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Super-resolution imaging of proteins inside live mammalian cells with mLIVE-PAINT
Get PDFSuper-resolution microscopy has revolutionized biological imaging, enabling the visualization of structures at the nanometer length scale. Its application in live cells, however, has remained challenging. To address this, we adapted LIVE-PAINT, an approach we established in yeast, for application in live mammalian cells. Using the 101A/101B coiled-coil peptide pair as a peptide-based targeting system, we successfully demonstrate the super-resolution imaging of two distinct proteins in mammalian cells, one localized in the nucleus, and the second in the cytoplasm. This study highlights the versatility of LIVE-PAINT, suggesting its potential for live-cell super-resolution imaging across a range of protein targets in mammalian cells. We name the mammalian cell version of our original method mLIVE-PAINT
Multimodal machine learning to predict surgical site infection with healthcare workload impact assessment
Get PDFRemote monitoring is essential for healthcare digital transformation, however, this poses greater burdens on healthcare providers to review and respond as the data collected expands. This study developed a multimodal neural network to automate assessments of patient-generated data from remote postoperative wound monitoring. Two interventional studies including adult gastrointestinal surgery patients collected wound images and patient-reported outcome measures (PROMs) for 30-days postoperatively. Neural networks for PROMs and images were combined to predict surgical site infection (SSI) diagnosis within 48 h. The multimodal neural network model to predict confirmed SSI within 48 h remained comparable to clinician triage (0.762 [0.690-0.835] vs 0.777 [0.721-0.832]), with an excellent performance on external validation. Simulated usage indicated an 80% reduction in staff time (51.5 to 9.1 h) without compromising diagnostic accuracy. This multimodal approach can effectively support remote monitoring, alleviating provider burden while ensuring high-quality postoperative care.</p
The Development of a Canine Single-chain Phage Antibody Library to Isolate Recombinant Antibodies for use in Translational Cancer Research
Get PDFThe development of canine immunotolerant monoclonal antibodies can accelerate the invention of new medicines for both canine and human diseases. A methodology was developed to clone the naïve, somatically mutated variable domain repertoire from canine B-cell mRNA using 5’RACE PCR. A set of degenerate primers were then designed and used to clone variable domain genes into archival “holding” plasmid libraries. These archived variable domain genes were then combinatorially ligated to produce a scFv M13 phage library. Next-generation long-read and short-read DNA sequencing methodologies were developed to annotate features of the cloned library including CDR diversity and IGHV/IGKV/IGLV subfamily distribution. A synthetic IgG was developed from this scFv library to the canine immune checkpoint receptor PD-1. This synthetic platform can be used to clone and annotate archived antibody variable domain genes for use in perpetuity in order to develop improved preclinical models for the treatment of complex human disease
Can pharmaceutical use during pregnancy affect the reproductive health of the offspring?
Get PDFCare is required when administrating pharmaceuticals to pregnant women, bearing in mind not only the mother-to-be’s health but also that of the unborn offspring. Until now, studies of fetal outcomes have primarily focused on avoiding major effects, but some outcomes could become apparent only later. This perspective discusses whether fetal exposure to pharmaceuticals administered to a pregnant woman could affect the developing reproductive system, potentially resulting in fertility problems, even with consequences for subsequent generations. Different circumstances in which pregnant women can be administered pharmaceuticals are examined, some where there is a necessity for treatment, but others that may be dispensable
Lipodystrophy Severity Score to Assess Disease Burden in Lipodystrophy
Get PDFContextLipodystrophy syndromes are rare disorders characterized by deficient adipose tissue, leading to insulin resistance, dyslipidemia, and organ system abnormalities.ObjectiveOur goal was to develop a lipodystrophy severity score (LDS) to holistically capture the diverse manifestations of lipodystrophy into a numerical score to aid in prediction of clinical outcomes and/or treatment impact.DesignAn 8-domain LDS was developed by eight disease experts in consultation with patient organizations. The LDS was rated for feasibility and content validity by 28 additional clinicians and 9 patient representatives. LDS was compared to Clinical Global Impression (CGI) of severity for 20 putative patient profiles, each at two different time points, and by comparing change in LDS to global impression of change. For external validation, LDS was calculated in two cohorts of patients with lipodystrophy treated with metreleptin.ResultsLDS domains include Diabetes/Insulin Resistance, Microvascular Complications of Diabetes, Lipids, Cardiovascular, Liver, Kidney, Reproductive, and Other. Each domain is assessed by one or more questions assessing both lifetime and recent complications of lipodystrophy. The LDS had high content validity and feasibility, and high reliability by intraclass correlation coefficients (>0.95). Global and domain-specific LDS were strongly correlated with CGI, as were changes in scores across visits (R=0.79-0.99, P<0.001 for all). In generalized lipodystrophy, metreleptin significantly reduced LDS (from 46 to 26 at 12 months, P<0.001). The reductions were smaller in partial lipodystrophy (from 65 to 61 at 12 months, P=0.04).ConclusionsThe LDS can reflect the severity of diverse manifestations of lipodystrophy and monitor changes following interventions
Work hours and amenity trade-offs
No full textWe present a compensating wage differentials model that incorporates complementarity and substitutability in firms' provision of amenities and workers' preferences for them. These interactions help explain why some amenities tend to be bundled, while others are more often traded off. Our empirical analysis examines amenity substitution in the US labor market using data from the National Longitudinal Survey of Youth 1997 cohort. We highlight how shorter or more flexible total work hours are traded off with other workplace amenities. Our findings suggest that women may need to forgo amenities they value to secure shorter, more flexible work hours
Investigating Global Correlations Between Earthquake-generated Tsunamis and Subduction Zone Characteristics
No full textTsunamigenic earthquakes pose a large hazard in subduction zones, but it is currently unclear in which - if any - tectonic setting they preferentially occur. Here, we compile the global Subduction Nature & Interconnected Tsunamigenic earthquake Characteristics (SNITCH) database with parameters on subduction geometry, tectonics, and megathrust seismicity, and 329 tsunami events caused by earthquakes that were recorded in subduction zones between 1962 and 2018. We aim to identify potential correlations between tsunamigenic earthquake behaviour and subduction zone characteristics. We first use a bivariate regression analysis to find first-order correlations between the normalised number of earthquake-generated tsunami events Nt and the megathrust seismicity and tectonic parameters characterising a subduction zone. We confirm self-evident correlations between Nt and the number and magnitude of earthquakes and subduction kinematics. We then apply a multivariate Fisher analysis to see which combination of tectonic parameters best distinguishes subduction zone segments in which relatively many and few tsunami events caused by earthquakes have occurred. Despite the scarcity of the tsunami data, we consistently find that the type of margin (i.e., erosional or accretionary), the trench-normal component of the subduction and convergence velocity, the amount of trench sediments, and the roughness of the incoming plate are related to the number of earthquake-generated tsunami events. Our results therefore suggest that tsunamigenic earthquakes may occur more frequently in tectonic settings where plates subduct relatively fast beneath a sediment-starved, erosional margin with a complex, shallow subduction interface, characterised by multiple faults and fractures
The political economy of an investment facilitation for development agreement in Brazil, India, and China
No full textThis chapter examines the politics of the negotiations surrounding the Investment Facilitation for Development (IFD) Agreement within the World Trade Organization (WTO). Historically, developing and emerging economies have opposed multilateral investment rules over concerns that they would favor developed countries and limit policy space. However, proposals for the IFD Agreement have gained momentum, thanks in part to Global South members such as Brazil and China, which have also advanced their preferences through bilateral and regional arrangements outside of the WTO. Despite promises to focus on technical aspects and avoid politically charged topics, negotiations continue to raise objections from other emerging economies such as India and South Africa over extending the WTO’s mandate and preserving policy space. The chapter compares the competing interests and strategies of India, Brazil, and China as they attempt to establish investment facilitation standards inside and outside of the WTO. While the standards they promote are similar, their political motivations may create obstacles to the consolidation of a final multilateral agreement
Surface darkening by abundant and diverse algae on an Antarctic ice cap
No full textAlgal blooms play important roles in physical and biological processes on glacial surfaces. Despite this, their occurrence and impacts within an Antarctic context remain understudied. Here, we present evidence of the large-scale presence, diversity and bioalbedo effects of algal blooms on Antarctic ice cap systems based on fieldwork conducted on Robert Island (South Shetland Islands, Antarctica). Algal blooms are observed covering up to 2.7 km2 (~20%) of the measured area of the Robert Island ice cap, with cell densities of up to 1.4 × 106 cells ml−1. Spectral characterisation reveal that these blooms increase melting of the ice cap surface, contributing up to 2.4% of total melt under the observed conditions. Blooms are composed of typical cryoflora taxa, dominated by co-occurring Chlorophyceae, Trebouxiophyceae, and Ancylonema. However, morphological variation and genetic diversity in Ancylonema highlight the influence of regional endemism and point to a large and under-characterised diversity in Antarctic cryoflora
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