NMDA receptor-targeted enrichment of CaMKIIα improves fear memory

Calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) is an essential player in long-term potentiation and memory formation. However, the establishment of effective molecular interventions with CaMKIIα to improve memory remains a long-standing challenge. Here we report a novel intrabody targeting GluN1, a subunit of N-methyl-D-aspartate receptors (NMDARs). We identify this anti-GluN1 intrabody (termed VHH Anti-GluN1; VHHAN1) by a synthetic phage display library selection and yeast-two-hybrid screenings. We validate specific targeting of VHHAN1 to GluN1 in heterologous cells and the mouse hippocampus. We further show that adeno-associated virus (AAV)-mediated expression of CaMKIIα fused with VHHAN1 is locally enriched at excitatory postsynaptic regions of the mouse hippocampus. We also find that the AAV- and VHHAN1-mediated postsynaptic enrichment of CaMKIIα in the hippocampus improves contextual fear memory in mice. This novel approach opens a new avenue to enhance memory ability in health and diseases.

Multiplex suppression of four quadruplet codons via tRNA directed evolution

Genetic code expansion technologies supplement the natural codon repertoire with assignable variants in vivo, but are often limited by heterologous translational components and low suppression efficiencies. Here, we explore engineered Escherichia coli tRNAs supporting quadruplet codon translation by first developing a library-cross-library selection to nominate quadruplet codon–anticodon pairs. We extend our findings using a phage-assisted continuous evolution strategy for quadruplet-decoding tRNA evolution (qtRNA-PACE) that improved quadruplet codon translation efficiencies up to 80-fold. Evolved qtRNAs appear to maintain codon-anticodon base pairing, are typically aminoacylated by their cognate tRNA synthetases, and enable processive translation of adjacent quadruplet codons. Using these components, we showcase the multiplexed decoding of up to four unique quadruplet codons by their corresponding qtRNAs in a single reporter. Cumulatively, our findings highlight how E. coli tRNAs can be engineered, evolved, and combined to decode quadruplet codons, portending future developments towards an exclusively quadruplet codon translation system.

Combating the Challenges of Intellectual Freedom: The Perspective of Librarians in Academic Libraries in Kwara State, Nigeria

Background: Censorship of library materials denies people's right to access, use, retrieve, and store materials of their desire. Intellectual freedom is critical to eliminating the constraint of censorship. Issues such as illiteracy, societal standards, and selection policy hadbeen identified as challenges to intellectual freedom. The existing body of literature revealed that library materials are subjected to censorship and this denies readers’ rights to access desirable information at any point in time. Aim: This research examined the perception of librarians on combating the challenges of intellectual freedom. Methodology: The target population for this study included professional librarians working in eight (8) selected academic libraries in Kwara State, Nigeria. A stratified random sampling technique was used to select 60 respondents from the 8 academic libraries involved in the study. A questionnaire of 6 research questions was developed for the collection of data. Findings: The results indicated: the majority of the respondents agree that there are equal opportunities for library users to access library materials, obscene and controversial materials are subjected to censorship, library selection policy restricts library users’ access to desired materials. Lifting restriction of access to library materials was identified as the way to combat the challenges of intellectual freedom. Recommendations: The authors recommends that government should ensure that the Freedom of Information Bill (FOI) is passed to enable library patrons’ have access to all information materials and that library stakeholders should create awareness, publicity, or enlightenment on intellectual freedom to inform the users of their rights to hold, use, and access information materials of their choice.

IMPLEMENTASI VIRTUAL PRIVATE NETWORK (VPN) DI PERPUSTAKAAN UNIVERSITAS ISLAM MALANG

This study aims to explain to use a VPN in the UNISMA Library. The research method used is descriptive-qualitative and data was obtained through interviews with five informants, observation, and documentation. Data analysis techniques by collecting data, data reduction, data presentation and drawing conclusions. While the validity of the data was obtained through triangulation. The results showed that the use of VPN in the UNISMA Library to speed up internet connection and data privacy. UNISMA library uses a proxy server router operating system for VPN networks. To be able to make Mikrotik a VPN server, configuration is required which includes IP pool configuration, IP router configuration, PPP configuration, DHCP server configuration, NAT by pass firewall configuration and IP security configuration. The library selection of VPN products considers the aspects of strong authentication, encryption that is strong enough, meets standards, integration with other field network services.

Recent advances in phenotypic drug discovery

There is a great need for innovative new medicines to treat unmet medical needs. The discovery and development of innovative new medicines is extremely difficult, costly, and inefficient. In the last decade, phenotypic drug discovery (PDD) was reintroduced as a strategy to provide first-in-class medicines. PDD uses empirical, target-agnostic lead generation to identify pharmacologically active molecules and novel therapeutics which work through unprecedented drug mechanisms. The economic and scientific value of PDD is exemplified through game-changing medicines for hepatitis C virus, spinal muscular atrophy, and cystic fibrosis. In this short review, recent advances are noted for the implementation and de-risking of PDD (for compound library selection, biomarker development, mechanism identification, and safety studies) and the potential for artificial intelligence. A significant barrier in the decision to implement PDD is balancing the potential impact of a novel mechanism of drug action with an under-defined scientific path forward, with the desire to provide infrastructure and metrics to optimize return on investment, which a known mechanism provides. A means to address this knowledge gap in the future is to empower precompetitive research utilizing the empirical concepts of PDD to identify new mechanisms and pharmacologically active compounds.

Multimodal small-molecule screening for human prion protein binders

Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) NMR spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mm), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. Whereas orthogonal binder discovery methods could yield high-affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.

Multimodal small-molecule screening for human prion protein binders

ABSTRACTPrion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mM), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. While orthogonal binder discovery methods could yield high affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.

EasyVS: a user-friendly web-based tool for molecule library selection and structure-based virtual screening

Summary EasyVS is a web-based platform built to simplify molecule library selection and virtual screening. With an intuitive interface, the tool allows users to go from selecting a protein target with a known structure and tailoring a purchasable molecule library to performing and visualizing docking in a few clicks. Our system also allows users to filter screening libraries based on molecule properties, cluster molecules by similarity and personalize docking parameters. Availability and implementation EasyVS is freely available as an easy-to-use web interface at http://biosig.unimelb.edu.au/easyvs. Contact [email protected] or [email protected] Supplementary information Supplementary data are available at Bioinformatics online.