GTF2IRD1 regulates transcription by binding an evolutionarily conserved DNA motif ‘GUCE’

AbstractGTF2IRD1 is a member of a family of transcription factors whose defining characteristic is varying numbers of a helix–loop–helix like motif, the I-repeat. Here, we present functional analysis of human GTF2IRD1 in regulation of three genes (HOXC8, GOOSECOID and TROPONIN ISLOW). We define a regulatory motif (GUCE–GTF2IRD1 Upstream Control Element) common to all three genes. GUCE is bound in vitro by domain I-4 of GTF2IRD1 and mediates transcriptional regulation by GTF2IRD1 in vivo. Definition of this site will assist in identification of other downstream targets of GTF2IRD1 and elucidation of its role in the human developmental disorder Williams–Beuren syndrome

Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies.

BACKGROUND: Over the past decade malaria intervention coverage has been scaled up across Africa. However, it remains unclear what overall reduction in transmission is achievable using currently available tools. METHODS AND FINDINGS: We developed an individual-based simulation model for Plasmodium falciparum transmission in an African context incorporating the three major vector species (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting to parasite prevalence data from 34 transmission settings across Africa. We incorporated the effect of the switch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticide treated nets (LLINs) from the year 2000 onwards. We then explored the impact on transmission of continued roll-out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening and treatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varying transmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting with low, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality. In all settings we considered a realistic target of 80% coverage of interventions. In the low-transmission setting (EIR approximately 3 ibppy [infectious bites per person per year]), LLINs have the potential to reduce malaria transmission to low levels (90%) or novel tools and/or substantial social improvements will be required, although considerable reductions in prevalence can be achieved with existing tools and realistic coverage levels. CONCLUSIONS: Interventions using current tools can result in major reductions in P. falciparum malaria transmission and the associated disease burden in Africa. Reduction to the 1% parasite prevalence threshold is possible in low- to moderate-transmission settings when vectors are primarily endophilic (indoor-resting), provided a comprehensive and sustained intervention program is achieved through roll-out of interventions. In high-transmission settings and those in which vectors are mainly exophilic (outdoor-resting), additional new tools that target exophagic (outdoor-biting), exophilic, and partly zoophagic mosquitoes will be required

Including PrEP for key populations in combination HIV prevention: a mathematical modelling analysis of Nairobi as a case-study

Background: The role of PrEP in combination HIV prevention remains uncertain. We aimed to identify an optimal portfolio of interventions to reduce HIV incidence for a given budget, and to identify the circumstances in which PrEP could be used in Nairobi, Kenya. Methods: A mathematical model was developed to represent HIV transmission among specific key populations (female sex workers (FSW), male sex workers (MSW), and men who have sex with men (MSM)) and among the wider population of Nairobi. The scale-up of existing interventions (condom promotion, anti-retroviral therapy (ART) and male circumcision) for key populations and the wider population as have occurred in Nairobi is represented. The model includes a detailed representation of a Pre-Exposure Prophylaxis (PrEP) intervention and is calibrated to prevalence and incidence estimates specific to key populations and the wider population. Findings: In the context of a declining epidemic overall but with a large sub-epidemic among MSM and MSW, an optimal prevention portfolio for Nairobi should focus on condom promotion for MSW and MSM in particular, followed by improved ART retention, earlier ART, and male circumcision as the budget allows. PrEP for MSW could enter an optimal portfolio at similar levels of spending to when earlier ART is included, however PrEP for MSM and FSW would be included only at much higher budgets. If PrEP for MSW cost as much $500, average annual spending on the interventions modelled would need to be less than$3·27 million for PrEP for MSW to be excluded from an optimal portfolio. Estimated costs per infection averted when providing PrEP to all FSW regardless of their risk of infection, and to high risk FSW only, are $65,160 (95$43,520 - $90,250) and$10,920 (95% credible interval: $4,700 -$51,560) respectively. Interpretation: PrEP could be a useful contribution to combination prevention, especially for underserved key populations in Nairobi. An ongoing demonstration project will provide important information regarding practical aspects of implementing PrEP for key populations in this setting

Implementation of the Time-to-Event Continuous Reassessment Method Design in a Phase I Platform Trial Testing Novel Radiotherapy-Drug Combinations-CONCORDE

\ua9 2022 by American Society of Clinical Oncology. PURPOSE CONCORDE is the first phase I drug-radiotherapy (RT) combination platform in non-small-cell lung cancer, designed to assess multiple different DNA damage response inhibitors in combination with radical thoracic RT. Time-to-event continuous reassessment method (TiTE-CRM) methodology will inform dose escalation individually for each different DNA damage response inhibitor-RT combination and a randomized calibration arm will aid attribution of toxicities. We report in detail the novel statistical design and implementation of the TiTE-CRM in the CONCORDE trial. METHODS Statistical parameters were calibrated following recommendations by Lee and Cheung. Simulations were performed to assess the operating characteristics of the chosen models and were written using modified code from the R package dfcrm. RESULTS The results of the simulation work showed that the proposed statistical model setup can answer the research questions under a wide range of potential scenarios. The proposed models work well under varying levels of recruitment and with multiple adaptations to the original methodology. CONCLUSION The results demonstrate how TiTE-CRM methodology may be used in practice in a complex dose-finding platform study. We propose that this novel phase I design has potential to overcome some of the logistical barriers that for many years have prevented timely development of novel drug-RT combinations

Implementation of the Time-to-Event Continuous Reassessment Method Design in a Phase I Platform Trial Testing Novel Radiotherapy-Drug Combinations-CONCORDE

PURPOSE: CONCORDE is the first phase I drug-radiotherapy (RT) combination platform in non-small-cell lung cancer, designed to assess multiple different DNA damage response inhibitors in combination with radical thoracic RT. Time-to-event continuous reassessment method (TiTE-CRM) methodology will inform dose escalation individually for each different DNA damage response inhibitor-RT combination and a randomized calibration arm will aid attribution of toxicities. We report in detail the novel statistical design and implementation of the TiTE-CRM in the CONCORDE trial. METHODS Statistical parameters were calibrated following recommendations by Lee and Cheung. Simulations were performed to assess the operating characteristics of the chosen models and were written using modified code from the R package dfcrm. RESULTS The results of the simulation work showed that the proposed statistical model setup can answer the research questions under a wide range of potential scenarios. The proposed models work well under varying levels of recruitment and with multiple adaptations to the original methodology. CONCLUSION The results demonstrate how TiTE-CRM methodology may be used in practice in a complex dose-finding platform study. We propose that this novel phase I design has potential to overcome some of the logistical barriers that for many years have prevented timely development of novel drug-RT combinations

Motivations for the use and consumption of wildlife products

The dominant approach to combating the illegal wildlife trade has traditionally been to restrict the supply of wildlife products. Yet conservationists increasingly recognize the importance of implementing demand‐side interventions that target the end consumers in the trade chain. Their aim is to curb the consumption of wildlife or shift consumption to more sustainable alternatives. However, there are still considerable knowledge gaps in understanding of the diversity of consumer motivations in the context of illegal wildlife trade, which includes hundreds of thousands of species, different uses, and diverse contexts. Based on consultation with multiple experts from a diversity of backgrounds, nationalities, and focal taxa, we developed a typology of common motivations held by wildlife consumers that can be used to inform conservation interventions. We identified 5 main motivational categories for wildlife use: experiential, social, functional, financial, and spiritual, each containing subcategories. This framework is intended to facilitate the segmentation of consumers based on psychographics and allow the tailoring of interventions—whether behavior change campaigns, enforcement efforts, or incentive programs—to the specific context in which they will be used. Underlining the importance of consumer research and collaborating with local actors is an important step toward promoting a more systematic approach to the design of demand reduction interventions

The role of rapid diagnostics in managing Ebola epidemics

Ebola emerged in West Africa around December 2013 and swept through Guinea, Sierra Leone and Liberia, giving rise to 27,748 confirmed, probable and suspected cases reported by 29 July 2015. Case diagnoses during the epidemic have relied on polymerase chain reaction-based tests. Owing to limited laboratory capacity and local transport infrastructure, the delays from sample collection to test results being available have often been 2 days or more. Point-of-care rapid diagnostic tests offer the potential to substantially reduce these delays. We review Ebola rapid diagnostic tests approved by the World Health Organization and those currently in development. Such rapid diagnostic tests could allow early triaging of patients, thereby reducing the potential for nosocomial transmission. In addition, despite the lower test accuracy, rapid diagnostic test-based diagnosis may be beneficial in some contexts because of the reduced time spent by uninfected individuals in health-care settings where they may be at increased risk of infection; this also frees up hospital beds. We use mathematical modelling to explore the potential benefits of diagnostic testing strategies involving rapid diagnostic tests alone and in combination with polymerase chain reaction testing. Our analysis indicates that the use of rapid diagnostic tests with sensitivity and specificity comparable with those currently under development always enhances control, whether evaluated at a health-care-unit or population level. If such tests had been available throughout the recent epidemic, we estimate, for Sierra Leone, that their use in combination with confirmatory polymerase chain-reaction testing might have reduced the scale of the epidemic by over a third

Expression of the transcription factor, TFII-I, during post-implantation mouse embryonic development

<p>Abstract</p> <p>Background</p> <p>General transcription factor (TFII-I) is a multi-functional transcription factor encoded by the Gtf2i gene, that has been demonstrated to regulate transcription of genes critical for development. Because of the broad range of genes regulated by TFII-I as well as its potential role in a significant neuro-developmental disorder, developing a comprehensive expression profile is critical to the study of this transcription factor. We sought to define the timing and pattern of expression of TFII-I in post-implantation embryos at a time during which many putative TFII-I target genes are expressed.</p> <p>Findings</p> <p>Antibodies to the N-terminus of TFII-I were used to probe embryonic mouse sections. TFII-I protein is widely expressed in the developing embryo. TFII-I is expressed throughout the period from E8-E16. However, within this period there are striking shifts in localization from cytoplasmic predominant to nuclear. TFII-I expression varies in both a spatial and temporal fashion. There is extensive expression in neural precursors at E8. This expression persists at later stages. TFII-I is expressed in developing lung, heart and gut structures. There is no evidence of isoform specific expression. Available data regarding expression patterns at both an RNA and protein level throughout development are also comprehensively reviewed.</p> <p>Conclusions</p> <p>Our immunohistochemical studies of the temporal and spatial expression patterns of TFII-I in mouse embryonic sections are consistent with the hypothesis that hemizygous deletion of <it>GTF2I </it>in individuals with Williams-Beuren Syndrome contributes to the distinct cognitive and physiological symptoms associated with the disorder.</p

A new model for the characterization of infection risk in gunshot injuries:Technology, principal consideration and clinical implementation

<p>Abstract</p> <p>Introduction</p> <p>The extent of wound contamination in gunshot injuries is still a topic of controversial debate. The purpose of the present study is to develop a model that illustrates the contamination of wounds with exogenous particles along the bullet path.</p> <p>Material and methods</p> <p>To simulate bacteria, radio-opaque barium titanate (3-6 μm in diameter) was atomized in a dust chamber. Full metal jacket or soft point bullets caliber .222 (n = 12, v₀= 1096 m/s) were fired through the chamber into a gelatin block directly behind it. After that, the gelatin block underwent multi-slice CT in order to analyze the permanent and temporary wound cavity.</p> <p>Results</p> <p>The permanent cavity caused by both types of projectiles showed deposits of barium titanate distributed over the entire bullet path. Full metal jacket bullets left only few traces of barium titanate in the temporary cavity. In contrast, the soft point bullets disintegrated completely, and barium titanate covered the entire wound cavity.</p> <p>Discussion</p> <p>Deep penetration of potential exogenous bacteria can be simulated easily and reproducibly with barium titanate particles shot into a gelatin block. Additionally, this procedure permits conclusions to be drawn about the distribution of possible contaminants and thus can yield essential findings in terms of necessary therapeutic procedures.</p