Synthesis and <em>In Vitro</em> Evaluation of a HER2-Specific ImmunoSCIFI Probe

Secondary Cerenkov-induced fluorescence imaging (SCIFI) is an emerging biomedical optical imaging modality that leverages Cerenkov luminescence, primarily generated by β-emitting radioisotopes, to excite fluorophores that offer near-infrared emissions with optimal tissue penetrance. Dual-functionalized immunoconjugates composed of an antibody, a near-infrared fluorophore, and a β-emitting radioisotope have potential utility as novel SCIFI constructs with high specificity for molecular biomarkers of disease. Here, we report the synthesis and characterization of [89Zr]Zr-DFO-trastuzumab-BOD665, a self-excitatory HER2-specific “immunoSCIFI” probe capable of yielding near-infrared fluorescence in situ without external excitation. The penetration depth of the SCIFI signal was measured in hemoglobin-infused optical tissue phantoms that indicated a 2.05-fold increase compared to 89Zr-generated Cerenkov luminescence. Additionally, the binding specificity of the immunoSCIFI probe for HER2 was evaluated in a cellular assay that showed significantly higher binding to SKBR3 (high HER2 expression) relative to MDA-MB-468 (low HER2) breast cancer cells based on measurements of total flux in the near-infrared region with external excitation blocked. Taken together, the results of this study indicate the potential utility of immunoSCIFI constructs for interrogation of molecular biomarkers of disease

Gestational diabetes mellitus in Cameroon: prevalence, risk factors and screening strategies

Copyright \ua9 2024 Sobngwi, Sobngwi-Tambekou, Katte, Echouffo-Tcheugui, Balti, Kengne, Fezeu, Ditah, Tchatchoua, Dehayem, Unwin, Rankin, Mbanya and Bell.Background: The burden of gestational diabetes (GDM) and the optimal screening strategies in African populations are yet to be determined. We assessed the prevalence of GDM and the performance of various screening tests in a Cameroonian population. Methods: We carried out a cross-sectional study involving the screening of 983 women at 24-28 weeks of pregnancy for GDM using serial tests, including fasting plasma (FPG), random blood glucose (RBG), a 1-hour 50g glucose challenge test (GCT), and standard 2-hour oral glucose tolerance test (OGTT). GDM was defined using the World Health Organization (WHO 1999), International Association of Diabetes and Pregnancy Special Group (IADPSG 2010), and National Institute for Health Care Excellence (NICE 2015) criteria. GDM correlates were assessed using logistic regressions, and c-statistics were used to assess the performance of screening strategies. Findings: GDM prevalence was 5\ub79%, 17\ub77%, and 11\ub70% using WHO, IADPSG, and NICE criteria, respectively. Previous stillbirth [odds ratio: 3\ub714, 95%CI: 1\ub727-7\ub776)] was the main correlate of GDM. The optimal cut-points to diagnose WHO-defined GDM were 5\ub79 mmol/L for RPG (c-statistic 0\ub762) and 7\ub71 mmol/L for 1-hour 50g GCT (c-statistic 0\ub776). The same cut-off value for RPG was applicable for IADPSG-diagnosed GDM while the threshold was 6\ub75 mmol/L (c-statistic 0\ub761) for NICE-diagnosed GDM. The optimal cut-off of 1-hour 50g GCT was similar for IADPSG and NICE-diagnosed GDM. WHO-defined GDM was always confirmed by another diagnosis strategy while IADPSG and GCT independently identified at least 66\ub79 and 41\ub70% of the cases. Interpretation: GDM is common among Cameroonian women. Effective detection of GDM in under-resourced settings may require simpler algorithms including the initial use of FPG, which could substantially increase screening yield

Identification and validation of novel biomarkers and therapeutics for pulpitis using connectivity mapping

Aim: To create an irreversible pulpitis gene signature from microarray data of healthy and inflamed dental pulps, followed by a bioinformatics approach using connectivity mapping to identify therapeutic compounds that could potentially treat pulpitis. // Methodology: The Gene Expression Omnibus (GEO) database, an international public repository of genomics data sets, was searched for human microarray datasets assessing pulpitis. An irreversible pulpitis gene expression signature was generated by differential expression analysis. The statistically significant connectivity map (ssCMap) method was used to identify compounds with a highly correlating gene expression pattern. qPCR was used to validate novel pulpitis genes. An ex vivo pulpitis model was used to test the effects of the compounds identified, and the level of inflammatory cytokines was measured with qPCR, ELISA and multiplex array. Means were compared using the t-test or ANOVA with the level of significance set at p ≤ .05. // Results: Pulpitis gene signatures were created using differential gene expression analysis at cutoff points p = .0001 and .000018. Top upregulated genes were selected as potential pulpitis biomarkers. Among these, IL8, IL6 and MMP9 were previously identified as pulpitis biomarkers. Novel upregulated genes, chemokine (C-C motif) ligand 21 (CCL21), metallothionein 1H (MT1H) and aquaporin 9 (AQP9) were validated in the pulp tissue of teeth clinically diagnosed with irreversible pulpitis using qPCR. ssCMap analysis identified fluvastatin (Statin) and dequalinium chloride (Quaternary ammonium) as compounds with the strongest correlation to the gene signatures (p = .0001). Fluvastatin reduced IL8, IL6, CCL21, AQP9 (p < .001) and MMP9 (p < .05) in the ex vivo pulpitis model, while dequalinium chloride reduced AQP9 (p < .001) but had no significant effect on the other biomarkers. // Conclusions: AQP9, MT1H and CCL21 were identified and validated as novel biomarkers for pulpitis. Fluvastatin and dequalinium chloride identified by the ssCMap as potential therapeutics for pulpitis reduced selected pulpitis biomarkers in an ex vivo pulpitis model. In vivo testing of these licenced drugs is warranted

Can biodiverse streetscapes mitigate the effects of noise and air pollution on human wellbeing?

Most of the global population are urban, with inhabitants exposed to raised levels of pollution. Pollutants negatively impact human wellbeing, and can alter the structure and diversity of ecosystems. Contrastingly, urban biodiversity can positively contribute to human wellbeing. We know little, however, about whether the negative impacts of pollution on wellbeing could be lessened for householders living on more biodiverse streets, as the complex interlinkages between pollution, biodiversity and wellbeing have rarely been examined. Here, we used structural equation modelling to simultaneously test whether biodiversity (actual and perceived) mediates the relationship between traffic-related pollution (noise, dB; nitrogen dioxide, NO2) or air pollution (PM2.5) and wellbeing (mental wellbeing, happiness). In summer 2019, we conducted questionnaires and biodiversity surveys, and collected noise and air pollution data, from households (n = 282) across the streetscapes of Leeds, UK. Biodiversity (actual or perceived) showed no mediating effects. However, increased flowering plant richness was positively associated with mental wellbeing. Traffic-related pollution negatively affected pollinator and flowering plant richness, but not wellbeing. This could be because householders are not exposed to high levels of noise or NO2 because they do not maintain front gardens on noisier streets. There was no measurable effect of air pollution on biodiversity or wellbeing. These findings shed light on the complex mechanisms through which biodiversity could improve human wellbeing. Enhancing the diversity of plant species in streetscapes would have a positive effect on wellbeing, further emphasising the important role that biodiverse urban streetscapes play in improving the liveability of cities

Protective clothing reduces lower limb injury severity against propelled sand debris in a laboratory setting

The contribution of energised environmental debris to injury patterns of the blast casualty is not known. The extent to which personal protective equipment (PPE) limits the injuries sustained by energised environmental debris following an explosive event is also not known. In this study, a cadaveric model exposed to a gas-gun mediated sand blast was utilised which reproduced soft-tissue injuries representative of those seen clinically following blast. Mean sand velocity across experiments was 506 ± 80 ms−1. Cadaveric samples wearing standard-issue PPE were shown to have a reduced injury severity to sand blast compared to control: a statistically significant reduction was seen in the total surface area (143 mm2 vs. 658 mm2, p = 0.004) and depth of injuries (0 vs. 23 deep injuries, odds ratio = 0.0074, 95% confidence intervals 0.0004–0.1379). This study is the first to recreate wounds from propelled sand in a human cadaveric model. These findings implicate environmental debris, such as sand ejected from a blast event, as a critical mechanism of injury in the blast casualty. Tier 1 pelvic PPE was shown to reduce markedly the severity of injury. This injury mechanism should be a key focus of future research and mitigation strategies

Computer-aided diagnosis for (123I)FP-CIT imaging: impact on clinical reporting

BACKGROUND: For (123I)FP-CIT imaging, a number of algorithms have shown high performance in distinguishing normal patient images from those with disease, but none have yet been tested as part of reporting workflows. This study aims to evaluate the impact on reporters' performance of a computer-aided diagnosis (CADx) tool developed from established machine learning technology. Three experienced (123I)FP-CIT reporters (two radiologists and one clinical scientist) were asked to visually score 155 reconstructed clinical and research images on a 5-point diagnostic confidence scale (read 1). Once completed, the process was then repeated (read 2). Immediately after submitting each image score for a second time, the CADx system output was displayed to reporters alongside the image data. With this information available, the reporters submitted a score for the third time (read 3). Comparisons between reads 1 and 2 provided evidence of intra-operator reliability, and differences between reads 2 and 3 showed the impact of the CADx. RESULTS: The performance of all reporters demonstrated a degree of variability when analysing images through visual analysis alone. However, inclusion of CADx improved consistency between reporters, for both clinical and research data. The introduction of CADx increased the accuracy of the radiologists when reporting (unfamiliar) research images but had less impact on the clinical scientist and caused no significant change in accuracy for the clinical data. CONCLUSIONS: The outcomes for this study indicate the value of CADx as a diagnostic aid in the clinic and encourage future development for more refined incorporation into clinical practice

What traits are carried on mobile genetic elements, and why?

Although similar to any other organism, prokaryotes can transfer genes vertically from mother cell to daughter cell, they can also exchange certain genes horizontally. Genes can move within and between genomes at fast rates because of mobile genetic elements (MGEs). Although mobile elements are fundamentally self-interested entities, and thus replicate for their own gain, they frequently carry genes beneficial for their hosts and/or the neighbours of their hosts. Many genes that are carried by mobile elements code for traits that are expressed outside of the cell. Such traits are involved in bacterial sociality, such as the production of public goods, which benefit a cell's neighbours, or the production of bacteriocins, which harm a cell's neighbours. In this study we review the patterns that are emerging in the types of genes carried by mobile elements, and discuss the evolutionary and ecological conditions under which mobile elements evolve to carry their peculiar mix of parasitic, beneficial and cooperative genes

Chimpanzees overcome the tragedy of the commons with dominance

Competition over common-pool resources (CPR) is a ubiquitous challenge for social animals. Many species face similar dilemmas, yet our understanding of the evolutionary trajectory of CPR social strategies remains unexplored. Here, we provide a first look at the social strategies of our closest living relatives, chimpanzees (Pan troglodytes), in two novel resource dilemma experiments. Dyads of chimpanzees were presented with renewable resource systems, collapsible at a quantity-dependent threshold. Dyads had to continuously resist overconsumption to maximize collective gains. In study 1, dyads of chimpanzees sustained a renewing juice source. Inequality of juice acquisition between partners predicted sustaining success, indicating that one individual dominated the task while the partner inhibited. Dyads in study 2 fed together on accumulating carrot pieces but could end the accumulation any time by grabbing an immediate selfish source of carrots. Dyads with low tolerance were more successful at collectively sustaining the resource than highly tolerant dyads. Further, the dominant individual was more likely to cause collapse in dyads with low tolerance than dyads with high tolerance. These results indicate that chimpanzees use a dominance-based monopolisation strategy moderated by social tolerance to overcome the tragedy of the commons

The limit to behavioral inertia and the power of default in voluntary contribution games

It is well documented that people are reluctant to switch from a default option. We experimentally test the robustness of this behavioral inertia in a collective decision-making setting by varying the default option type and the decision-making environment. We examine the impacts of automatic-participation and no-participation default options on subjects’ participation in a public goods provision and their contributions. Two variants of public goods game are employed: the linear and the threshold public goods games. The study shows the evidence of partial stickiness rather than complete stickiness of default options as indicated in empirical studies. Our experimental results square with the evidence of behavioral inertia only when the automatic-participation default is used. This default boosts contributions in the linear public goods game but not in the threshold public goods game. The evidence of partial stickiness is robust to the variation of the game employed, but the effect on contribution is sensitive to it