Broad Antibody Mediated Cross-Neutralization and Preclinical Immunogenicity of New Codon-Optimized HIV-1 Clade CRF02_AG and G Primary Isolates

Creation of an effective vaccine for HIV has been an elusive goal of the scientific community for almost 30 years. Neutralizing antibodies are assumed to be pivotal to the success of a prophylactic vaccine but previous attempts to make an immunogen capable of generating neutralizing antibodies to primary “street strain” isolates have resulted in responses of very limited breadth and potency. The objective of the study was to determine the breadth and strength of neutralizing antibodies against autologous and heterologous primary isolates in a cohort of HIV-1 infected Nigerians and to characterize envelopes from subjects with particularly broad or strong immune responses for possible use as vaccine candidates in regions predominated by HIV-1 CRF02_AG and G subtypes. Envelope vectors from a panel of primary Nigerian isolates were constructed and tested with plasma/sera from the same cohort using the PhenoSense HIV neutralizing antibody assay (Monogram Biosciences Inc, USA) to assess the breadth and potency of neutralizing antibodies. The immediate goal of this study was realized by the recognition of three broadly cross-neutralizing sera: (NG2-clade CRF02_AG, NG3-clade CRF02_AG and NG9- clade G). Based on these findings, envelope gp140 sequences from NG2 and NG9, complemented with a gag sequence (Clade G) and consensus tat (CRF02_AG and G) antigens have been codon-optimized, synthesized, cloned and evaluated in BALB/c mice. The intramuscular administration of these plasmid DNA constructs, followed by two booster DNA immunizations, induced substantial specific humoral response against all constructs and strong cellular responses against the gag and tat constructs. These preclinical findings provide a framework for the design of candidate vaccine for use in regions where the HIV-1 epidemic is driven by clades CRF02_AG and G

Language development after cochlear implantation: an epigenetic model

Growing evidence supports the notion that dynamic gene expression, subject to epigenetic control, organizes multiple influences to enable a child to learn to listen and to talk. Here, we review neurobiological and genetic influences on spoken language development in the context of results of a longitudinal trial of cochlear implantation of young children with severe to profound sensorineural hearing loss in the Childhood Development after Cochlear Implantation study. We specifically examine the results of cochlear implantation in participants who were congenitally deaf (N = 116). Prior to intervention, these participants were subject to naturally imposed constraints in sensory (acoustic–phonologic) inputs during critical phases of development when spoken language skills are typically achieved rapidly. Their candidacy for a cochlear implant was prompted by delays (n = 20) or an essential absence of spoken language acquisition (n = 96). Observations thus present an opportunity to evaluate the impact of factors that influence the emergence of spoken language, particularly in the context of hearing restoration in sensitive periods for language acquisition. Outcomes demonstrate considerable variation in spoken language learning, although significant advantages exist for the congenitally deaf children implanted prior to 18 months of age. While age at implantation carries high predictive value in forecasting performance on measures of spoken language, several factors show significant association, particularly those related to parent–child interactions. Importantly, the significance of environmental variables in their predictive value for language development varies with age at implantation. These observations are considered in the context of an epigenetic model in which dynamic genomic expression can modulate aspects of auditory learning, offering insights into factors that can influence a child’s acquisition of spoken language after cochlear implantation. Increased understanding of these interactions could lead to targeted interventions that interact with the epigenome to influence language outcomes with intervention, particularly in periods in which development is subject to time-sensitive experience

Vacancy-Driven Gelation Using Defect-Rich Nanoassemblies of 2D Transition Metal Dichalcogenides and Polymeric Binder for Biomedical Applications

A new approach of vacancy-driven gelation to obtain chemically crosslinked hydrogels from defect-rich 2D molybdenum disulfide (MoS2) nanoassemblies and polymeric binder is reported. This approach utilizes the planar and edge atomic defects available on the surface of the 2D MoS2 nanoassemblies to form mechanically resilient and elastomeric nanocomposite hydrogels. The atomic defects present on the lattice plane of 2D MoS2 nanoassemblies are due to atomic vacancies and can act as an active center for vacancy-driven gelation with a thiol-activated terminal such as four-arm poly(ethylene glycol)-thiol (PEG-SH) via chemisorption. By modulating the number of vacancies on the 2D MoS2 nanoassemblies, the physical and chemical properties of the hydrogel network can be controlled. This vacancy-driven gelation process does not require external stimuli such as UV exposure, chemical initiator, or thermal agitation for crosslinking and thus provides a nontoxic and facile approach to encapsulate cells and proteins. 2D MoS2 nanoassemblies are cytocompatible, and encapsulated cells in the nanocomposite hydrogels show high viability. Overall, the nanoengineered hydrogel obtained from vacancy-driven gelation is mechanically resilient and can be used for a range of biomedical applications including tissue engineering, regenerative medicine, and cell and therapeutic delivery

Nanocomposite clay-based bioinks for skeletal tissue engineering

Biofabrication is revolutionizing substitute tissue manufacturing. Skeletal stem cells (SSCs) can be blended with hydrogel biomaterials and printed to form three-dimensional structures that can closely mimic tissues of interest. Our bioink formulation takes into account the potential for cell printing including a bioink nanocomposite that contains low fraction polymeric content to facilitate cell encapsulation and survival, while preserving hydrogel integrity and mechanical properties following extrusion. Clay inclusion to the nanocomposite strengthens the alginate-methylcellulose network providing a biopaste with unique shear-thinning properties that can be easily prepared under sterile conditions. SSCs can be mixed with the clay-based paste, and the resulting bioink can be printed in 3D structures ready for implantation. In this chapter, we provide the methodology for preparation, encapsulation, and printing of SSCs in a unique clay-based bioink