A novel structural class of photoswitchable oligonucleotide

Directed Michaelis–Arbuzov reactions of support-bound internucleotide O-benzyl- or O-methyl-phosphite triesters with meta-phenylazobenzylamine or alkane-/glycol-linked a,x-diamines were effected in the presence of iodine. The corresponding tritylated phosphoramidate-linked 11-mers were fully deprotected and released from the support under standard conditions and the fast- and slow-diastereoisomers of both the E- and the Z-meta-phenylazobenzyl-appended oligomers were readily resolved by RP-HPLC. The primary amine-functionalised oligonucleotides were either purified, detritylated and then finally treated with Nhydroxysuccinimidyl carboxylic acid ester derivatives of photoswitchable moieties (Route A) or first derivatised and then subsequently purified and detritylated (Route B). This latter route enabled resolution of fast- and slow-isomers of the trityl-on oligomers bearing novel photoswitchable azopyridine or 9-alkoxyanthracene moieties using RP-HPLC, following which the pure diastereoisomers were detritylated and characterised by MALDI-MS.

Visuomotor transformation for interception:catching while fixating

Catching a ball involves a dynamic transformation of visual information about ball motion into motor commands for moving the hand to the right place at the right time. We previously formulated a neural model for this transformation to account for the consistent leftward movement biases observed in our catching experiments. According to the model, these biases arise within the representation of target motion as well as within the transformation from a gaze-centered to a body-centered movement command. Here, we examine the validity of the latter aspect of our model in a catching task involving gaze fixation. Gaze fixation should systematically influence biases in catching movements, because in the model movement commands are only generated in the direction perpendicular to the gaze direction. Twelve participants caught balls while gazing at a fixation point positioned either straight ahead or 14 degrees to the right. Four participants were excluded because they could not adequately maintain fixation. We again observed a consistent leftward movement bias, but the catching movements were unaffected by fixation direction. This result refutes our proposal that the leftward bias partly arises within the visuomotor transformation, and suggests instead that the bias predominantly arises within the early representation of target motion, specifically through an imbalance in the represented radial and azimuthal target motion.

Adaptations of lateral hand movements to early and late visual occlusion in catching

Recent studies suggested that the control of hand movements in catching involves continuous vision-based adjustments. More insight into these adjustments may be gained by examining the effects of occluding different parts of the ball trajectory. Here, we examined the effects of such occlusion on lateral hand movements when catching balls approaching from different directions, with the occlusion conditions presented in blocks or in randomized order. The analyses showed that late occlusion only had an effect during the blocked presentation, and early occlusion only during the randomized presentation. During the randomized presentation movement biases were more leftward if the preceding trial was an early occlusion trial. The effect of early occlusion during the randomized presentation suggests that the observed leftward movement bias relates to the rightward visual acceleration inherent to the ball trajectories used, while its absence during the blocked presentation seems to reflect trial-by-trial adaptations in the visuomotor gain, reminiscent of dynamic gain control in the smooth pursuit system. The movement biases during the late occlusion block were interpreted in terms of an incomplete motion extrapolation--a reduction of the velocity gain--caused by the fact that participants never saw the to-be-extrapolated part of the ball trajectory. These results underscore that continuous movement adjustments for catching do not only depend on visual information, but also on visuomotor adaptations based on non-visual information.

Behavioural and physiological responses of heifer calves to acute stressors: long-term consistency and relationship with adult reactivity to milking

The present study investigated the long-term consistency of individual differences in dairy cattles’ responses in tests of behavioural and hypothalamo–pituitary–adrenocortical (HPA) axis reactivity, as well as the relationship between responsiveness in behavioural tests and the reaction to first milking. Two cohorts of heifer calves, Cohorts 1 (N = 25) and 2 (N = 16), respectively, were examined longitudinally from the rearing period until adulthood. Cohort 1 heifers were subjected to open field (OF), novel object (NO), restraint, and response to a human tests at 7 months of age, and were again observed in an OF test during first pregnancy between 22 and 24 months of age. Subsequently, inhibition of milk ejection and stepping and kicking behaviours were recorded in Cohort 1 heifers during their first machine milking. Cohort 2 heifers were individually subjected to OF and NO tests as well as two HPA axis reactivity tests (determining ACTH and/or cortisol response profiles after administration of exogenous CRH and ACTH, respectively) at 6 months of age and during first lactation at approximately 29 months of age. Principal component analysis (PCA) was used to condense correlated response measures (to behavioural tests and to milking) within ages into independent dimensions underlying heifers’ reactivity. Heifers demonstrated consistent individual differences in locomotion and vocalisation during an OF test from rearing to first pregnancy (Cohort 1) or first lactation (Cohort 2). Individual differences in struggling in a restraint test at 7 months of age reliably predicted those in OF locomotion during first pregnancy in Cohort 1 heifers. Cohort 2 animals with high cortisol responses to OF and NO tests and high avoidance of the novel object at 6 months of age also exhibited enhanced cortisol responses to OF and NO tests at 29 months of age. Measures of HPA axis reactivity, locomotion, vocalisation and adrenocortical and behavioural responses to novelty were largely uncorrelated, supporting the idea that stress responsiveness in dairy cows is mediated by multiple independent underlying traits. Inhibition of milk ejection and stepping and kicking behaviours during first machine milking were not related to earlier struggling during restraint, locomotor responses to OF and NO tests, or the behavioural interaction with a novel object. Heifers with high rates of OF and NO vocalisation and short latencies to first contact with the human at 7 months of age exhibited better milk ejection during first machine milking. This suggests that low underlying sociality might be implicated in the inhibition of milk ejection at the beginning of lactation in heifers.

CD44 increases the efficiency of distant metastasis of breast cancer

Metastasis is the predominant cause of death from cancer yet we have few biomarkers to predict patients at increased risk of metastasis and are unable to effectively treat disseminated disease. Analysis of 448 primary breast tumors determined that expression of the hylauronan receptor CD44 associated with high grade (p = 0.046), ER- (p = 0.001) and PR-negative tumors (p = 0.029), and correlated with increased distant recurrence and reduced disease-free survival in patients with lymph-node positive or large tumors. To determine its functional role in distant metastasis, CD44 was knocked-down in MDA-MB-231 cells using two independent shRNA sequences. Loss of CD44 attenuated tumor cell adhesion to endothelial cells and reduced cell invasion but did not affect proliferation in vitro. To verify the importance of CD44 to post-intravasation events, tumor formation was assessed by quantitative in vivo imaging and post-mortem tissue analysis following an intra-cardiac injection of transfected cells. CD44 knock-down increased survival and decreased overall tumor burden at multiple sites, including the skeleton in vivo. We conclude that elevated CD44 expression on tumour cells within the systemic circulation increases the efficiency of post-intravasation events and distant metastasis in vivo, consistent with its association with increased distant recurrence and reduced disease-free survival in patients.

FKBPL: a marker of good prognosis in breast cancer

FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL's prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14-1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07-1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13-1.58, p < 0.001, and HR = 1.25, 95% CI 1.04-1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05-1.65, p = 0.02 and HR = 1.23 95% CI 0.99-1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic.

Making space: English women, letter-writing, and the life of the mind, c.1650-1750

This article uses women's letter-writing from the late seventeenth and early eighteenth centuries to explore the home as a site of female intellectual endeavour. Far from representing a static backdrop to the action of domestic life, the home played a dynamic role in women's experiences of the life of the mind and shaped the ways in which women thought and wrote. Letters were penned in dining rooms, parlours and closets, by firesides, and on desks and laps. In their letters, women projected images of themselves scribbling epistles to friends in order to maintain their mental intimacy. Space was both real and imagined and the physical realities of a hand-written and hand-delivered letter gave way to the imaginative possibilities brought by networks of epistolary exchange and the alternative spaces of creative thought. By reinstating the home more fully in the history of female intellectual experience, a more nuanced view of the domestic arena can be developed: one that sees the home not as a site of exclusion and confinement, but as a space for scholarship and exchange. 

Collaborative Scholarship on the Margins: An Epistolary Network

This article explores collaborative scholarship on the margins of intellectual life in eighteenth-century England via a close examination of George Ballard's collected correspondence from women letter-writers. Ballard was both a man of trade and an antiquary, and his modest social status inhibited his freedom to move in scholarly circles. Ballard's only published book documented the lives and works of "learned ladies" of Britain from the fifteenth to the eighteenth centuries, and his female correspondents included the Anglo-Saxon scholar Elizabeth Elstob. His collected correspondence provides an insight into a network that operated outside of the major institutions of scholarship and far from the coffee houses of metropolitan life, but which supported its participants in their intellectual endeavours. By examining the collection materially, and by plotting the correspondents geographically, a more precise picture can be drawn of how women and lower-status men could engage in intellectual life from the peripheries of scholarly society. 

Women, letter-writing and the life of the mind in England, c.1650-1750

Drawing on national and regional letter collections dating from the late seventeenth and early eighteenth centuries, this article explores women's experiences of the life of the mind through an analysis of their letter-writing. This study also highlights the shortcomings of the compartmentalised nature of scholarship on women's writing and intellectual lives and proposes the letter both as a beneficial historical source and methodological tool for research on women's mental worlds. By employing an inclusive definition of intellectual and creative life, and eschewing traditional benchmarks of achievement, this article contends that women took a full part in the cultures of knowledge of their time.