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The idea of faculty engaging in meaningful dialogue with different publics instead of simply communicating their research to interested audiences has gradually morphed from a novel concept to a mainstay within most parts of the academy. Given the wide variety of public engagement modalities, it may be unsurprising that we still lack a comprehensive and granular understanding of factors that influence faculty willingness to engage with public audiences. Those nuances are not always captured by quantitative surveys that rely on pre-determined categories to assess scholars’ willingness to engage. While closed-ended categories are useful to examine which factors influence the willingness to engage more than others, it is unlikely that pre-determined categories comprehensively represent the range of factors that undermine or encourage engagement, including perceptual influences, institutional barriers, and scholars’ lived experiences. To gain insight into these individual perspectives and lived experiences, we conducted focus group discussions with faculty members at a large midwestern land-grant university in the United States. Our findings provide context to previous studies of public engagement and suggest four themes for future research. These themes affirm the persistence of institutional barriers to engaging with the public, particularly the expectations in the promotion process for tenure-track faculty. However, we also find a perception that junior faculty and graduate students are challenging the status quo by introducing a new wave of attention to public engagement. This finding suggests a “trickle-up” effect through junior faculty and graduate students expecting institutional support for public engagement. Our findings highlight the need to consider how both top-down factors such as institutional expectations and bottom-up factors such as graduate student interest shape faculty members’ decisions to participate in public engagement activities.

The idea of faculty engaging in meaningful dialogue with different publics instead of simply communicating their research to interested audiences has gradually morphed from a novel concept to a mainstay within most parts of the academy. Given the wide variety of public engagement modalities, it may be unsurprising that we still lack a comprehensive and granular understanding of factors that influence faculty willingness to engage with public audiences. Those nuances are not always captured by quantitative surveys that rely on pre-determined categories to assess scholars' willingness to engage. While closed-ended categories are useful to examine which factors influence the willingness to engage more than others, it is unlikely that pre-determined categories comprehensively represent the range of factors that undermine or encourage engagement, including perceptual influences, institutional barriers, and scholars' lived experiences. To gain insight into these individual perspectives and lived experiences, we conducted focus group discussions with faculty members at a large midwestern land-grant university in the United States. Our findings provide context to previous studies of public engagement and suggest four themes for future research. These themes affirm the persistence of institutional barriers to engaging with the public, particularly the expectations in the promotion process for tenure-track faculty. However, we also find a perception that junior faculty and graduate students are challenging the status quo by introducing a new wave of attention to public engagement. This finding suggests a \"trickle-up\" effect through junior faculty and graduate students expecting institutional support for public engagement. Our findings highlight the need to consider how both top-down factors such as institutional expectations and bottom-up factors such as graduate student interest shape faculty members' decisions to participate in public engagement activities.

Escherichia coli RNA polymerase is a multisubunit enzyme consisting of$\\alpha\\sb2\\beta\\beta\\sp\\prime\\sigma\\omega$subunits. The$\\beta$and$\\beta\\sp\\prime$subunits share regions of homology with the two largest subunits of multisubunit RNA polymerases and are believed to contain the catalytic regions of the enzyme. In this dissertation, I describe results of two separate studies, both aimed at probing functional domains in these two subunits. The first study involved the generation and characterization of mutants that confer resistance to an inhibitor of elongation, streptolydigin (stl). Stl inhibits elongation by interfering with phosphodiester bond formation. Stl $\\sp{\\rm r}$mutants are confined to a region of four contiguous amino acids in rpoB, in the middle of the rifampicin resistance (rif $\\sp{\\rm r})$region. While many rif $\\sp{\\rm r}$mutants profoundly affect transcription, stl $\\sp{\\rm r}$mutants do not display defects in cell growth, transcription elongation or termination. Although this region is probably not involved in transcription, it may be in the vicinity of sites important in nucleotide addition. That stl $\\sp{\\rm r}$mutants are confined to this region suggests, but does not prove, that this is the binding site of stl and implies that stl inhibits transcription by interfering with a region other than that to which it binds. The second study consisted of the in vitro investigation of the transcriptional defects of mutants in$\\beta$and$\\beta\\sp\\prime$isolated as allele specific suppressors of a rho-defect. These mutants exhibit defects in elongation rate consistent with their defects in$K\\sb{d}$for nucleotides. I further demonstrate that the$\\beta$mutation, N1072H in conserved region H, demonstrates defects in promoter clearance consistent with its affecting the coupling between nucleotide addition and translocation. The$\\beta\\sp\\prime$mutation, R352C in conserved region C of rpoC, primarily affects polymerase-promoter interactions in vitro. In addition, two mutants in the rif $\\sp{\\rm r}$region of rpoB, B8 and B2, exhibit altered promoter binding properties, suggesting that regions in both subunits may be important in DNA binding.

Mutations in the gene encoding the microtubule-severing protein spastin (spastic paraplegia 4 [SPG4]) cause hereditary spastic paraplegia (HSP), associated with neurodegeneration, spasticity, and motor impairment. Complicated forms (complicated HSP [cHSP]) further include cognitive deficits and dementia; however, the etiology and dysfunctional mechanisms of cHSP have remained unknown. Here, we report specific working and associative memory deficits upon spastin depletion in mice. Loss of spastin-mediated severing leads to reduced synapse numbers, accompanied by lower miniature excitatory postsynaptic current (mEPSC) frequencies. At the subcellular level, mutant neurons are characterized by longer microtubules with increased tubulin polyglutamylation levels. Notably, these conditions reduce kinesin-microtubule binding, impair the processivity of kinesin family protein (KIF) 5, and reduce the delivery of presynaptic vesicles and postsynaptic [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Rescue experiments confirm the specificity of these results by showing that wild-type spastin, but not the severing-deficient and disease-associated K388R mutant, normalizes the effects at the synaptic, microtubule, and transport levels. In addition, short hairpin RNA (shRNA)-mediated reduction of tubulin polyglutamylation on spastin knockout background normalizes KIF5 transport deficits and attenuates the loss of excitatory synapses. Our data provide a mechanism that connects spastin dysfunction with the regulation of kinesin-mediated cargo transport, synapse integrity, and cognition.

Background Research to date has focused on strategies and resources used by effective champions of healthcare change efforts, rather than personal characteristics that contribute to their success. We sought to identify and describe champion attributes influencing outcomes of healthcare change efforts. To examine attributes of champions, we used postpartum contraceptive care as a case study, because recommended services are largely unavailable, and implementation requires significant effort. Methods We conducted a comparative case study of the implementation of inpatient postpartum contraceptive care at 11 U.S. maternity hospitals in 2017–18. We conducted site visits that included semi-structured key informant interviews informed by the Consolidated Framework for Implementation Research (CFIR). Phase one analysis (qualitative content analysis using a priori CFIR codes and cross-case synthesis) showed that implementation leaders (“champions”) strongly influenced outcomes across sites. To understand champion effects, phase two inductive analysis included (1) identifying and elaborating key attributes of champions; (2) rating the presence or absence of each attribute in champions; and 3) cross-case synthesis to identify patterns among attributes, context, and implementation outcomes. Results We completed semi-structured interviews with 78 clinicians, nurses, residents, pharmacy and revenue cycle staff, and hospital administrators. All identified champions were obstetrician-gynecologists. Six key attributes of champions emerged: influence, ownership, physical presence at the point of change, persuasiveness, grit, and participative leadership style. These attributes promoted success by enabling champions to overcome institutional siloing, build and leverage professional networks, create tension for change, cultivate a positive learning climate, optimize compatibility with existing workflow, and engage key stakeholders. Not all champion attributes were required for success, and having all attributes did not guarantee success. Conclusions Effective champions appear to leverage six key attributes to facilitate healthcare change efforts. Prospective evaluations of the interactions among champion attributes, context, and outcomes may further elucidate how champions exert their effects.

Cancerous cells have an acutely increased demand for energy, leading to increased levels of human glucose transporter 1 (hGLUT1). This up-regulation suggests hGLUT1 as a target for therapeutic inhibitors addressing a multitude of cancer types. Here, we present three inhibitor-bound, inward-open structures of WT-hGLUT1 crystallized with three different inhibitors: cytochalasin B, a nine-membered bicyclic ring fused to a 14-membered macrocycle, which has been described extensively in the literature of hGLUTs, and two previously undescribed Phe amide-derived inhibitors. Despite very different chemical backbones, all three compounds bind in the central cavity of the inward-open state of hGLUT1, and all binding sites overlap the glucose-binding site. The inhibitory action of the compounds was determined for hGLUT family members, hGLUT1–4, using cell-based assays, and compared with homology models for these hGLUT members. This comparison uncovered a probable basis for the observed differences in inhibition between family members. We pinpoint regions of the hGLUT proteins that can be targeted to achieve isoform selectivity, and show that these same regions are used for inhibitors with very distinct structural backbones. The inhibitor cocomplex structures of hGLUT1 provide an important structural insight for the design of more selective inhibitors for hGLUTs and hGLUT1 in particular.

The GluA2 subunit of AMPA-type glutamate receptors (AMPARs) regulates excitatory synaptic transmission in neurons. In addition, the transsynaptic cell adhesion molecule N -cadherin controls excitatory synapse function and stabilizes dendritic spine structures. At postsynaptic membranes, GluA2 physically binds N -cadherin, underlying spine growth and synaptic modulation. We report that N -cadherin binds to PSD-95/SAP90/DLG/ZO-1 (PDZ) domain 2 of the glutamate receptor interacting protein 1 (GRIP1) through its intracellular C terminus. N -cadherin and GluA2-containing AMPARs are presorted to identical transport vesicles for dendrite delivery, and live imaging reveals cotransport of both proteins. The kinesin KIF5 powers GluA2/ N -cadherin codelivery by using GRIP1 as a multilink interface. Notably, GluA2 and N -cadherin use different PDZ domains on GRIP1 to simultaneously bind the transport complex, and interference with either binding motif impairs the turnover of both synaptic cargoes. Depolymerization of microtubules, deletion of the KIF5 motor domain, or specific blockade of AMPAR exocytosis affects delivery of GluA2/ N -cadherin vesicles. At the functional level, interference with this cotransport reduces the number of spine protrusions and excitatory synapses. Our data suggest the concept that the multi-PDZ-domain adaptor protein GRIP1 can act as a scaffold at trafficking vesicles in the combined delivery of AMPARs and N -cadherin into dendrites.

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3 – 15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer. The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Cancer develops through a process of somatic evolution 1 , 2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection. Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Background Increasing access to healthy foods and beverages in disadvantaged communities is a public health priority due to alarmingly high rates of obesity. The Virtual Supermarket Program (VSP) is a Baltimore City Health Department program that uses online grocery ordering to deliver food to low-income neighborhoods. This study evaluates stakeholder preferences and barriers of program implementation. Methods This study assessed the feasibility, sustainability and efficacy of the VSP by surveying 93 customers and interviewing 14 programmatic stakeholders who had recently used the VSP or been involved with program design and implementation. Results We identified the following themes: The VSP addressed transportation barriers and food availability. The VSP impacted customers and the city by including improving food purchasing behavior, creating a food justice “brand for the city”, and fostering a sense of community. Customers appreciated using Supplemental Nutrition Assistance Program (SNAP) benefits to pay for groceries, but policy changes are needed allow online processing of SNAP benefits. Conclusions This evaluation summarizes lessons learned and serves as a guide to other public health leaders interested in developing similar programs. Provisions in the U.S. Department of Agriculture (USDA) Farm Bill 2014 allow for select grocers to pilot online transactions with SNAP benefits. If these pilots are efficacious, the VSP model could be easily disseminated.