Minor structural modifications to alchemix influence mechanism of action and pharmacological activity

Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumors. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in G1 supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies

Holocene fire regimes and treeline migration rates in sub-arctic Canada

Holocene climate change resulted in major vegetation reorganization in sub-arctic Canada near modern treeline. However, little is known of the effects of long-term climate change on boreal forest composition and fire regimes below treeline in this region. We present a high-resolution vegetation and fire history from two sites within the modern boreal forest in the central Northwest Territories, Canada, to provide new insight on sub-arctic vegetation response to Holocene climate dynamics and the role of fire in boreal ecosystems. Palynological analysis of sediments retrieved from Waite and Danny's lakes (informal) is used to reconstruct regional vegetation dynamics and boreal fire regimes. The longer Danny's Lake record documents treeline expansion beginning at ca. 7430–7220 cal yr BP. Integration of our new data with previous work shows that treeline expanded between ca. 4050 cal. yr BP and ca. 3840 cal yr BP at a rate of ca. 50 m/yr in response to the 1–2 °C increase in temperature estimated for the Holocene Thermal Maximum. Forest fires were relatively frequent during the early Holocene, before declining in frequency in response to development of cooler and wetter climate conditions associated with the Neoglacial (beginning after ca. 2200–2320 cal yr BP). We document a trend of increasing fire frequency in the 20th century that is correlated with warming at this time. These dynamics south of modern treeline provide insight into factors creating heterogeneity in plant community responses to large-scale climate events in high northern latitudes and suggest that large scale reorganization of boreal vegetation and fire regimes can be expected over the coming decades

Scintigraphic assessment of bone status at one year following hip resurfacing : comparison of two surgical approaches using SPECT-CT scan

Objectives: To study the vascularity and bone metabolism of the femoral head/neck following hip resurfacing arthroplasty, and to use these results to compare the posterior and the trochanteric-flip approaches. Methods: In our previous work, we reported changes to intra-operative blood flow during hip resurfacing arthroplasty comparing two surgical approaches. In this study, we report the vascularity and the metabolic bone function in the proximal femur in these same patients at one year after the surgery. Vascularity and bone function was assessed using scintigraphic techniques. Of the 13 patients who agreed to take part, eight had their arthroplasty through a posterior approach and five through a trochanteric-flip approach. Results: One year after surgery, we found no difference in the vascularity (vascular phase) and metabolic bone function (delayed phase) at the junction of the femoral head/neck between the two groups of patients. Higher radiopharmaceutical uptake was found in the region of the greater trochanter in the trochanteric-flip group, related to the healing osteotomy. Conclusions: Our findings using scintigraphic techniques suggest that the greater intra-operative reduction in blood flow to the junction of the femoral head/neck, which is seen with the posterior approach compared with trochanteric flip, does not result in any difference in vascularity or metabolic bone function one year after surgery

Evidences for a quasi 60-year North Atlantic Oscillation since 1700 and its meaning for global climate change

The North Atlantic Oscillation (NAO) obtained using instrumental and documentary proxy predictors from Eurasia is found to be characterized by a quasi 60-year dominant oscillation since 1650. This pattern emerges clearly once the NAO record is time integrated to stress its comparison with the temperature record. The integrated NAO (INAO) is found to well correlate with the length of the day (since 1650) and the global surface sea temperature record HadSST2 and HadSST3 (since 1850). These findings suggest that INAO can be used as a good proxy for global climate change, and that a 60-year cycle exists in the global climate since at least 1700. Finally, the INAO ~60-year oscillation well correlates with the ~60- year oscillations found in the historical European aurora record since 1700, which suggests that this 60-year dominant climatic cycle has a solar-astronomical origin

Size and shape constancy in consumer virtual reality

With the increase in popularity of consumer virtual reality headsets, for research and other applications, it is important to understand the accuracy of 3D perception in VR. We investigated the perceptual accuracy of near-field virtual distances using a size and shape constancy task, in two commercially available devices. Participants wore either the HTC Vive or the Oculus Rift and adjusted the size of a virtual stimulus to match the geometric qualities (size and depth) of a physical stimulus they were able to refer to haptically. The judgments participants made allowed for an indirect measure of their perception of the egocentric, virtual distance to the stimuli. The data show under-constancy and are consistent with research from carefully calibrated psychophysical techniques. There was no difference in the degree of constancy found in the two headsets. We conclude that consumer virtual reality headsets provide a sufficiently high degree of accuracy in distance perception, to allow them to be used confidently in future experimental vision science, and other research applications in psychology

New occurrences of the White River Ash (east lobe) in Subarctic Canada and utility for estimating freshwater reservoir effect in lake sediment archives

The freshwater reservoir effect (FRE) in the Canadian Subarctic complicates development of high-resolution age-depth models based on radiocarbon dates from lake sediments. Volcanic ashfall layers (tephras) provide chronostratigraphic markers that can be used to estimate age offsets. We describe the first recorded occurrence of a visible tephra in a lacustrine sequence in the central Northwest Territories. The tephra, observed in Pocket Lake, near Yellowknife, is geochemically and stratigraphically attributed to the White River Ash east lobe (WRAe; 833–850 CE; 1117–1100 cal BP), which originated from an eruption of Mount Churchill, Alaska. We also observed the WRAe as a cryptotephra in Bridge Lake, 130 km to the NE, suggesting that records of this tephra are potentially widespread in CNT lakes. The identification of this tephra presents opportunities for use of the WRAe as a dating tool in the region and to quantify the magnitude of the FRE in order to correct radiocarbon age-depth models. Two well-dated sediment cores from Pocket Lake, containing a visible WRAe record, indicate a FRE of 200 years at the time of the ash deposition, which matches closely with the estimated FRE of 245 years at the lake sediment-water interface. Although additional results from other lakes in the region are required, this finding implies that FRE estimates for the late Holocene in the region, may be based either on down-core WRAe/radiocarbon age model offsets, or on radiocarbon dates obtained from the sediment-water interface

Organic matter control on the distribution of arsenic in lake sediments impacted by ~ 65 years of gold ore processing in subarctic Canada

Climate change is profoundly affecting seasonality, biological productivity, and hydrology in high northern latitudes. In sensitive subarctic environments exploitation of mineral resources led to contamination and it is not known how cumulative effects of resource extraction and climate warming will impact ecosystems. Gold mines near Yellowknife, Northwest Territories, subarctic Canada, operated from 1938 to 2004 and released > 20,000 t of arsenic trioxide (As2O3) to the environment through stack emissions. This release resulted in elevated arsenic concentrations in lake surface waters and sediments relative to Canadian drinking water standards and guidelines for the protection of aquatic life. A meta-analytical approach is used to better understand controls on As distribution in lake sediments within a 30-km radius of historic mineral processing activities. Arsenic concentrations in the near-surface sediments range from 5 mg·kg− 1 to over 10,000 mg·kg− 1 (median 81 mg·kg− 1; n = 105). Distance and direction from the historic roaster stack are significantly (p < 0.05) related to sedimentary As concentration, with highest As concentrations in sediments within 11 km and lakes located downwind. Synchrotron-based μXRF and μXRD confirm the persistence of As2O3 in near surface sediments of two lakes. Labile organic matter (S1) is significantly (p < 0.05) related to As and S concentrations in sediments and this relationship is greatest in lakes within 11 km from the mine. These relations are interpreted to reflect labile organic matter acting as a substrate for microbial growth and mediation of authigenic precipitation of As-sulphides in lakes close to the historic mine where As concentrations are highest. Continued climate warming is expected to lead to increased biological productivity and changes in organic geochemistry of lake sediments that are likely to play an important role in the mobility and fate of As in aquatic ecosystems

Repeated Training with Augmentative Vibrotactile Feedback Increases Object Manipulation Performance

Most users of prosthetic hands must rely on visual feedback alone, which requires visual attention and cognitive resources. Providing haptic feedback of variables relevant to manipulation, such as contact force, may thus improve the usability of prosthetic hands for tasks of daily living. Vibrotactile stimulation was explored as a feedback modality in ten unimpaired participants across eight sessions in a two-week period. Participants used their right index finger to perform a virtual object manipulation task with both visual and augmentative vibrotactile feedback related to force. Through repeated training, participants were able to learn to use the vibrotactile feedback to significantly improve object manipulation. Removal of vibrotactile feedback in session 8 significantly reduced task performance. These results suggest that vibrotactile feedback paired with training may enhance the manipulation ability of prosthetic hand users without the need for more invasive strategies

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought

Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension?

<p>Abstract</p> <p>Background</p> <p>Pulmonary hypertension (PH) is a life-threatening disease with poor prognosis. Encouraging efforts have been made to target the main vasoproliferative aspects of the disease. Promising emerging therapeutics are tyrosine kinase inhibitors such as imatinib.</p> <p>Case presentation</p> <p>Here, we discuss the relevance of previously published cases and add another well-characterised patient who developed pre-capillary PH under long-term therapy with the multi-tyrosine kinase inhibitor dasatinib approved for therapy of chronic myeloic leukaemia (CML) and Philadelphia chromosome positive acute lymphocytic leukaemia (mean time of all patients on dasatinib: 26 months). Hence, we discuss the possibility of dasatinib itself causing PH after long-term therapy and turn specialist's attention to this possible severe side effect.</p> <p>At present, the true incidence of dasatinib-associated PH remains illusive and systematic data regarding haemodynamics are missing.</p> <p>Conclusion</p> <p>We therefore recommend systematic screening of dasatinib-treated patients for pulmonary hypertension and subsequent collection of haemodynamic data.</p