8.2 ka event North Sea hydrography determined by bivalve shell stable isotope geochemistry

This is the final version. Available on open access from Nature Research via the DOI in this recordThe abrupt 8.2 ka cold event has been widely described from Greenland and North Atlantic records. However, its expression in shelf seas is poorly documented, and the temporal resolution of most marine records is inadequate to precisely determine the chronology of major events. A robust hydrographical reconstruction can provide an insight on climatic reaction times to perturbations to the Atlantic Meridional Overturning Circulation. Here we present an annually-resolved temperature and water column stratification reconstruction based on stable isotope geochemistry of Arctica islandica shells from the Fladen Ground (northern North Sea) temporally coherent with Greenland ice core records. Our age model is based on a growth increment chronology obtained from four radiometrically-dated shells covering the 8290–8100 cal BP interval. Our results indicate that a sudden sea level rise (SSLR) event-driven column stratification occurred between ages 8320–8220 cal BP. Thirty years later, cold conditions inhibited water column stratification but an eventual incursion of sub-Arctic waters into the North Sea re-established density-driven stratification. The water temperatures reached their minimum of ~3.7 °C 55 years after the SSLR. Intermittently-mixed conditions were later established when the sub-Arctic waters receded.Natural Environment Research Council (NERC)European Union FP

Microscopy Quality Control in Médecins Sans Frontières Programs in Resource-Limited Settings

Derryck Klarkowski and Daniel Orozco describe the Médecins Sans Frontières program for monitoring the quality of microscopy for malaria, pulmonary tuberculosis, and leishmaniasis

A case report in cardiovascular magnetic resonance: the contrast agent matters in amyloid

BACKGROUND: Cardiac amyloidosis is a progressive but underdiagnosed and underappreciated cause of heart failure. In the last few years, cardiovascular magnetic resonance (CMR) has become the gold standard for non invasive diagnosis of cardiac amyloidosis with the characteristic subendocardial late gadolinium enhancement. CASE PRESENTATION: We describe a case of a patient who, in the process of aligning protocols for a trial between different centers, had a paired study with two different contrast agents, Dotarem® and MultiHance®. MultiHance® surprisingly failed to demonstrate the characteristic imaging pattern, showing only non specific late gadolinium enhancement at the inferior right ventricular insertion point and different myocardial extracellular volume fraction compared to the one obtained with Dotarem®. MultiHance® is used by many centres, because its partial blood protein binding is a strength for MR angiography, but late gadolinium enhancement, particularly non-ischemic, appears to be compromised. CONCLUSIONS: This case report suggests that contrast agents should be selected with caution, especially with new therapies lining up for amyloid and CMR being used as exploratory end point in clinical trials

Quantitative proteomic analysis of Parkin substrates in Drosophila neurons.

Parkin (PARK2) is an E3 ubiquitin ligase that is commonly mutated in Familial Parkinson's Disease (PD). In cell culture models, Parkin is recruited to acutely depolarised mitochondria by PINK1. PINK1 activates Parkin activity leading to ubiquitination of multiple proteins, which in turn promotes clearance of mitochondria by mitophagy. Many substrates have been identified using cell culture models in combination with depolarising drugs or proteasome inhibitors, but not in more physiological settings.Here we utilized the recently introduced BioUb strategy to isolate ubiquitinated proteins in flies. Following Parkin Wild-Type (WT) and Parkin Ligase dead (LD) expression we analysed by mass spectrometry and stringent bioinformatics analysis those proteins differentially ubiquitinated to provide the first survey of steady state Parkin substrates using an in vivo model. We further used an in vivo ubiquitination assay to validate one of those substrates in SH-SY5Y cells.We identified 35 proteins that are more prominently ubiquitinated following Parkin over-expression. These include several mitochondrial proteins and a number of endosomal trafficking regulators such as v-ATPase sub-units, Syx5/STX5, ALiX/PDCD6IP and Vps4. We also identified the retromer component, Vps35, another PD-associated gene that has recently been shown to interact genetically with parkin. Importantly, we validated Parkin-dependent ubiquitination of VPS35 in human neuroblastoma cells.Collectively our results provide new leads to the possible physiological functions of Parkin activity that are not overtly biased by acute mitochondrial depolarisation

Inherited epidermolysis bullosa

Inherited epidermolysis bullosa (EB) encompasses a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues. All types and subtypes of EB are rare; the overall incidence and prevalence of the disease within the United States is approximately 19 per one million live births and 8 per one million population, respectively. Clinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs. Each EB subtype is known to arise from mutations within the genes encoding for several different proteins, each of which is intimately involved in the maintenance of keratinocyte structural stability or adhesion of the keratinocyte to the underlying dermis. EB is best diagnosed and subclassified by the collective findings obtained via detailed personal and family history, in concert with the results of immunofluorescence antigenic mapping, transmission electron microscopy, and in some cases, by DNA analysis. Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct whenever possible the extracutaneous complications. Prognosis varies considerably and is based on both EB subtype and the overall health of the patient

A Neural Approach to Ordinal Regression for the Preventive Assessment of Developmental Dyslexia

Developmental Dyslexia (DD) is a learning disability related to the acquisition of reading skills that affects about 5% of the population. DD can have an enormous impact on the intellectual and personal development of affected children, so early detection is key to implementing preventive strategies for teaching language. Research has shown that there may be biological underpinnings to DD that affect phoneme processing, and hence these symptoms may be identifiable before reading ability is acquired, allowing for early intervention. In this paper we propose a new methodology to assess the risk of DD before students learn to read. For this purpose, we propose a mixed neural model that calculates risk levels of dyslexia from tests that can be completed at the age of 5 years. Our method first trains an auto-encoder, and then combines the trained encoder with an optimized ordinal regression neural network devised to ensure consistency of predictions. Our experiments show that the system is able to detect unaffected subjects two years before it can assess the risk of DD based mainly on phonological processing, giving a specificity of 0.969 and a correct rate of more than 0.92. In addition, the trained encoder can be used to transform test results into an interpretable subject spatial distribution that facilitates risk assessment and validates methodology.Comment: 12 pages, 4 figure

A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom

Autologous stem cell transplantation (ASCT) is considered to be the best method to achieve deep haematological/organ responses and improve survival in selected patients with AL amyloidosis. This field has been led by US centres and is less utilised in Europe. The introduction of effective chemotherapy agents for AL prompted us to re‐evaluate UK outcomes of ASCT in affected patients. A total of 264 AL amyloidosis patients treated with an ASCT between 1994 and 2018 were identified. Patient baseline characteristics, transplant‐related mortality (TRM) and overall survival (OS) were analysed. The median OS post‐ASCT was 87 months [95% confidence interval (CI): 77–106 months]. The median time from ASCT to next treatment was 48 months (95% CI: 29–55 months). A haematological response was achieved in 94·8% of patients and was a strong predictor of time to next treatment [P < 0·0001, hazard ratio (HR) = 1·75, 95% CI = 1·35–2·28] and OS (P = 0·007, HR = 1·91, 95% CI = 1·19–3·07). Organ response was: cardiac (n = 28, 60·9%), renal (n = 101, 76%) and liver (n = 7, 13·5%). Overall TRM was 8·7%, with a significant reduction over time (1994–2000: 18·8%; 2001–2006: 13·6%; 2007–2012: 6·2%; 2013–2018: 1·1%). In conclusion, ASCT is significantly safer and remains a highly effective treatment with excellent long‐term survival; it should be more widely considered as a treatment option for systemic AL amyloidosis

Impact of early response on outcomes in AL amyloidosis following treatment with frontline Bortezomib

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p  20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement

Hydrodynamics of a 5D Einstein-dilaton black hole solution and the corresponding BPS state

We apply the potential reconstruction approach to generate a series of asymptotically AdS (aAdS) black hole solutions, with a self-interacting bulk scalar field. Based on the method, we reproduce the pure AdS solution as a consistency check and we also generate a simple analytic 5D black hole solution. We then study various aspects of this solution, such as temperature, entropy density and conserved charges. Furthermore, we study the hydrodynamics of this black hole solution in the framework of fluid/gravity duality, e.g. the ratio of the shear viscosity to the entropy density. In a degenerate case of the 5D black hole solution, we find that the c function decreases monotonically from UV to IR as expected. Finally, we investigate the stability of the degenerate solution by studying the bosonic functional energy of the gravity and the Witten-Nester energy $E_{WN}$. We confirm that the degenerate solution is a BPS domain wall solution. The corresponding superpotential and the solution of the killing spinor equation are found explicitly.Comment: V2: 23 pages, no figure, minor changes, typos corrected, new references and comments added, version accepted by JHE