Acura Pharmaceuticals (United States)

Abstract To combat antibiotic-resistant priority pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, novel antibiotics are urgently needed1-3. DNA polymerases, essential for DNA replication but structurally distinct between bacteria and eukaryotes, represent promising yet underexplored targets4,5. The replicative polymerase in Gram-positive bacteria, PolC, is specifically inhibited by ibezapolstat, a guanine nucleobase analogue with an aromatic modification at the N2-position6,7. Following the success of ibezapolstat against Clostridioides difficile infections (CDI) in Phase 2 studies8,9, next-generation compounds with distinct pharmacokinetic properties are being designed to target other Gram-positive pathogens10. However, mechanistic insight into the mode of action of PolC inhibitors is lacking. Here, using cryo-electron microscopy, we show that ibezapolstat and next-generation inhibitor ACX-801 use the nucleobase analogue to pair with DNA within the active site of E. faecium PolC, similar to dGTP. The N2-linked aromatic group is positioned perpendicularly to the nucleobase and inserted into an induced binding pocket. Our results explain reduced susceptibility due to mutation of F1276, that plays a pivotal role in the creation of this pocket and engages in interactions with both the aromatic and nucleobase moieties. This work lays the foundation for rational development of an innovative class of antimicrobials against Gram-positive priority pathogens.

Viral gene therapy intends to bring genetic materials to the cell using a modified virus. This delivery system is called a viral vector. The viral vector often takes the property of the virus in regards to delivery, so the choice of virus leads to various outputs. Viruses differ from one another depending on their tropism, hitting certain tissues better than others; immunogenicity; and size. This review compiles evidence of recent innovations in the delivery of gene therapy using viral vectors with a specific emphasis on inducible and chimeric viral vectors that address long-standing limitations of traditional viral vectors. Conventional viral vectors, despite being the current standard for gene therapy delivery, pose risks and have significant flaws. Many elicit severe immunogenic responses and often hit unintended cells and tissues. This review discusses two new categories of viral vectors: chimeric vectors, which are a combination of two or more vectors, and inducible viral vectors, which use spatio-temporal awareness to improve efficiency and targeting. Chimeric vectors adopt key features from multiple different vectors to create a hybrid. These hybrid vectors can target new cell types, lower immunogenicity, and make downstream purification easier. Meanwhile, inducible vectors rely on external stimuli to dictate their expression. Inducers include small molecules, RNA, and light. While concerns remain around scalability of these therapies, the next level targeting capabilities make them promising for further use in the gene therapy space.

This paper attempts to predict financial trends by analyzing tweets on the Twitter micro-blogging platform. It provides an enhanced model that builds on the functionality of the pre-existing RoBERTa large model that can be used to determine the general sentiment of financial tweets. The model is fine-tuned to work best with financial tweets, with an ideal hyperparameter configuration given for an easy-to-train, accurate model. A case study is also provided regarding one potential use of this model by utilizing a Twitter API to access and analyze the latest tweets for financial keywords, and providing an interface for users to be able to access and understand the sentiment and trends surrounding the keyword.

This article attempts to understand the representations of American exceptionalism in Indian diasporic popular film through an analysis of reconfiguration of model minority racialization in Gurinder Chadha's films Bend It Like Beckham and Bride and Prejudice. The films underscore that the model minority racialization of Indians in the United States is being constructed in transnational South Asian diasporic framework through an engagement with British imperial history and the British colonial subject, and with Indian nationalism. While United States’ imperialist structures invoke model minority racialization in form, they simultaneously evacuate its content through racialization of Indians as potential terrorists. Thus, in a post–9/11 world marked by convergences between racialization processes of Britain and United States, the Indian diaspora is characterized by a project of transnational racial management. The diaspora is, thus, structured by management of anxieties generated by Indian gendered and racialized bodies: anxieties of economic success gendered male are diffused through fear of potential terrorists; anxieties of sexual and cultural purity are managed by racialization of women as native informants, who come to embody continuities between the national and the global.

“Two-fourths is the same as 1/2!” “Four-eighths is the same as 1/2!” The excited, engaged kindergarten students zoom around their classroom, paper pizza pieces clutched in their hands, as they look for equivalent fractions by comparing their pieces with other children's pieces. Some children have halves and some have fourths, eighths, thirds, or sixths. Equivalent fractions? In kindergarten?

A scant ten years ago, campuses began to embrace time-sharing as an alternative to remote batch computing. Only two years ago, or so, did we experience an unwavering infusion of microcomputing into research and instruction. And only within the past year have we witnessed the impact of supercomputing on the academic environment. All of these transitions have precipitated significant changes to the complexion of academic computing. These changes have compelled us to examine the strategies we use for delivering services to the academic community. Empirically, the length of time between major transitions has shortened. Our key challenge, therefore, is to anticipate the next transition now and concomitantly adapt our strategies for delivering services.

_________ Innovation insurance, say these writers, involves planning to enhance the success of a potential innovation by identifying and __avoiding pitfalls.