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Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.

Herbert McCabe was, by widespread acclaim, one of the greatest Catholic thinkers in the English speaking world during the final quarter of the last century. He was also deeply committed to radical left‐wing politics. What is the relationship between these two facts? I lay out what I take to be the key themes in McCabe's politics before arguing that, in contrast to significant strands in present day political theology, he had a keen sense of the respective roles of faith and reason in guiding political action. This allowed him to commit himself to a politics which was more radical than much of what has followed him, whilst having a clear sense of how Christian faith ought to be allowed to condition political engagement. The article concludes by drawing out lessons from McCabe for thinking about faith and politics. Not least of these is that we ought to avoid the lure, often articulated in terms of the ‘unifying’ role of the Church, to eschew conflict.

Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and p-values for case-case and case-control comparisons for risk factors in relation to levels of grade and quartiles (Q1-Q4) of KI67 were estimated using polytomous logistic regression models. Case-case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs Q1 = 1.54 (1.22, 1.95)]; obesity and high grade [grade 3 vs 1 = 1.68 (1.31, 2.16)]; and current use of combined hormone therapy (HT) and low grade [grade 3 vs 1 = 0.27 (0.16, 0.44)] tumors. In case-control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43 (1.14, 1.81) for KI67 Q4 vs 0.83 (0.60, 1.14) for KI67 Q1]; obesity among women ≥50 years with high but not low grade tumors [1.55 (1.17, 2.06) for grade 3 vs 0.88 (0.66, 1.16) for grade 1]; and HT with low but not high grade tumors [3.07 (2.22, 4.23) for grade 1 vs 0.85 (0.55, 1.30) for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors. This article is protected by copyright. All rights reserved.

Gabriel Uzquiano has offered an account of indefinite extensibility for sets in the context of a modal logic. The modal operators are interpreted in terms of linguistic extensibility. After reviewing the proposal, I argue that the view should be understood as a version of in rebus structuralism about set theory. As such it is subject to the usual problems for in rebus structuralism. In particular, there is no good extra set-theoretic reason to assent to an ontology of sufficient cardinality to make true the theorems of ZFC.

It is common for contemporary ontologists to claim that they are not concerned with what exists simpliciter, but rather with what exists ’fundamentally’, or what ’really’ exists. I argue that positions of this sort cannot satisfy reasonable constraints concerning the acquisition of language. I assess and dismiss possible responses to this complaint before commenting on the prospects for a metaphysics without bespoke existence claims.

Dynamic combinatorial chemistry (DCC) represents an approach whereby traditional supramolecular scaffolds used for protein surface recognition might be exploited to achieve selective high affinity target recognition. Synthesis, in situ screening and amplification under selection pressure, allows the generation of ligands, that bear different moieties capable of making multivalent non-covalent interactions with target proteins. Generic tetracarboxyphenyl porphyrin scaffolds bearing four hydrazide moieties have been used to form dynamic combinatorial libraries (DCLs) using, aniline catalyzed, reversible hydrazone exchange reactions, in 10 % DMSO, 5 mM NH₄OAc, pH 6.75. High resolution mass spectrometry (HRMS) was used to monitor library composition and establish conditions under which equilibria were established.

Se realizó un análisis transcriptómico mediante RNAseq de tejido radicular del portainjerto almendro × melocotonero ‘Garnem’ [P. amygdalus × P. persica]. Las plantas se sometieron a un tratamiento osmótico en solución PEG6000 en condiciones controladas (0 h – 2 h – 24 h). Tras el análisis en plataforma Illunina de 10 bibliotecas creadas a partir de raíz de plantas control y tratamiento, se anotaron e identificaron 26.700 genes diferencialmente expresados a las 2 h y a las 24 h involucrados en la respuesta a sequía. Este estudio proporciona una valiosa información de los cambios transcriptómicos iniciados durante las primeras horas de la señalización del estrés en raíces de ‘Garnem’ y sus mecanismos de adaptación. Asimismo, los resultados obtenidos serán de gran interés en la selección de nuevos patrones Prunus tolerantes a sequía. Published

Children with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,294 families with children with DDs, and meta-analysed these data with published data on 3,287 children with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the child, the relatedness of their parents and the age of both father and mother. We identified 95 genes enriched for damaging de novo mutation at genome-wide significance (P < 5 x 10-7), including fourteen genes for which compelling data for causation was previously lacking. The large number of genome-wide significant findings allow us to demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42.5% of our cohort likely carry pathogenic de novo single nucleotide variants (SNVs) and indels in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder being gain-of-function. We established that most haploinsufficient developmental disorders have already been identified, but that many gain-of-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that de novo dominant developmental disorders have an average birth prevalence of 1 in 168 to 1 in 377, depending on parental age.

Besides the identification point system to assure adequate set-up of instrumentation, European Commission Decision 2002/657/EC includes performance criteria regarding relative ion abundances in mass spectrometry and chromatographic retention time. In confirmatory analysis, the relative abundance of two product ions, acquired in selected reaction monitoring mode, the ion ratio should be within certain ranges for confirmation of the identity of a substance. The acceptable tolerance of the ion ratio varies with the relative abundance of the two product ions and for retention time, CD 2002/657/EC allows a tolerance of 5%. Because of rapid technical advances in analytical instruments and new approaches applied in the field of contaminant testing in food products (multi-compound and multi-class methods) a critical assessment of these criteria is justified. In this study a large number of representative, though challenging sample extracts were prepared, including muscle, urine, milk and liver, spiked with 100 registered and banned veterinary drugs at levels ranging from 0.5 to 100 µg/kg. These extracts were analysed using SRM mode using different chromatographic conditions and mass spectrometers from different vendors. In the initial study, robust data was collected using four different instrumental set-ups. Based on a unique and highly relevant data set, consisting of over 39 000 data points, the ion ratio and retention time criteria for applicability in confirmatory analysis were assessed. The outcomes were verified based on a collaborative trial including laboratories from all over the world. It was concluded that the ion ratio deviation is not related to the value of the ion ratio, but rather to the intensity of the lowest product ion. Therefore a fixed ion ratio deviation tolerance of 50% (relative) is proposed, which also is applicable for compounds present at sub-ppb levels or having poor ionisation efficiency. Furthermore, it was observed that retention time shifts, when using gradient elution, as is common practice nowadays, are mainly observed for early eluting compounds. Therefore a maximum retention time deviation of 0.2 min (absolute) is proposed. These findings should serve as input for discussions on the revision of currently applied criteria and the establishment of a new, globally accepted, criterion document for confirmatory analysis.