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Drug development is a long and arduous process that requires many researchers at different types of institutions. These include researchers in university settings, researchers in government settings, researchers in non-profit organizations and researchers in the pharmaceutical industry. The pharmaceutical industry itself is heterogeneous, ranging from tiny biotech companies to large multi-national organizations. This chapte emphasizes drug development efforts by the pharmaceutical industry but will also make note of the many collaborations between pharma and researchers at other types of institutions.
Biospecimen repositories play a vital role in enabling investigation of biologic mechanisms, identification of disease-related biomarkers, advances in diagnostic assays, recognition of microbial evolution, and characterization of new therapeutic targets for intervention. They rely on the complex integration of scientific need, regulatory oversight, quality control in collection, processing and tracking, and linkage to robust phenotype information. The COVID-19 pandemic amplified many of these considerations and illuminated new challenges, all while academic health centers were trying to adapt to unprecedented clinical demands and heightened research constraints not witnessed in over 100 years. The outbreak demanded rapid understanding of SARS-CoV-2 to develop diagnostics and therapeutics, prompting the immediate need for access to high quality, well-characterized COVID-19-associated biospecimens. We surveyed 60 Clinical and Translational Science Award (CTSA) hubs to better understand the strategies and barriers encountered in biobanking before and in response to the COVID-19 pandemic. Feedback revealed a major shift in biorepository model, specimen-acquisition and consent process from a combination of investigator-initiated and institutional protocols to an enterprise-serving strategy. CTSA hubs were well equipped to leverage established capacities and expertise to quickly respond to the scientific needs of this crisis through support of institutional approaches in biorepository management.
The DHVI Division of Structural Biology seeks to use atomic level structural information for design of an effective HIV-1 vaccine. Through visualization of the HIV-1 envelope (Env) and its interactions with the human immune system, we obtain structural information that we translate into the rational development vaccine immunogens
We use negative stain electron microscopy (NSEM), cryo-electron microscopy (cryo-EM), and x-ray crystallography as the major structural techniques for visualization of HIV-1 Env, and combine these with biochemical and biophysical studies, as well as computational methods to obtain a basic understanding of the functions and interactions of the HIV-1 Env.
1.The DHVI NSEM pipeline runs on a daily basis to quality control vaccine immunogens for animal studies and other applications. Offering rapid sample turnover and economical operations, the NSEM pipeline is the most widely utilized resource of the DHVI Division of Structural Biology. Over the last year, the NSEM team has focused efforts on improving operational speed and data processing allowing high-quality visualization of a large variety of samples including HIV-1 Env immunogens, antibodies, nanoparticles, and VLPs. In the last year we have also expanded our NSEM studies to the analyses of serum samples and mucosal fluids.
2. To understand the mechanism of HIV-1 entry we have determined structures of HIV-1 entry intermediates. We have determined a 3.8 Å resolution structure of a single CD4 bound to a closed HIV-1 Env trimer revealing new contacts of CD4 with Env. We have also structurally characterized an Env designed to prevent CD4-induced rearrangements by targeted disruption of an allosteric network modulating Env conformational changes.
3. We have structurally characterized the HIV-1 glycan-V3 targeting DH270 Broadly Neutralizing Antibody Lineage. The structures revealed movements in the V1 loop and interactive glycans, shifts in antibody orientations, antibody VH-VL orientations, and antibody elbow angles, as the lineage progressed to maturation.
4. We have solved a structure in complex with the HIV-1 Env immunogen Man5-enriched CH505.N279K.G458Y.SOSIP.664 of the unmutated common ancestor (UCA) of the HIV-1 CD4-binding site targeting CH235 Broadly Neutralizing Antibody Lineage. The structure revealed interactions of the N279K and G458Y mutations with the CDR L3 loop of CH235 UCA thus providing a structural understanding of the role of these mutations in facilitating binding to the CH235 UCA. (see also Henderson et al abstract)
5. Using NSEM and cryo-EM we have characterized the structural properties of a novel class of 2G12-mimetic, yet non domain-swapped Fab dimer glycan-reactive (FDG) antibodies. These studies showed that the Fab-dimerized 2G12-like motif is more common than previously thought, and that creation of a Fab-dimerized paratope for an HIV-1 neutralizing antibody does not require VH domain-swapping.
6. Finally, the structural team is an integral part of the CHAVD Kalma Immunogen Design Team, wherein we are defining the structural basis of bnAb affinity maturation to guide sequential immunogen design.
These results highlight the power of structural information on HIV-1 vaccine design, from leveraging a basic understanding of HIV-1 entry mechanism for immunogen design, to rapid visualization of Env immunogens by NSEM for quality control, discovery of novel antibody interactions, and atomic level visualization of antibody/Env interactions.
The end of the last Ice Age in Britain (c. 11500 BP) created major disruption to the biosphere. Open habitats were succeeded by more wooded landscapes, and changes occurred to the fauna following the abrupt disappearance of typical glacial herd species, such as reindeer and horse (Conneller & Higham 2015). Understanding the impact of these changes on humans and how quickly they were able to adapt may soon become clearer, due to recent discoveries in the Colne Valley on the western edge of Greater London, north of the River Thames. An exceptionally well-preserved open-air site was discovered in 2014 as part of a wider project of archaeological investigation and excavation carried out by Wessex Archaeology (2015), on behalf of CEMEX UK. The site, at Kingsmead Quarry in Horton, is unusual because it has good organic preservation and, in addition to worked flint artefacts, it has yielded groups of articulated horse bone. The extreme rarity of such sites of this period in Britain makes this discovery especially significant and re-emphasises the potential importance of the Colne Valley (Lacaille 1963; Lewis 2011; Morgi et al. 2011).
Burkart et al. conflate the domain-specificity of cognitive processes with the statistical pattern of variance in behavioural measures that partly reflect those processes. General intelligence is a statistical abstraction, not a cognitive trait, and we argue that the former does not warrant inferences about the nature or evolution of the latter.
In the current manuscript, we provide an overview of a research program at the University of Georgia's Center for Family Research designed to expand upon rapid and ongoing developments in the fields of genetics and epigenetics. By placing those developments in the context of translational research on family and community determinants of health and well-being among rural African Americans, we hope to identify novel, modifiable environments and biological processes. In the first section of the article, we review our earlier work on genotypic variation effects on the association between family context and mental and physical health outcomes as well as differential responses to family-based intervention. We then transition to discuss our more recent research on the association of family and community environments with epigenetic processes. In this second section of the article, we begin by briefly reviewing terminology and basic considerations before describing evidence that early environments may influence epigenetic motifs that potentially serve as mediators of long-term effects of early family and community environments on longer term health outcomes. We also provide evidence that genotype may sometimes influence epigenetic outcomes. Finally, we describe our recent efforts to use genome-wide characterization of epigenetic patterns to better understand the biological impact of protective parenting on long-term shifts in inflammatory processes and its potential implications for young adult health. As will be clear, research on epigenetics as a mediator of the connections between family/community processes and a range of health outcomes is still in its infancy, but the potential to develop important insights regarding mechanisms linking modifiable environments to biological processes and long-term health outcomes already is coming into view.
A review of recently published temporal data from Shuidonggou Locality 1 indicates that a 40–43 cal ka date for the inception of Initial Upper Paleolithic (IUP) blade-oriented technologies in East Asia is warranted. Comparison of the dates from Shuidonggou to other Asian IUP dates in Korea, Siberia, and Mongolia supports this assertion, indicating that the initial appearance of the IUP in East Asia generally corresponds in time to the fluorescence of the IUP in eastern Europe and western Asia. This conclusion preliminarily suggests that either a version of the IUP originated independently in East Asia just prior to 40 cal ka, or more likely, that an early, initial diffusion of the IUP into East Asia occurred ∼41 cal ka, a hypothesis consistent with current estimates for the evolution or arrival of modern humans in the region.