Airborne radar sounding evidence for deformable sediments and outcropping bedrock beneath Thwaites Glacier, West Antarctica

The geologic and morphologic records of prior ice sheet configurations show evidence of rapid, back-stepping, meltwater intensive retreats. However, the potential for such a retreat in a contemporary glacier depends on the lithology of the current ice sheet bed, which lies beneath kilometers of ice, making its physical properties difficult to constrain. We use radar sounding and marine bathymetry data to compare the bed configuration of Thwaites Glacier to the bed of paleo-Pine Island Glacier. Using observed and modeled radar scattering, we show that the tributaries and upper trunk of Thwaites Glacier are underlain by ice flow-aligned bedforms consistent with deformable sediment and that the lower trunk is grounded on a region of high bed roughness consistent with outcropping bedrock. This is the same configuration as paleo-Pine Island Glacier during its retreat across the inner continental shelf

Rate and equilibrium constants for the addition of triazolium salt derived N-heterocyclic carbenes to heteroaromatic aldehydes

Heteroaromatic aldehydes are often used preferentially or exclusively in a range of NHC-catalysed processes that proceed through the generation of a reactive diaminoenol or Breslow Intermediate (BI), with the reason for their unique reactivity currently underexplored. This manuscript reports measurement of rate and equilibrium constants for the reaction between N-aryl triazolium NHCs and heteroaromatic aldehydes, providing insight into the effect of the NHC and heteroaromatic aldehyde structure up to formation of the BI. Variation in NHC catalyst and heteroaromatic aldehyde structure markedly affect the observed kinetic parameters of adduct formation, decay to starting materials and onward reaction to BI. In particular, large effects are observed with both 3-halogen (Br, F) and 3-methyl substituted pyridine-2-carboxaldehyde derivatives which substantially favour formation of the tetrahedral intermediate relative to benzaldehyde derivatives. Key observations indicate that increased steric hindrance leads to a reduction in both k2 and k−1 for large (2,6-disubstituted)-N-Ar groups within the triazolium scaffold, and sterically demanding aldehyde substituents in the 3-position, but not in the 6-position of the pyridine-2-carboxaldehyde derivatives. As part of this study, the isolation and characterisation of twenty tetrahedral adducts formed upon addition of N-aryl triazolium derived NHCs into heteroaromatic aldehydes are described. These adducts are key intermediates in NHC-catalysed umpolung addition of heteroaromatic aldehydes and are BI precursors

Partnering with Parteras: Multi-Collaborator International Service-Learning Project Impacts on Traditional Birth Attendants in Mexico

Medical students are increasingly seeking global health service-learning opportunities; however, the impact of these interventions is often not assessed. In this article, the authors describe a model for global health service-learning programs as well as a pilot tool for assessing program impacts on populations traditionally difficult to evaluate.  Specifically, a group of medical students from the United States, in collaboration with local health officials and a global NGO, successfully implemented a training program for parteras, or traditional birth attendants, in Mexico. The training included educational objectives from the Ministry of Health.  A pilot assessment tool was developed which included oral pretest and posttest self-reported knowledge and task-specific ability in 12 program-specific categories. The assessment was administered in an effort to determine educational impact: parteras, who were receptive to students as teachers, reported increased knowledge and skill in all topics except nutrition and postpartum care. The results of the assessment suggest that undergraduate medical students, when collaborating with a facilitating organization, community-based healthcare workers, and local ministries of health, can improve lay birth attendants’ confidence in basic obstetric knowledge and skills through global service-learning. Moreover, creative assessments are required to understand impacts on difficult to access populations.

Glucose Promotes Stress Resistance in the Fungal Pathogen \u3ci\u3eCandida albicans\u3c/i\u3e

Metabolic adaptation, and in particular the modulation of carbon assimilatory pathways during disease progression, is thought to contribute to the pathogenicity of Candida albicans. Therefore, we have examined the global impact of glucose upon the C. albicans transcriptome, testing the sensitivity of this pathogen to wide-ranging glucose levels (0.01, 0.1, and 1.0%). We show that, like Saccharomyces cerevisiae, C. albicans is exquisitely sensitive to glucose, regulating central metabolic genes even in response to 0.01% glucose. This indicates that glucose concentrations in the bloodstream (approximate range 0.05–0.1%) have a significant impact upon C. albicans gene regulation. However, in contrast to S. cerevisiae where glucose down-regulates stress responses, some stress genes were induced by glucose in C. albicans. This was reflected in elevated resistance to oxidative and cationic stresses and resistance to an azole antifungal agent. Cap1 and Hog1 probably mediate glucose-enhanced resistance to oxidative stress, but neither is essential for this effect. However, Hog1 is phosphorylated in response to glucose and is essential for glucose-enhanced resistance to cationic stress. The data suggest that, upon entering the bloodstream, C. albicans cells respond to glucose increasing their resistance to the oxidative and cationic stresses central to the armory of immunoprotective phagocytic cells

Glucose Promotes Stress Resistance in the Fungal Pathogen \u3ci\u3eCandida albicans\u3c/i\u3e

Metabolic adaptation, and in particular the modulation of carbon assimilatory pathways during disease progression, is thought to contribute to the pathogenicity of Candida albicans. Therefore, we have examined the global impact of glucose upon the C. albicans transcriptome, testing the sensitivity of this pathogen to wide-ranging glucose levels (0.01, 0.1, and 1.0%). We show that, like Saccharomyces cerevisiae, C. albicans is exquisitely sensitive to glucose, regulating central metabolic genes even in response to 0.01% glucose. This indicates that glucose concentrations in the bloodstream (approximate range 0.05–0.1%) have a significant impact upon C. albicans gene regulation. However, in contrast to S. cerevisiae where glucose down-regulates stress responses, some stress genes were induced by glucose in C. albicans. This was reflected in elevated resistance to oxidative and cationic stresses and resistance to an azole antifungal agent. Cap1 and Hog1 probably mediate glucose-enhanced resistance to oxidative stress, but neither is essential for this effect. However, Hog1 is phosphorylated in response to glucose and is essential for glucose-enhanced resistance to cationic stress. The data suggest that, upon entering the bloodstream, C. albicans cells respond to glucose increasing their resistance to the oxidative and cationic stresses central to the armory of immunoprotective phagocytic cells

Data-driven models of dominantly-inherited Alzheimer’s disease progression

Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease-progression modelling to characterise dominantly-inherited Alzheimer’s disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset (EYO). We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers: 163 PSEN1; 17 PSEN2; and 31 APP) and a baseline visit (age 19–66; up to four visits each, 1·1±1·9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential-equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then sub-cortical regions (approximately 24±11 years before onset); CSF p-tau (17±8 years), tau and Aβ42 changes; neurodegeneration first in the putamen and nucleus accumbens (up to 6±2 years); then cognitive decline (7±6 years), cerebral hypometabolism (4±4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than EYO: root-mean-squared error of 1·35 years versus 5·54 years. The models reveal hidden detail on dominantly-inherited Alzheimer's disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials

The EBV-Encoded Oncoprotein, LMP1, Recruits and Transforms Fibroblasts via an ERK-MAPK-Dependent Mechanism

open access articleLatent membrane protein 1 (LMP1), the major oncoprotein encoded by Epstein–Barr virus (EBV), is expressed at widely variable levels in undifferentiated nasopharyngeal carcinoma (NPC) biopsies, fueling intense debate in the field as to the importance of this oncogenic protein in disease pathogenesis. LMP1-positive NPCs are reportedly more aggressive, and in a similar vein, the presence of cancer-associated fibroblasts (CAFs) surrounding “nests” of tumour cells in NPC serve as indicators of poor prognosis. However, there is currently no evidence linking LMP1 expression and the presence of CAFs in NPC. In this study, we demonstrate the ability of LMP1 to recruit fibroblasts in vitro in an ERK-MAPK-dependent mechanism, along with enhanced viability, invasiveness and transformation to a myofibroblast-like phenotype. Taken together, these findings support a putative role for LMP1 in recruiting CAFs to the tumour microenvironment in NPC, ultimately contributing to metastatic disease

Advanced model compounds for understanding acid-catalyzed lignin depolymerization : identification of renewable aromatics and a lignin-derived solvent

This work was funded by the EP/J018139/1, EP/K00445X/1 grants (NJW and PCJK), an EPSRC Doctoral Prize Fellowship (CSL), and the European Union (Marie Curie ITN ‘SuBiCat’ PITN-GA-2013-607044, CWL, NJW, PCJK, PJD, KB, JdeV).The development of fundamentally new approaches for lignin depolymerization is challenged by the complexity of this aromatic biopolymer. While overly simplified model compounds often lack relevance to the chemistry of lignin, the direct use of lignin streams poses significant analytical challenges to methodology development. Ideally, new methods should be tested on model compounds that are complex enough to mirror the structural diversity in lignin but still of sufficiently low molecular weight to enable facile analysis. In this contribution, we present a new class of advanced (β-O-4)-(β-5) dilinkage models that are highly realistic representations of a lignin fragment. Together with selected β-O-4, β-5, and β–β structures, these compounds provide a detailed understanding of the reactivity of various types of lignin linkages in acid catalysis in conjunction with stabilization of reactive intermediates using ethylene glycol. The use of these new models has allowed for identification of novel reaction pathways and intermediates and led to the characterization of new dimeric products in subsequent lignin depolymerization studies. The excellent correlation between model and lignin experiments highlights the relevance of this new class of model compounds for broader use in catalysis studies. Only by understanding the reactivity of the linkages in lignin at this level of detail can fully optimized lignin depolymerization strategies be developed.PostprintPeer reviewe