said Attorney General Holder.

John Wyss, aka “Bones,” 55, of Monroe, Wis., was found guilty of one count of engaging in a child exploitation enterprise, one count of conspiracy to advertise child pornography and one count of conspiracy to distribute child pornography.

"Today, I’m very pleased to announce that we’re awarding almost $27 million to support NCMEC’s great work. The funds will continue all the great programs I just named – and many more, like the national resource center and information clearinghouse," said Acting Assistant Attorney General Leary.

Simon Jasper McCarty, 39, was sentenced by U.S. District Judge J. Michael Seabright of the District of Hawaii.

John Wyss, aka “Bones,” 55, of Monroe, Wis., was sentenced by U.S. District Judge Maurice Hicks in the Western District of Louisiana.

Roland J. Flath, 72, of Fond du Lac, Wis., was sentenced in U.S. District Court in the Eastern District of Wisconsin by Judge J.P. Stadtmueller.

A Massachusetts man was sentenced today to serve 45 years in prison for his participation in an international criminal network, known as Dreamboard, dedicated to the sexual abuse of children and the creation and dissemination of graphic images and videos of child sexual abuse throughout the world.

Anthony K. Mastrogiovanni, 30, of Crofton, Md., pleaded guilty today to the sexual exploitation of minors to produce child pornography

Anthony K. Mastrogiovanni, 30, of Crofton, Md., was sentenced today to serve 25 years in prison for sexually exploiting more than 30 male juveniles – ranging from 9 to 16 years of age – in Maryland and Louisiana to produce child pornography.

The U.S. Department of Justice today hosted a meeting to launch a joint task force between the United Kingdom and the United States to counter online child exploitation

A former disc jockey for area high school parties pleaded guilty today in the District of Puerto Rico to producing child pornography.

Hector Orjuela Jr., 47, was sentenced today to serve 30 years in prison, followed by a lifetime of supervised release, for molesting children under the age of 12 and producing child pornography.