The chronology and kinematics of late Palaeozoic deformation in the NW contact metamorphic aureole of the Land's End Granite

A structural investigation of coastal exposures between Cape Cornwall and Pendeen Watch, in the NW contact metamorphic aureole of the Land’s End Granite, has confirmed a similar deformation chronology as in a reference section around Porthleven. D1 deformation is represented by an ubiquitous bedding-parallel S1 cleavage although F1 folds have not been recognised. D2 deformation is more localised and characterised by open F2 folds that verge WSW to NW and are associated with an ENE to SE dipping S2 crenulation cleavage. These structures are commonly obscured by later deformation and contact metamorphism and have not been described previously. A set of steeply inclined NNW-SSE trending, and subordinate set of moderately SE dipping, post-D2 metamorphic quartz veins formed coevally during an episode of strike-slip deformation prior to, or during, the early stages of D3 deformation. D3 deformation is widespread and represented by F3 folds and a WNW to NW dipping S3 crenulation cleavage; it has been recorded previously as D2 deformation. Two orders of F3 folds are developed; first order folds have a wavelength of up to 50 m, verge ESE, and result in vertical or steeply inclined bedding and S1 cleavage on their short limbs. Second order folds usually have a wavelength of 1 m or less and usually verge ESE, unless on the short limb of first order folds, where they verge WNW. Previously published data, indicating a dominant NW to WNW vergence of F3 folds on the northern flank of the Land’s End Granite are incorrect. D3 structures are consistent with formation during the extensional reactivation of large-scale thrust faults. Granite emplacement post-dates all three episodes of ductile deformation but granites and their host rocks are deformed by a late brittle expression of D3 deformation. The Land’s End pluton has been accommodated, at the current exposure level, primarily by roof uplift that has resulted in the tilting of D3 and earlier structures to the NW by 40-50º; this may have been accompanied by differential vertical axis rotations of the host rock. The last significant Palaeozoic deformation episode formed F4 folds and S4 cleavage and was a consequence of Mid- to Late Permian ENE-WSW shortening

Complementary Nucleobase Interactions Drive the Hierarchical Self-Assembly of Core-Shell Bottlebrush Block Copolymers toward Cylindrical Supramolecules

The self-assembly of amphiphilic block copolymers has facilitated the preparation of a wide variety of nano-objects of diverse morphology. Ready access to these nanostructures has opened up new possibilities in catalysis, sensing, and nanomedicine. In comparison, the self-assembly of large building blocks (i.e., amphiphilic bottlebrush polymers) has received less attention, owing in part to the relatively more challenging synthesis of these macromolecules. Bottlebrush amphiphiles can self-assemble into uniquely stable spherical nanostructures and can also produce dynamic cylinders with lengths modulated by environmental conditions, motivating further research in this area. Herein, we report the synthesis of core–shell bottlebrush polymers (BBPs) containing complementary nucleobase functionalities via a combination of ring-opening metathesis polymerization (ROMP) and reversible addition–fragmentation chain transfer (RAFT) polymerization, using a “grafting-from” approach, and their hierarchical self-assembly in aqueous media. Mixtures of BBPs containing thymine or adenine units in their core blocks were found to self-assemble into higher-order cylindrical supramolecules upon heating above a critical temperature. This temperature was demonstrated to correspond to the lower critical solution temperature (LCST) of the corona-forming poly(4-acryloylmorpholine) block, providing evidence for a unique one-dimensional BBP assembly mechanism. Moreover, the formation of extended supramolecular assemblies was preferentially observed when both thymine- and adenine-functionalized BBPs were present in equimolar concentrations, pointing toward an alternating, isodesmic mechanism of organization occurring via nucleobase interactions located at their chain termini. We anticipate that these discoveries will provide the basis for future studies regarding BBP self-assembly, especially with regard to the formation of stimuli-responsive anisotropic nanostructures

Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa.

Cytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A5*1 (expresser allele); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343) (low/non-expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago

Long-term behavioural rewriting of maladaptive drinking memories via reconsolidation-update mechanisms

BACKGROUND: Alcohol use disorders can be conceptualised as a learned pattern of maladaptive alcohol-consumption behaviours. The memories encoding these behaviours centrally contribute to long-term excessive alcohol consumption and are therefore an important therapeutic target. The transient period of memory instability sparked during memory reconsolidation offers a therapeutic window to directly rewrite these memories using targeted behavioural interventions. However, clinically-relevant demonstrations of the efficacy of this approach are few. We examined key retrieval parameters for destabilising naturalistic drinking memories and the ability of subsequent counterconditioning to effect long-term reductions in drinking. METHODS: Hazardous/harmful beer-drinking volunteers (N = 120) were factorially randomised to retrieve (RET) or not retrieve (No RET) alcohol reward memories with (PE) or without (No PE) alcohol reward prediction error. All participants subsequently underwent disgust-based counterconditioning of drinking cues. Acute responses to alcohol were assessed pre- and post-manipulation and drinking levels were assessed up to 9 months. RESULTS: Greater long-term reductions in drinking were found when counterconditioning was conducted following retrieval (with and without PE), despite a lack of short-term group differences in motivational responding to acute alcohol. Large variability in acute levels of learning during counterconditioning was noted. 'Responsiveness' to counterconditioning predicted subsequent responses to acute alcohol in RET + PE only, consistent with reconsolidation-update mechanisms. CONCLUSIONS: The longevity of behavioural interventions designed to reduce problematic drinking levels may be enhanced by leveraging reconsolidation-update mechanisms to rewrite maladaptive memory. However, inter-individual variability in levels of corrective learning is likely to determine the efficacy of reconsolidation-updating interventions and should be considered when designing and assessing interventions

Development and face validation of strategies for improving consultation skills

While formative workplace based assessment can improve learners' skills, it often does not because the procedures used do not facilitate feedback which is sufficiently specific to scaffold improvement. Provision of pre-formulated strategies to address predicted learning needs has potential to improve the quality and automate the provision of written feedback. To systematically develop, validate and maximise the utility of a comprehensive list of strategies for improvement of consultation skills through a process involving both medical students and their clinical primary and secondary care tutors. Modified Delphi study with tutors, modified nominal group study with students with moderation of outputs by consensus round table discussion by the authors. 35 hospital and 21 GP tutors participated in the Delphi study and contributed 153 new or modified strategies. After review of these and the 205 original strategies, 265 strategies entered the nominal group study to which 46 year four and five students contributed, resulting in the final list of 249 validated strategies. We have developed a valid and comprehensive set of strategies which are considered useful by medical students. This list can be immediately applied by any school which uses the Calgary Cambridge Framework to inform the content of formative feedback on consultation skills. We consider that the list could also be mapped to alternative skills frameworks and so be utilised by schools which do not use the Calgary Cambridge Framework

Towards W b bbar + j at NLO with an automatized approach to one-loop computations

We present results for the O(alpha_s) virtual corrections to q g -> W b bbar q' obtained with a new automatized approach to the evaluation of one-loop amplitudes in terms of Feynman diagrams. Together with the O(alpha_s) corrections to q q' -> W b bbar g, which can be obtained from our results by crossing symmetry, this represents the bulk of the next-to-leading order virtual QCD corrections to W b bbar + j and W b + j hadronic production, calculated in a fixed-flavor scheme with four light flavors. Furthermore, these corrections represent a well defined and independent subset of the 1-loop amplitudes needed for the NNLO calculation of W b bbar. Our approach was tested against several existing results for NLO amplitudes including selected O(alpha_s) one-loop corrections to W + 3 j hadronic production. We discuss the efficiency of our method both with respect to evaluation time and numerical stability.Comment: 14 pages, 3 figure

Intra-operative Raman spectroscopy and ex vivo Raman mapping for assessment of cartilage degradation

The development of a label-free, non-destructive and safe analytical method such as Raman spectroscopy for assessing cartilage degradation is highly desirable. Compared to non-optical imaging modalities, Raman mapping offers a more sensitive means of directly assessing the chemical composition of cartilage in three-dimensional space and the potential to monitor cartilage degeneration to inform intervention and treatment strategies. Herein, we report the application of Raman spectroscopic methods ex vivo and at arthroscopy to identify molecular alterations in cartilage specimens containing minor focal lesions characteristic of the early disease phase. Our initial ex vivo analysis, obtained by single-point Raman spectroscopy of cartilage samples, supports previous findings based on S-O stretching vibration bands associated with sulphated glycosaminoglycans (sGAGs). We extended the analyses to the high-wavenumber region where we observed that vibrational bands assigned to C-H and O-H stretching modes discriminated early cartilage alterations from healthy cartilage samples. Furthermore, we performed a proof-of-concept in-clinic study using a custom-built optical probe to acquire Raman spectral measurements for the first time in patients undergoing arthroscopy of knee joints. Spectra were obtained with adequate signal-to-noise ratios that similarly discriminated between lesion and adjacent cartilage sites and identified reductions in sGAGs in apparently healthy cartilage. Building on this, we present initial results from Raman mapping to spatially resolve the molecular constituents of cartilage through its depth and across a lesion. Mapping revealed a non-uniform and reduced sGAG distribution within the lesion and peripheral cartilage that was otherwise visually normal, similar to the in-clinic observations, showing that the degradative influence of the lesion extended beyond its border. This was accompanied by a decreased fluorescence signal intensity, which suggests that fluorescence may provide valuable information as an adjunct to the Raman signal in discriminating normal and degenerating cartilage. This work demonstrates the value of Raman mapping over single-point Raman measurements for the analysis of the anisotropy of articular cartilage and highlights the potential of the technology for in vivo articular joint arthroscopy applications