Modern languages and mentoring: Lessons from digital learning in Wales

This article considers the role that mentoring, and in particular online mentoring, can play in tackling the decline in modern language learning at GCSE level in Wales. • It evaluates Digi-Languages, a blended learning experience that pairs university student linguists with secondary school learners of languages to improve MFL uptake at GCSE. • This article examines the conception, design and early outcomes of DigiLanguages. • The article evaluates the experiential learning of the mentees (Year 9 learners) and explores the ethos underpinning resource development and the project’s key messaging around culture and languages. • The article provides recommendations for the expansion of Digi-Languages to support broader language policy objectives in Wales, including the Welsh Government’s policy of one million Welsh speakers by 2050. • The article concludes with suggestions for the extension of Digi-Languages to other regions of the UK and overseas and its potential as a model for stimulating inter-cultural conversations on the lifelong value of languages

Inflect: Optimizing Computational Workflows for Thermal Proteome Profiling Data Analysis

The CETSA and Thermal Proteome Profiling (TPP) analytical methods are invaluable for the study of protein–ligand interactions and protein stability in a cellular context. These tools have increasingly been leveraged in work ranging from understanding signaling paradigms to drug discovery. Consequently, there is an important need to optimize the data analysis pipeline that is used to calculate protein melt temperatures (Tm) and relative melt shifts from proteomics abundance data. Here, we report a user-friendly analysis of the melt shift calculation workflow where we describe the impact of each individual calculation step on the final output list of stabilized and destabilized proteins. This report also includes a description of how key steps in the analysis workflow quantitatively impact the list of stabilized/destabilized proteins from an experiment. We applied our findings to develop a more optimized analysis workflow that illustrates the dramatic sensitivity of chosen calculation steps on the final list of reported proteins of interest in a study and have made the R based program Inflect available for research community use through the CRAN repository [McCracken, N. Inflect: Melt Curve Fitting and Melt Shift Analysis. R package version 1.0.3, 2021]. The Inflect outputs include melt curves for each protein which passes filtering criteria in addition to a data matrix which is directly compatible with downstream packages such as UpsetR for replicate comparisons and identification of biologically relevant changes. Overall, this work provides an essential resource for scientists as they analyze data from TPP and CETSA experiments and implement their own analysis pipelines geared toward specific applications

Boosting Detection of Low-Abundance Proteins in Thermal Proteome Profiling Experiments by Addition of an Isobaric Trigger Channel to TMT Multiplexes

The study of low-abundance proteins is a challenge to discovery-based proteomics. Mass spectrometry (MS) applications, such as thermal proteome profiling (TPP), face specific challenges in the detection of the whole proteome as a consequence of the use of nondenaturing extraction buffers. TPP is a powerful method for the study of protein thermal stability, but quantitative accuracy is highly dependent on consistent detection. Therefore, TPP can be limited in its amenability to study low-abundance proteins that tend to have stochastic or poor detection by MS. To address this challenge, we incorporated an affinity-purified protein complex sample at submolar concentrations as an isobaric trigger channel into a mutant TPP (mTPP) workflow to provide reproducible detection and quantitation of the low-abundance subunits of the cleavage and polyadenylation factor (CPF) complex. The inclusion of an isobaric protein complex trigger channel increased detection an average of 40× for previously detected subunits and facilitated detection of CPF subunits that were previously below the limit of detection. Importantly, these gains in CPF detection did not cause large changes in melt temperature (Tm) calculations for other unrelated proteins in the samples, with a high positive correlation between Tm estimates in samples with and without isobaric trigger channel addition. Overall, the incorporation of an affinity-purified protein complex as an isobaric trigger channel within a tandem mass tag (TMT) multiplex for mTPP experiments is an effective and reproducible way to gather thermal profiling data on proteins that are not readily detected using the original TPP or mTPP protocols

Green revolution in Sub-Saharan Africa: Implications of imposed innovation for the wellbeing of rural smallholders

Green Revolution policies are again being pursued to drive agricultural growth and reduce poverty in Sub-Saharan Africa. However conditions have changed since the well-documented successes of the 1960s and 1970s benefited smallholders in southern Asia and beyond. We argue that under contemporary constraints the mechanisms for achieving improvements in the lives of smallholder farmers through such policies are unclear and that both policy rationale and means of governing agricultural innovation are crucial for pro-poor impacts. To critically analyze Rwanda’s Green Revolution policies and impacts from a local perspective, a mixed methods, multidimensional wellbeing approach is applied in rural areas in mountainous western Rwanda. Here Malthusian policy framing has been used to justify imposed rather than ‘‘induced innovation”. The policies involve a substantial transformation for rural farmers from a traditional polyculture system supporting subsistence and local trade to the adoption of modern seed varieties, inputs, and credit in order to specialize in marketable crops and achieve increased production and income. Although policies have been deemed successful in raising yields and conventionally measured poverty rates have fallen over the same period, such trends were found to be quite incongruous with local experiences. Disaggregated results reveal that only a relatively wealthy minority were able to adhere to the enforced modernization and policies appear to be exacerbating landlessness and inequality for poorer rural inhabitants. Negative impacts were evident for the majority of households as subsistence practices were disrupted, poverty exacerbated, local systems of knowledge, trade, and labor were impaired, and land tenure security and autonomy were curtailed. In order to mitigate the effects we recommend that inventive pro-poor forms of tenure and cooperation (none of which preclude improvements to input availability, market linkages, and infrastructure) may provide positive outcomes for rural people, and importantly in Rwanda, for those who have become landless in recent years. We conclude that policies promoting a Green Revolution in Sub-Saharan Africa should not all be considered to be pro-poor or even to be of a similar type, but rather should be the subject of rigorous impact assessment. Such assessment should be based not only on consistent, objective indicators but pay attention to localized impacts on land tenure, agricultural practices, and the wellbeing of socially differentiated people

Admixture Mapping of Quantitative Trait Loci for BMI in African Americans: Evidence for Loci on Chromosomes 3q, 5q, and 15q

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93743/1/oby_1443_sm_2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/93743/2/oby_1443_sm_1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/93743/3/oby.2009.24.pd

Recovering Protein-Protein and Domain-Domain Interactions from Aggregation of IP-MS Proteomics of Coregulator Complexes

Coregulator proteins (CoRegs) are part of multi-protein complexes that transiently assemble with transcription factors and chromatin modifiers to regulate gene expression. In this study we analyzed data from 3,290 immuno-precipitations (IP) followed by mass spectrometry (MS) applied to human cell lines aimed at identifying CoRegs complexes. Using the semi-quantitative spectral counts, we scored binary protein-protein and domain-domain associations with several equations. Unlike previous applications, our methods scored prey-prey protein-protein interactions regardless of the baits used. We also predicted domain-domain interactions underlying predicted protein-protein interactions. The quality of predicted protein-protein and domain-domain interactions was evaluated using known binary interactions from the literature, whereas one protein-protein interaction, between STRN and CTTNBP2NL, was validated experimentally; and one domain-domain interaction, between the HEAT domain of PPP2R1A and the Pkinase domain of STK25, was validated using molecular docking simulations. The scoring schemes presented here recovered known, and predicted many new, complexes, protein-protein, and domain-domain interactions. The networks that resulted from the predictions are provided as a web-based interactive application at http://maayanlab.net/HT-IP-MS-2-PPI-DDI/

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development