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Mutually exclusive loss‐of‐function alterations in gene pairs are those that occur together less frequently than may be expected and may denote a synthetically lethal relationship (SSL) between the genes. SSLs can be exploited therapeutically to selectively kill cancer cells. Here, we analysed mutation, copy number variation, and methylation levels in samples from The Cancer Genome Atlas, using the hypergeometric and the Poisson binomial tests to identify mutually exclusive inactivated genes. We focused on gene pairs where one is an inactivated tumour suppressor and the other a gene whose protein product can be inhibited by known drugs. This provided an abundance of potential targeted therapeutics and repositioning opportunities for several cancers. These data are available on the MexDrugs website, https://bioinformaticslab.sussex.ac.uk/mexdrugs. [ABSTRACT FROM AUTHOR]

Cold‐water corals (CWCs) are important species that provide habitat for other taxa but are sensitive to mechanical damage from bottom trawling. CWC conservation has been implemented in the form of marine protected areas (MPAs), but recovery from impact may be particularly slow in the deep‐sea environment; consequently, the use of restoration techniques has been considered. To gain some insight into CWC recruitment and growth, in 2011 we deployed small seabed moorings in the Darwin Mounds MPA (~1,000 m water depth). This site hosts hundreds of CWC mounds, that had previously (until 2003) been impacted by deep‐water trawling. In 2019, we carried out in situ visual surveys of these moorings and the surrounding seabed environment, then recovered two of the moorings. The mooring buoys, glass floats with plastic covers, were extensively colonized by a diverse epifauna that included the CWCs Desmophyllum pertusum and D. dianthus. The presence of coral recruits indicated that environmental conditions, and larval supply, remained favorable for the settlement and growth of CWCs within the MPA. Based on our observations, we consider four possible restoration methods, together with a "do‐nothing" option, for the Darwin Mounds CWCs that have shown little, if any, natural recovery despite 16 years of protection. We conclude that seabed emplacement of high‐relief artificial substrata is likely to be the most efficient and cost‐efficient means of promoting enhanced recovery of the CWCs. [ABSTRACT FROM AUTHOR]

Complexity theory predicts that self‐organized, regularly patterned ecosystems store more biomass and are more resilient than spatially uniform systems. Self‐organized ecosystems are well‐known from the terrestrial realm, with "tiger bushes" being the archetypical example and mussel beds and tropical coral reefs the marine examples. We here identify regular spatial patterns in cold‐water coral reefs (nicknamed "tiger reefs") from video transects and argue that these are likely the result of self‐organization. We used variograms and Lomb–Scargle analysis of seven annotated video transects to analyze spatial patterns in live coral and dead coral (i.e., skeletal remains) cover at the Logachev coral mound province (NE Atlantic Ocean) and found regular spatial patterns with length scales between 62 and 523 m in live and dead coral distribution along these transects that point to self‐organization of cold‐water coral reefs. Self‐organization theory shows that self‐organized ecosystems can withstand large environmental changes by adjusting their spatial configuration. We found indications that cold‐water corals can similarly adjust their spatial configuration, possibly providing resilience in the face of climate change. Dead coral framework remains in the environment for extended periods of time, providing a template for spatial patterns that facilitates live coral recovery. The notion of regular spatial patterns in cold‐water coral reefs is interesting for cold‐water coral restoration, as transplantation will be more successful when it follows the patterns that are naturally present. This finding also underlines that anthropogenic effects such as ocean acidification and bottom trawling that destroy the dead coral template undermine cold‐water coral resilience. Differences in the pattern periodicities of live and dead coral cover further present an interesting new angle to investigate past and present environmental conditions in cold‐water coral reefs. [ABSTRACT FROM AUTHOR]

The deep sea is amongst the most food‐limited habitats on Earth, as only a small fraction (<4%) of the surface primary production is exported below 200 m water depth. Here, cold‐water coral (CWC) reefs form oases of life: their biodiversity compares with tropical coral reefs, their biomass and metabolic activity exceed other deep‐sea ecosystems by far. We critically assess the paradox of thriving CWC reefs in the food‐limited deep sea, by reviewing the literature and open‐access data on CWC habitats. This review shows firstly that CWCs typically occur in areas where the food supply is not constantly low, but undergoes pronounced temporal variation. High currents, downwelling and/or vertically migrating zooplankton temporally boost the export of surface organic matter to the seabed, creating 'feast' conditions, interspersed with 'famine' periods during the non‐productive season. Secondly, CWCs, particularly the most common reef‐builder Desmophyllum pertusum (formerly known as Lophelia pertusa), are well adapted to these fluctuations in food availability. Laboratory and in situ measurements revealed their dietary flexibility, tissue reserves, and temporal variation in growth and energy allocation. Thirdly, the high structural and functional diversity of CWC reefs increases resource retention: acting as giant filters and sustaining complex food webs with diverse recycling pathways, the reefs optimise resource gains over losses. Anthropogenic pressures, including climate change and ocean acidification, threaten this fragile equilibrium through decreased resource supply, increased energy costs, and dissolution of the calcium‐carbonate reef framework. Based on this review, we suggest additional criteria to judge the health of CWC reefs and their chance to persist in the future. [ABSTRACT FROM AUTHOR]

Degradation of the fungicide benzovindiflupyr was slow in standard regulatory laboratory studies in soil and aquatic systems, suggesting it is a persistent molecule. However, the conditions in these studies differed significantly from actual environmental conditions, particularly the exclusion of light, which prevents potential contributions from the phototrophic microorganisms that are ubiquitous in both aquatic and terrestrial environments. Higher tier laboratory studies that include a more comprehensive range of degradation processes can more accurately describe environmental fate under field conditions. Indirect aqueous photolysis studies with benzovindiflupyr showed that the photolytic half‐life in natural surface water can be as short as 10 days, compared with 94 days in pure buffered water. Inclusion of a light–dark cycle in higher tier aquatic metabolism studies, to include the contribution of phototrophic organisms, reduced the total system half‐life from >1 year in dark test systems to as little as 23 days. The relevance of these additional processes was confirmed in an outdoor aquatic microcosm study in which the half‐life of benzovindiflupyr was 13–58 days. In laboratory soil degradation studies, the degradation rate of benzovindiflupyr was significantly faster in cores with an undisturbed surface microbiotic crust, incubated in a light–dark cycle (half‐life of 35 days), than in regulatory studies with sieved soil in the dark (half‐life >1 year). A radiolabeled field study validated these observations, showing residue decline with a half‐life of approximately 25 days over the initial 4 weeks. Conceptual models of environmental fate based on standard regulatory studies may be incomplete, and additional higher tier laboratory studies can be valuable in elucidating degradation processes and improving the prediction of persistence under actual use conditions. Environ Toxicol Chem 2023;42:995–1009. © 2023 SETAC [ABSTRACT FROM AUTHOR]

Gene therapy holds great promise as a biomedicine for treating cancer, viral infection, and recessive gene disorders, while genetic detection has been used for disease diagnosis and prevention. The appropriate carrier is crucial to improve the delivery efficiency of nucleic acids. Although viral and non-viral delivery vectors have been developed, their poor nucleic acid loading efficiency, off-target toxicity, and immunogenicity significantly hamper their use. Metal-organic frameworks (MOFs) have attracted a lot of attention owing to their high surface areas and tunable structures. Recently, nano-metric MOFs are shown to be promising nonviral vectors in gene delivery and detection although at an early stage of development. This review focuses on highlighting the current status and promising breakthroughs of MOF use in nucleic acid delivery, including siRNA, miRNA and mRNA delivery, DNA gene delivery and transfection, as well as probes for detection of gene expression. This study will help promote the clinical transformation and application of gene modulation, gene delivery, and detection that use of MOFs can offer. [ABSTRACT FROM AUTHOR]

The foliar wash‐off coefficient is a parameter used by environmental fate models to estimate the amount of chemical removed from leaf surfaces by rainfall. In the European Union it is used by FOCUS surface water models to estimate soil loadings following rainfall after leaf surfaces have been treated with plant protection products. Currently, a default value of 0.5/cm is assumed for this parameter, although there is provision to provide experimental data to replace this default. The European Food Safety Authority proposed to increase the default parameter value to 1.0/cm. This increases the need for experimental refinement studies. However, no guidance for a harmonized protocol exists to estimate this parameter. We describe the results of a ring‐test conducted to start a process of developing a harmonized experimental protocol to measure the foliar wash‐off parameters, conducted by several laboratories across Europe. The proposed design uses whole plants (rather than individual leaves) to retain as much realism as possible. The extent of wash‐off is then determined by comparison of compound residues in two sets of plants (with and without a defined rainfall event) measured using a fully validated crop residue method. This initial ring test used tebuconazole (Folicur EW 250) sprayed at 100 g ai/ha onto tomato plants at BBCH25. Each laboratory measured the residues before and after a rainfall event of 20 mm/h for 1 h and calculated the percentage of wash‐off from these data. There was good agreement across the eight participating laboratories with a mean percentage of wash‐off of 66.8% and a 95% confidence interval of ±11.8%. Determination of robust wash‐off parameters was therefore considered feasible using the proposed test design. Environ Toxicol Chem 2023;42:535–541. © 2022 SETAC [ABSTRACT FROM AUTHOR]

The hypoxic tumour microenvironment (hTME), arising from inadequate and chaotic vascularity, can present a major obstacle for the treatment of solid tumours. Hypoxic tumour cells compromise responses to treatment since they can generate resistance to radiotherapy, chemotherapy and immunotherapy. The hTME impairs the delivery of a range of anti‐cancer drugs, creates routes for metastasis and exerts selection pressures for aggressive phenotypes; these changes potentially occur within an immunosuppressed environment. Therapeutic strategies aimed at the hTME include targeting the molecular changes associated with hypoxia. An alternative approach is to exploit the prevailing lack of oxygen as a principle for the selective activation of prodrugs to target cellular components within the hTME. This review focuses on the design concepts and rationale for the use of unidirectional Hypoxia‐Activated Prodrugs (uHAPs) to target the hTME as exemplified by the uHAPs AQ4N and OCT1002. These agents undergo irreversible reduction in a hypoxic environment to active forms that target DNA topoisomerase IIα (TOP2A). This nuclear enzyme is essential for cell division and is a recognised chemotherapeutic target. An activated uHAP interacts with the enzyme‐DNA complex to induce DNA damage, cell cycle arrest and tumour cell death. uHAPs are designed to overcome the shortcomings of conventional HAPs and offer unique pharmacodynamic properties for effective targeting of TOP2A in the hTME. uHAP therapy in combination with standard of care treatments has the potential to enhance outcomes by co‐addressing the therapeutic challenge presented by the hTME. [ABSTRACT FROM AUTHOR]

Background and Purpose: Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia‐induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia‐activated prodrug of lidocaine. Experimental Approach The rat Langendorff‐perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine. Key Results: In isolated hearts, OCT2013 and lidocaine prevented ischaemia‐induced VF equi‐effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi‐effectively; OCT2013 had no effect on cardiac output even at 64 mg·kg−1 i.v., whereas lidocaine reduced it even at 1 mg·kg−1. In adult rat ventricular myocytes, OCT2013 had no effect on Ca2+ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate‐dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi‐effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013‐perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable. Conclusions and Implications: OCT2013 is inactive but is bio‐reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia‐activated and ischaemia‐selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity. [ABSTRACT FROM AUTHOR]

Purpose: To provide a new approach to jointly assess microstructural and molecular properties of the human placenta in vivo fast and efficiently and to present initial evidence in cohorts of healthy pregnancies and those affected by pre‐eclampsia. Methods: Slice and diffusion preparation shuffling, built on the previously proposed ZEBRA method, is presented as a robust and fast way to obtain T1 and apparent diffusivity coefficient (ADC) values. Joint modeling and evaluation is performed on a cohort of healthy and pre‐eclamptic participants at 3T. Results: The datasets show the ability to obtain robust and fast T1‐ADC measurements. Significant decay over gestation in T1 (−11 ms/week, P<.05) and a trend toward significance in ADC (−0.23 mm/s2/week, P =.08) values can be observed in a control cohort. Values for the pre‐eclamptic pregnancies show a negative trend for both ADC and T1. Conclusions: The presented sequence allows the simultaneous acquisition of 2 of the most promising quantitative parameters to study placental insufficiency—identified individually as relevant in previous studies—in under 2 minutes. This allows dynamic assessment of physiological processes, reduced inconsistency in spatial comparisons due to reduced motion artefacts and opens novel avenues for analysis. Initial results in pre‐eclamptic placentas, with depicted changes in both ADC and T1, illustrate its potential to identify cases of placental insufficiency. Future work will focus on expanding the field‐of‐view using multi‐band acceleration techniques and the expansion to larger and more diverse patient groups. [ABSTRACT FROM AUTHOR]

Degradation of agrochemicals in soil is frequently faster under field conditions than in laboratory studies. Field studies are carried out on relatively undisturbed soil, whereas laboratory studies typically use sieved soil, which can have a significant impact on the physical and microbial nature of the soil and may contribute to differences in degradation between laboratory and field studies. A laboratory study was therefore conducted to determine the importance of soil structure and variable soil moisture on the degradation of 2 fungicides (azoxystrobin and paclobutrazol) that show significant differences between laboratory and field degradation rates in regulatory studies. Degradation rates were measured in undisturbed cores of a sandy clay loam soil (under constant or variable moisture contents) and in sieved soil. For azoxystrobin, degradation rates under all conditions were similar (median degradation time [DegT50] 34–37 d). However, for paclobutrazol, degradation was significantly faster in undisturbed cores (DegT50 255 d in sieved soil and 63 d in undisturbed cores). Varying the moisture content did not further enhance degradation of either fungicide. Further examination into the impact of soil structure on paclobutrazol degradation, comparing undisturbed and sieved/repacked cores, revealed that the impact of sieving could not be mitigated by repacking the soil to a realistic bulk density. Examination of fungal and bacterial community structure using automated ribosomal spacer analysis showed significant initial differences between sieved/repacked and intact soil cores, although such differences were reduced at the end of the study (70 d). The present study demonstrates that disruption of soil structure significantly impacts microbial community structure, and for some compounds this may explain the differences between laboratory and field degradation rates. Environ Toxicol Chem 2021;40:2715–2725. © 2021 SETAC [ABSTRACT FROM AUTHOR]

Background: Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np‐LMS), including local recurrences and distant metastases. Methods: TP53, RB1, p16, and PTEN expression aberrations were determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 227 np‐LMS and a comparison group of 262 primary leiomyosarcomas (p‐LMS). Thirty‐five of the np‐LMS had a matched p‐LMS specimen in the TMAs. Correlative studies included differentiation scoring, ER and PR IHC, and CDKN2A/p16 fluorescence in situ hybridization. Results: Dysregulation of TP53, p16/RB1, and PTEN was demonstrated in 90%, 95%, and 41% of np‐LMS, respectively. PTEN inactivation was more common in soft tissue np‐LMS than uterine np‐LMS (55% vs 31%; P =.0005). Moderate‐strong ER expression was more common in uterine np‐LMS than soft tissue np‐LMS (50% vs 7%; P <.0001). Co‐inactivation of TP53 and RB1 was found in 81% of np‐LMS and was common in both soft tissue and uterine np‐LMS (90% and 74%, respectively). RB1, p16, and PTEN aberrations were nearly always conserved in p‐LMS and np‐LMS from the same patients. Conclusions: These studies show that nearly all np‐LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS. Aberrations of TP53, p16/RB1, and PTEN are found in 90%, 95%, and 41% of metastatic soft tissue and uterine leiomyosarcomas, respectively, with PTEN inactivation being more common in soft tissue cases. These key aberrations are generally conserved between primary and metastatic disease in a given patient. [ABSTRACT FROM AUTHOR]

Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning but are challenging to obtain. Here, manganese, a calcium analogue and clinically approved magnetic resonance imaging (MRI) contrast agent, is used as an imaging biomarker of myocardial viability in the first hours after experimental MI. Safe Mn2+ dosing is confirmed by measuring in vitro beating rates, calcium transients, and action potentials in cardiomyocytes, and in vivo heart rates and cardiac contractility in mice. Quantitative T1 mapping‐manganese‐enhanced MRI (MEMRI) reveals elevated and increasing Mn2+ uptake in viable myocardium remote from the infarct, suggesting MEMRI offers a quantitative biomarker of cardiac inotropy. MEMRI evaluation of infarct size at 1 h, 1 and 14 days after MI quantifies myocardial viability earlier than the current gold‐standard technique, late‐gadolinium‐enhanced MRI. These data, coupled with the re‐emergence of clinical Mn2+‐based contrast agents open the possibility of using MEMRI for direct evaluation of myocardial viability early after ischemic onset in patients. [ABSTRACT FROM AUTHOR]

Lung cancer is a serious threat to human health with the highest morbidity and mortality; metastatic lung cancer accounts for a majority of cancer‐related deaths. Hence, there is considerable interest in developing efficient lung‐targeted drug delivery systems to improve overall survival and quality of life of lung cancer patients. Based on the lung‐targeting characteristics of cubic crosslinked cyclodextrin metal–organic framework (CDF) nanoparticles, this study shows the synthesis of a nanoplatform using RGD‐functionalized CDF to co‐deliver low‐molecular‐weight heparin (LMWH) and doxorubicin (DOX) for treatment of lung cancer. Rational design of the DOX‐loaded RGD‐CDF‐LMWH nanoplatform (RCLD) is carried out. RCLD nanoparticles are efficiently targeted to lung tumors following intravenous administration; RCLD accumulation in the lung is 5.8 times greater than that in the liver. Moreover, RCLD inhibits migration and invasion of cancer cells in vitro and significantly diminishes lung tumor nodule count and area of spread in human A549 and murine B16F10 lung cancer models in vivo. Furthermore, RCLD does not show serum enzyme or histopathologic indicators of tissue damage or adverse hematologic effects. Therefore, the multiple antitumor activities of this novel RCLD nanoplatform, alongside its safety profile for normal tissues, strongly support its use for targeted treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: Placental function is key for successful human pregnancies. Perfusion may be a sensitive marker for the in vivo assessment of placental function. Arterial spin labeling (ASL) MRI enables noninvasive measurement of tissue perfusion and it was recently suggested that ASL with velocity‐selective (VS) labeling could be advantageous in the placenta. We systematically evaluated essential VS‐ASL sequence parameters to determine optimal settings for efficient placental perfusion measurements. Methods: Eleven pregnant women were scanned at 3T using VS‐ASL with 2D multislice echo planar imaging (EPI)‐readout. One reference VS‐ASL scan was acquired in all subjects; within subgroups the following parameters were systematically varied: cutoff velocity, velocity encoding direction, and inflow time. Visual evaluation and region of interest analyses were performed to compare perfusion signal differences between acquisitions. Results: In all subjects, a perfusion pattern with clear hyperintense focal regions was observed. Perfusion signal decreased with inflow time and cutoff velocity. Subject‐specific dependence on velocity encoding direction was observed. High temporal signal‐to‐noise ratios with high contrast on the perfusion images between the hyperintense regions and placental tissue were seen at ~1.6 cm/s cutoff velocity and ~1000 ms inflow time. Evaluation of measurements at multiple inflow times revealed differences in blood flow dynamics between placental regions. Conclusion: Placental perfusion measurements are feasible at 3T using VS‐ASL with 2D multislice EPI‐readout. A clear dependence of perfusion signal on VS labeling parameters and inflow time was demonstrated. Whereas multiple parameter combinations may advance the interpretation of placental circulation dynamics, this study provides a basis to select an effective set of parameters for the observation of placenta perfusion natural history and its potential pathological changes. [ABSTRACT FROM AUTHOR]

African elephants have major impacts on vegetation, particularly at high densities. Knob‐thorns (Senegalia nigrescens) are typically ring‐barked by elephant, and high levels of mortality are common at high elephant densities. Our study aimed to test whether ivory palm clusters (Hyphaene petersiana) form a biotic refuge for knob‐thorn against elephant herbivory. We measured the density, damage and mortality of knob‐thorns in sites differing according to ivory palm presence and elephant density, and thus, the probability of knob‐thorn encounter by elephants. The site with palms and low elephant density, had a high density of knob‐thorns, but lower proportions of damaged and dead trees, than sites without palms but with similar or higher elephant density. In the former, knob‐thorns were associated with palm clusters, particularly saplings and young adults. In this site, low proportions of damaged and dead knob‐thorns were recorded in palm clusters, compared with outside clusters, and to those in the other sites. Our study also showed that juvenile palms which protected knob‐thorns, suffered low mortality in contrast to subadult palms. We have no evidence but implicate elephants and suggest that in palm clusters, subadult palms are more accessible to elephants than knob‐thorns because of the different methods of utilisation. [ABSTRACT FROM AUTHOR]

Plant protection products (PPPs) undergo rigorous regulatory assessment to ensure that they do not pose unacceptable risks to the environment. Elucidation of their fate and behavior in soil is an integral part of this environmental risk assessment. The active substance degradation in soil of PPPs is first assessed in laboratory studies (typically following Organisation for Economic Co‐operation and Development [OECD] test guideline 307). Conditions in guideline laboratory studies are far removed from those occurring under agricultural use, and the contribution of crop roots has currently not been assessed. We integrated viable plant root systems, representative of 3 different crop types, into the OECD test guideline 307 design to assess their impact on the dissipation of the herbicide prometryn. Significantly faster decline of parent residue and higher formation of nonextractable residues were observed in all 3 planted systems. This led to a reduction in the time required for 50% of the compound to dissipate (DT50) of approximately one‐half in the presence of rye grass and hot pepper and of approximately one‐third in the presence of red clover. These findings imply that plants and their associated root networks can have a significant influence on PPP dissipation. Based on these data, greater environmental realism could be added to the standardized laboratory study design by the inclusion of plant root systems into higher tier studies, which, in turn, could serve to improve the environmental risk assessment process. Environ Toxicol Chem 2020;39:450–457. © 2019 SETAC [ABSTRACT FROM AUTHOR]

Purpose: To study placental function—both perfusion and an oxygenation surrogate (T2*)—simultaneously and quantitatively in‐vivo. Methods: Fifteen pregnant women were scanned on a 3T MR scanner. For perfusion measurements, a velocity selective arterial spin labeling preparation module was placed before a multi‐echo gradient echo EPI readout to integrate T2* and perfusion measurements in 1 joint perfusion‐oxygenation (PERFOX) acquisition. Joint motion correction and quantification were performed to evaluate changes in T2* and perfusion over GA. Results: The optimized integrated PERFOX protocol and post‐processing allowed successful visualization and quantification of perfusion and T2* in all subjects. Areas of high T2* and high perfusion appear to correspond to placental sub‐units and show a systematic offset in location along the maternal‐fetal axis. The areas of highest perfusion are consistently closer to the maternal basal plate and the areas of highest T2* closer to the fetal chorionic plate. Quantitative results show a strong negative correlation of gestational age with T2* and weak negative correlation with perfusion. Conclusions: A strength of the joint sequence is that it provides truly simultaneous and co‐registered estimates of local T2* and perfusion, however, to achieve this, the time per slice is prolonged compared to a perfusion only scan which can potentially limit coverage. The achieved interlocking can be particularly useful when quantifying transient physiological effects such as uterine contractions. PERFOX opens a new avenue to elucidate the relationship between maternal supply and oxygen uptake, both of which are central to placental function and dysfunction. [ABSTRACT FROM AUTHOR]

Background: Active surveillance (AS) is an accepted means of managing low-risk prostate cancer. Because of the rarity of downstream events, data from existing AS cohorts cannot yet address how differences in surveillance intensity affect metastasis and mortality. This study projected the comparative benefits of different AS schedules in men diagnosed with prostate cancer who had Gleason score (GS) ≤6 disease and risk profiles similar to those in North American AS cohorts.Methods: Times of GS upgrading were simulated based on AS data from the University of Toronto, Johns Hopkins University, the University of California at San Francisco, and the Canary Pass Active Surveillance Cohort. Times to metastasis and prostate cancer death, informed by models from the Scandinavian Prostate Cancer Group 4 trial, were projected under biopsy surveillance schedules ranging from watchful waiting to annual biopsies. Outcomes included the risk of metastasis, the risk of death, remaining life-years (LYs), and quality-adjusted LYs.Results: Compared with watchful waiting, AS biopsies reduced the risk of prostate cancer metastasis and prostate cancer death at 20 years by 1.4% to 3.3% and 1.0% to 2.4%, respectively; and 5-year biopsies reduced the risk of metastasis and prostate cancer death by 1.0% to 2.4% and 0.6% to 1.6%, respectively. There was little difference between annual and 5-year biopsy schedules in terms of LYs (range of differences, 0.04-0.16 LYs) and quality-adjusted LYs (range of differences, -0.02 to 0.09 quality-adjusted LYs).Conclusions: Among men diagnosed with GS ≤6 prostate cancer, obtaining a biopsy every 3 or 4 years appears to be an acceptable alternative to more frequent biopsies. Reducing surveillance intensity for those who have a low risk of progression reduces the number of biopsies while preserving the benefit of more frequent schedules. [ABSTRACT FROM AUTHOR]

Scar formation after wound healing is a major medical problem. A better understanding of the dynamic nuclear architecture of the genome during wound healing could provide insights into the underlying pathophysiology and enable novel therapeutic strategies. Here, we demonstrate that TGF‐β‐induced fibrotic stress increases formation of the dynamic secondary DNA structures called G‐quadruplexes in skin fibroblasts, which is coincident with increased expression of collagen 1. This G‐quadruplex formation is attenuated by a small molecule inhibitor of intracellular Ca2+ influx and an anti‐fibrotic compound. In addition, we identify G‐quadruplex‐forming sequences in the promoter region of COL1A1, which encodes collagen 1, and confirm their ability to form G‐quadruplex structures under physiologically relevant conditions. Our findings reveal a link between G‐quadruplexes and scar formation that may lead to novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Purpose: A combined diffusion‐relaxometry MR acquisition and analysis pipeline for in vivo human placenta, which allows for exploration of coupling between T2* and apparent diffusion coefficient (ADC) measurements in a sub 10‐minute scan time. Methods: We present a novel acquisition combining a diffusion prepared spin echo with subsequent gradient echoes. The placentas of 17 pregnant women were scanned in vivo, including both healthy controls and participants with various pregnancy complications. We estimate the joint T2*‐ADC spectra using an inverse Laplace transform. Results: T2*‐ADC spectra demonstrate clear quantitative separation between normal and dysfunctional placentas. Conclusions: Combined T2*‐diffusivity MRI is promising for assessing fetal and maternal health during pregnancy. The T2*‐ADC spectrum potentially provides additional information on tissue microstructure, compared to measuring these two contrasts separately. The presented method is immediately applicable to the study of other organs. [ABSTRACT FROM AUTHOR]

The thrombospondin type‐1 domain containing 7A (THSD7A) protein is known to be one of the antigens responsible for the autoimmune disorder idiopathic membranous nephropathy. The structure of this antigen is currently unsolved experimentally. Here we present a homology model of the extracellular portion of the THSD7A antigen. The structure was evaluated for folding patterns, epitope site prediction, and function was predicted. Results show that this protein contains 21 extracellular domains and with the exception of the first two domains, has a regular repeating pattern of TSP‐1‐like followed by F‐spondin‐like domains. Our results indicate the presence of a novel Trp‐ladder sequence of WxxxxW in the TSP‐1‐like domains. Of the 21 domains, 18 were shown to have epitope binding sites as predicted by epitopia. Several of the F‐spondin‐like domains have insertions in the canonical TSP fold, most notably the coiled coil region in domain 4, which may be utilized in protein‐protein binding interactions, suggesting that this protein functions as a heparan sulfate binding site. [ABSTRACT FROM AUTHOR]

In a recent article published in this Journal Burton Zwick [6] investigates the implications of the interest-induced wealth effect for the response of interest rates to monetary change and to changes in the expected inflation rate. He argues that the introduction of the interest-induced wealth effect into an otherwise conventional macroeconomic model can explain the complete snap-back of interest rates to their original level after a monetary change but prior to a complete adjustment of the price level and the delay in the response of nominal interest rates to a change in the expected inflation rate. He also explores the implications of the interest-induced wealth effect for the existence of neutrality and the dynamic adjustment of interest rates to monetary change at full employment. Zwick's analysis of the interest induced wealth effect is flawed in three ways: (1) He incorrectly integrates the interest-induced wealth effect into his IS-LM framework. (2) Although Zwick's model with wealth effects includes both price and interest-induced wealth effects, Zwick ignores the implications of the price-induced wealth effect. Therefore, his comparative static results for increases in the money supply and the expected inflation rate are inconsistent with the model he presents; and (3) Zwick misspecifies his wealth variable. He assumes that the nominal value of real assets is unaffected by changes in the price level and that the valuation of real assets is affected by nominal rather than real interest rates. [ABSTRACT FROM AUTHOR]

Diastolic dysfunction is a sensitive early indicator of heart failure and can provide additional data to conventional measures of systolic function. Transmitral Doppler ultrasound, which measures the one-dimensional flow of blood through the mitral valve, is currently the preferred method for the measurement of diastolic function, but the measurement of the left ventricular volume changes using high-temporal-resolution cinematic magnetic resonance imaging (CINE MRI) is an alternative approach which is emerging as a potentially more robust and user-independent technique. Here, we investigated the performance of high-temporal-resolution CINE MRI and compared it with ultrasound for the detection of diastolic dysfunction in a mouse model of myocardial infarction. An in-house, high-temporal-resolution, retrospectively gated CINE sequence was developed with a temporal resolution of 1 ms. Diastolic function in mice was assessed using a custom-made, open-source reconstruction package. Early (E) and late (A) left ventricular filling phases were easily identifiable, and these measurements were compared directly with high-frequency, pulsed-wave, Doppler ultrasound measurements of mitral valve inflow. A repeatability study established that high-temporal-resolution CINE MRI and Doppler ultrasound showed comparable accuracy when measuring E/A in normal control mice. However, when applied in a mouse model of myocardial infarction, high-temporal-resolution CINE MRI indicated diastolic heart failure (E/A = 0.94 ± 0.11), whereas ultrasound falsely detected normal cardiac function (E/A = 1.21 ± 0.11). The addition of high-temporal-resolution CINE MRI to preclinical imaging studies enhances the library of sequences available to cardiac researchers and potentially identifies diastolic heart failure early in disease progression. [ABSTRACT FROM AUTHOR]

Background Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of viable but nonculturable ( VBNC) H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne VBNC H. pylori could cause gastric infection. Materials and Methods We performed five mouse experiments to assess the infectivity of VBNC H. pylori in various exposure scenarios. VBNC viability was examined using Live/Dead staining and Biolog phenotype metabolism arrays. High doses of VBNC H. pylori in water were chosen to test the 'worst-case' scenario for different periods of time. One experiment also investigated the infectious capabilities of VBNC SS1 using gavage. Further, immunocompromised mice were exposed to examine infectivity among potentially vulnerable groups. After exposure, mice were euthanized and their stomachs were examined for H. pylori infection using culture and PCR methodology. Results VBNC cells were membrane intact and retained metabolic activity. Mice exposed to VBNC H. pylori via drinking water and gavage were not infected, despite the various exposure scenarios (immunocompromised, high doses) that might have permitted infection with VBNC H. pylori. The positive controls exposed to viable, culturable H. pylori did become infected. Conclusions While other studies that have used viable, culturable SS1 via gavage or drinking water exposures to successfully infect mice, in our study, waterborne VBNC SS1 failed to colonize mice under all test conditions. Future studies could examine different H. pylori strains in similar exposure scenarios to compare the relative infectivity of the VBNC vs the viable, culturable state, which would help inform future risk assessments of H. pylori in water. [ABSTRACT FROM AUTHOR]

Background: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed.Methods: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined.Results: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma.Conclusions: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

ABSTRACT The HSP90 molecular chaperone is involved in the activation and cellular stabilization of a range of 'client' proteins, of which oncogenic protein kinases and nuclear steroid hormone receptors are of particular biomedical significance. Work over the last two decades has revealed a conformational cycle critical to the biological function of HSP90, coupled to an inherent ATPase activity that is regulated and manipulated by many of the co-chaperones proteins with which it collaborates. Pharmacological inhibition of HSP90 ATPase activity results in degradation of client proteins in vivo, and is a promising target for development of new cancer therapeutics. Despite this, the actual function that HSP90s conformationally-coupled ATPase activity provides in its biological role as a molecular chaperone remains obscure. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 594-607, 2016. [ABSTRACT FROM AUTHOR]

Lysimeter studies can be used to identify and quantify soil degradates of agrochemicals (metabolites) that have the potential to leach to groundwater. However, the apparent metabolic profile of such lysimeter leachate samples will often be significantly more complex than would be expected in true groundwater samples. This is particularly true for S-metolachlor, which has an extremely complex metabolic pathway. Consequently, it was not practically possible to apply a conventional analytical approach to identify all metabolites in an S-metolachlor lysimeter study, because there was insufficient mass to enable the use of techniques such as nuclear magnetic resonance. Recent advances in high-resolution accurate mass spectrometry, however, allow innovative screening approaches to characterize leachate samples to a greater extent than previously possible. Leachate from the S-metolachlor study was screened for accurate masses (±5 ppm of the nominal mass) corresponding to more than 400 hypothetical metabolite structures. A refined list of plausible metabolites was constructed from these data to provide a comprehensive description of the most likely metabolites present. The properties of these metabolites were then evaluated using a principal component analysis model, based on molecular descriptors, to visualize the entire chemical space and to cluster the metabolites into a number of subclasses. This characterization and principal component analysis evaluation enabled the selection of suitable representative metabolites that were subsequently used as exemplars to assess the toxicological relevance of the leachate as a whole. Environ Toxicol Chem 2016;35:1401-1412. © 2015 SETAC [ABSTRACT FROM AUTHOR]

Previous studies that have assessed the association of pre-transplant antiphospholipase A2 receptor autoantibody ( PLA2R-Ab) concentration with a recurrence of membranous nephropathy ( rMN) post-kidney transplant have yielded variable results. We tested 16 consecutive transplant patients with a history of iMN for pre-transplant PLA2R-Ab. Enzyme-linked immunosorbent assay titers (Euroimmun, NJ, USA) >14 RU/mL were considered positive. A receiver operating characteristic ( ROC) analysis was performed after combining data from Quintana et al. (n = 21; Transplantation February 2015) to determine a PLA2R-Ab concentration which could predict rMN. Six of 16 (37%) patients had biopsy-proven rMN at a median of 3.2 yr post-transplant. Of these, five of six (83%) had a positive PLA2R-Ab pre-transplant with a median of 82 RU/mL (range = 31-1500). The only patient who had rMN with negative PLA2R-Ab was later diagnosed with B-cell lymphoma. One hundred percent (n = 10) of patients with no evidence of rMN (median follow-up = five yr) had negative pre-transplant PLA2R-Ab. In a combined ROC analysis (n = 37), a pre-transplant PLA2R-Ab > 29 RU/mL predicted rMN with a sensitivity of 85% and a specificity of 92%. Pre-transplant PLA2R-Ab could be a useful tool for the prediction of rMN. Patients with rMN in the absence of PLA2R-Ab should be screened for occult malignancy and/or alternate antigens. [ABSTRACT FROM AUTHOR]

Background: Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma.Methods: Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%.Results: A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited clinical benefit. The probability that the CBR was ≥25% in the LMS and UPS cohorts was 0.008 and 0.10, respectively. The median progression-free survival ranged from 0.9 months in patients with rhabdomyosarcoma to 2.2 months in patients with LMS. The median overall survival was 8.6 months. The most frequent adverse events were constitutional, gastrointestinal, and respiratory, and 36% of patients required dose reduction for toxicity. Serious adverse events attributed to therapy occurred in 11% of patients.Conclusions: Dasatinib may have activity in patients with UPS but is inactive as a single agent in the other sarcoma subtypes included herein. The Bayesian design allowed for the early termination of accrual in 5 subtypes because of lack of drug activity. [ABSTRACT FROM AUTHOR]

Resource use of Cape mountain zebra was studied in the Baviaanskloof Nature Reserve (BNR) over concerns of the poor performance in population growth. We assessed the seasonal diet, habitat suitability and forage quality of the Bergplaas area in BNR for mountain zebra. Grasses contributed 95.2% to the annual diet of mountain zebra, Tristachya leucothrix contributing the most (39.4%), followed by Themeda triandra (27.6%). Seasonally, T. triandra contributed most to the diet in winter, while T. leucothrix became more important in the summer and also was the only species preferred in all seasons. Mountain zebra concentrated their feeding in Kouga Grassy Fynbos and from our assessment this was the only habitat suitable for mountain zebra. Our analysis of mountain zebra dung indicated that the seasonal nitrogen and phosphorus content was below the threshold values prescribed for grazers, and our study suggests that mountain zebra at Bergplaas are severely resource limited. We emphasize the importance of fire and access to nutrient-rich lowlands in influencing the nutritional ecology of mountain zebra and provide conservation management recommendations. [ABSTRACT FROM AUTHOR]

Soil surface photolysis can be a significant dissipation pathway for agrochemicals under field conditions, although it is assumed that such degradation ceases once the agrochemical is transported away from the surface following rainfall or irrigation and subsequent drainage of soil porewater. However, as both downward and upward water movements occur under field conditions, relatively mobile compounds may return to the surface, prolonging exposure to ultraviolet light and increasing the potential for degradation by photolysis. To test this hypothesis, a novel experimental system was used to quantify the contribution of photolysis to the overall dissipation of a new herbicide, bicyclopyrone, under conditions that mimicked field studies more closely than the standard laboratory test guidance. Soil cores were taken from 3 US field study sites, and the surfaces were treated with [14C]-bicyclopyrone. The radioactivity was redistributed throughout the cores using a simulated rainfall event, following which the cores were incubated under a xenon-arc lamp with continuous provision of moisture from below and a wind simulator to induce evaporation. After only 2 d, most of the test compound had returned to the soil surface. Significantly more degradation was observed in the irradiated samples than in a parallel dark control sample. Degradation rates were very similar to those observed in both the thin layer photolysis study and the field dissipation studies and significantly faster than in the soil metabolism studies conducted in the dark. Thus, for highly soluble, mobile agrochemicals, such as bicyclopyrone, photolysis is not terminated permanently by rainfall or irrigation but can resume following transport to the surface in evaporating water. Environ Toxicol Chem 2015;34:2236-2243. © 2015 SETAC [ABSTRACT FROM AUTHOR]

Background Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne H. pylori could cause gastric infection. Materials and Methods Groups of immunocompetent C57/ BL6 Helicobacter-free mice were exposed to static concentrations (1.29 × 105, 106, 107, 108, and 109 CFU/L) of H. pylori in their drinking water for 4 weeks. One group of Helicobacter-free mice was exposed to uncontaminated water as a negative control. H. pylori morphology changes in water were examined using microscopy Live/Dead staining. Following exposure, H. pylori infection and inflammation status in the stomach were evaluated using quantitative culture, PCR, the rapid urease test, and histology. Results None of the mice in the negative control or 105 groups were infected. One of 20 cages (one of 40 mice) of the 106 group, three of 19 cages (four of 38 mice) of the 107 CFU/L group, 19 of 20 cages (33 of 40 mice) of the 108 group, and 20 of 20 cages (39 of 40 mice) of the 109 CFU/L group were infected. Infected mice had significantly higher gastric inflammation than uninfected mice (27.86% higher inflammation, p < .0001). Conclusions We offer proof that H. pylori in water is infectious in mice, suggesting that humans drinking contaminated water may be at risk of contracting H. pylori infection. Much work needs to be performed to better understand the risk of infection from drinking H. pylori-contaminated water. [ABSTRACT FROM AUTHOR]

Specific co-chaperone adaptors facilitate the recruitment of client proteins to the Hsp90 system. Tah1 binds the C-terminal conserved MEEVD motif of Hsp90, thus linking an eclectic set of client proteins to the R2TP complex for their assembly and regulation by Hsp90. Rather than the normal complement of seven α-helices seen in other tetratricopeptide repeat (TPR) domains, Tah1 unusually consists of the first five only. Consequently, the methionine of the MEEVD peptide remains exposed to solvent when bound by Tah1. In solution Tah1 appears to be predominantly monomeric, and recent structures have failed to explain how Tah1 appears to prevent the formation of mixed TPR domain-containing complexes such as Cpr6-(Hsp90)2-Tah1. To understand this further, the crystal structure of Tah1 in complex with the MEEVD peptide of Hsp90 was determined, which shows a helix swap involving the fifth α-helix between two adjacently bound Tah1 molecules. Dimerization of Tah1 restores the normal binding environment of the bound Hsp90 methionine residue by reconstituting a TPR binding site similar to that in seven-helix-containing TPR domain proteins. Dimerization also explains how other monomeric TPR-domain proteins are excluded from forming inappropriate mixed co-chaperone complexes. [ABSTRACT FROM AUTHOR]

Reasons for performing study Evaluation of erythrocyte regeneration in horses is challenging, as they do not release reticulocytes into the peripheral blood. This study investigated transferrin receptor 1 ( TfR1) expression in exosomes as a noninvasive method of characterising the regenerative response in anaemic horses. Objectives To quantify TfR1 in ultraprecipitate of serum in horses before and after phlebotomy-induced anaemia, and to identify exosomes as the source of TfR1. The hypothesis was that serum exosomal TfR1 expression would increase during a regenerative response. Study design Experimental model of anaemia. Methods Six horses were phlebotomised to achieve a 25% decrease in packed cell volume. Transferrin receptor 1 quantity in exosomes was determined by western blot and relative densitometry before and after phlebotomy. The size and density of the TfR1-associated particles were confirmed by transmission electron microscopy and density gradient centrifugation, respectively. Results Regenerative anaemia was confirmed by decreased packed cell volumes and decreased myeloid:erythroid ratios in the bone marrow. In all 6 horses, TfR1 expression increased between Days 7 and 10. Mean TfR1 levels peaked on Day 10 and at 3-fold higher than levels on Day 0. Appropriately sized particles were evident on transmission electron microscopy and sucrose density gradient fractions expected to contain exosomes also contained TfR1. Conclusions These data indicate that TfR1 expression in serum exosomes may provide a marker for regeneration in anaemic horses. [ABSTRACT FROM AUTHOR]

A 61-year-old man with a history of fish bone ingestion and poorly localized symptoms was seen. His clinical examination was unremarkable, but CT demonstrated a foreign body deeply embedded within his tongue. Intraoperative ultrasound (US) guidance facilitated identification of a bone, allowing a needle to be placed as a guide to dissection. Repeat US scanning through the incision permitted precisely targeted surgery. CT and US are the most effective imaging techniques for localizing fish bones. Intraoperative US can be used to accurately locate a submucosal fish bone in mobile tissue such as the tongue, and focused, image-guided dissection can reduce surgical tissue trauma. [ABSTRACT FROM AUTHOR]

A surface water mineralization study (according to the Organisation for Economic Co-operation and Development [OECD] guideline OECD 309) is a new requirement in European Union agrochemical regulations; therefore, industry has little experience with this test. The guideline allows for a number of options within the test design, notably the options to conduct the study under diffuse light and to include an inoculum of suspended sediment. The present study was designed to investigate the potential impact of these options on the degradation rate of a representative compound. The fungicide, isopyrazam, was chosen as it was previously shown to be susceptible to metabolism by phototrophic organisms under a fluorescent light-dark cycle. The impact of diffuse light was investigated at light intensities representative of those at depth in large, open water bodies (<7% of the incident intensity), and it was demonstrated that metabolism of isopyrazam by phototrophic microorganisms was rapid (median degradation time for 50% of the test compound [DT50] < 50 d), whereas degradation in continuous darkness was negligible. Furthermore, investigation at 2 different light intensities resulted in similar degradation rates, indicating that this transformation mechanism was not proportional to light intensity, provided that there was sufficient light for photosynthesis to occur. Inclusion of suspended sediment did not have a significant impact on the degradation rate of isopyrazam, except at extremely high sediment concentrations, which were not considered representative of conditions in large, open water bodies. Environ Toxicol Chem 2014;33:516-524. © 2013 SETAC [ABSTRACT FROM AUTHOR]

Polysialylation of neural cell adhesion molecule (NCAM) in small-cell lung cancer (SCLC) is thought to regulate NCAM-mediated cell-surface interactions, imparting antiadhesive properties to cells. However, SCLC cells in culture demonstrate anchorage-independent growth and spontaneously generate adherent forms. Here, the ability of polySia-NCAM to influence cell proliferation and adherence is unclear. We analyzed live SCLC cell polySia-NCAM expression by flow cytometry, using the novel combination of a polySia antibody-mimetic eGFP-tagged endosialidase and the viability dye DRAQ7. Enrichment for adherence (<30 population doublings) in SCLC cell lines resolved populations with increased (SHP-77 and COR-L279) or negligible (NCI-H69) polysialylation compared with nonadherent parent populations. Adherent forms retained NCAM expression as confirmed by immunofluorescence and immunoblotting. Initial transition to adherence and loss of polysialylation in NCI-H69 was linked to a reduced proliferation rate with no increase in cell death. This reduced proliferation rate was reiterated in vivo as determined by the growth of noninvasive subcutaneous xenografts in mice. Continued selection for enhanced substrate adherence in NCI-H69 (>150 population doublings) resolved cells with stable re-expression of polySia and increased growth rates both in vitro and in vivo. Endoneuraminidase removal of polySia from re-expressing cells showed that rapid adherence to extracellular matrix components was functionally independent of polySia. PolySia expression was not altered when isolated adherent forms underwent enforced cell-cell contact in three-dimensional culture. Coculture of polySia expression variants modulated overall polySia expression profiles indicating an influence of SCLC microcommunity composition independent of substrate adherence potential. We conclude that an obligatory linkage between substrate adherence potential and polySia expression is rejected for SCLC cells. We suggest that a degree of homeostasis operates to regulate polysialylation within heterogeneous cell populations. The findings suggest a new model for SCLC progression while the application of live cell profiling of polysialylation could be used to assess polySia-NCAM-targeted therapies. © 2013 International Society for Advancement of Cytometry [ABSTRACT FROM AUTHOR]

Differences are often apparent in the observed rates of degradation between laboratory water-sediment studies and outdoor studies in surface water environments. Indeed, previous work has shown that including phototrophic communities in laboratory systems can result in the enhancement of degradation, when compared against systems that exclude phototrophs, incubated in darkness. In phototroph-inclusive systems, a range of metabolic processes and community effects are absent in the standard laboratory systems: metabolism by macrophytes, algae, and periphyton, as well as enhancement of bacterial and fungal communities by macrophyte root structures, algal biofilms, and planktonic algae. Here, the authors demonstrate the metabolic capability of algae and macrophytes in isolation from bacterial and fungal communities. The authors have isolated subcommunities and individual species from complex, phototroph-inclusive test systems, and demonstrated significant degradation of the fungicide fludioxonil in their presence. They have also shown the intrinsic metabolic competence of Elodea canadensis as well as algae from three phyla ( Chlorophyta, Cyanophyta, and Bacillariophyta [diatoms]), demonstrating that phototrophic communities have the potential to play a direct role in metabolism in surface water environments. Thus, it seems that current laboratory test systems are failing to consider the role of active, competent organisms that are likely to be involved in the degradation of crop protection products in surface water environments. Environ. Toxicol. Chem. 2012; 31: 2138-2146. © 2012 SETAC [ABSTRACT FROM AUTHOR]

ABSTRACT This paper contributes to the scant literature on the labour market and on the economic consequences of temporary migrants to Australia under the Working Holiday Maker (WHM) programme. Data from two large surveys in 2008, one of WHMs and one of firms that employed WHMs, were used to evaluate the labour market and the economic impacts of WHMs by the application of descriptive analysis and econometric modelling. The analysis demonstrates that the net impact of WHMs is positive for the Australian economy and for employment by increasing the demand for Australian workers because WHMs spend more than they earn while in Australia. We estimate that every 100 WHM arrivals created about five net full-time equivalent jobs in Australia. Moreover, the supply of WHM labour is of particular importance to employers in regional areas, especially agricultural enterprises who employ them to supply farm labour. More than half of WHM jobs in Australia were in two industries: 'accommodation' and 'agriculture'. Nonetheless, the majority of jobs in which WHMs worked are low skilled, low paid, and in urban areas. In these jobs, WHMs compete with the local low-skilled labour force and with local youth who seek similar types of jobs. To manage effectively Australia's migration and labour trends and to place the WHM programme in context, it is necessary to understand the increasing demand for short-term casual labour and the associated lack of supply, especially in regional primary and urban hospitality industry. This paper adds to current understanding by examining these issues in detail. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Much attention is focused on the benzoquinone ansamycins as anticancer agents, with several derivatives of the natural product geldanamycin (GdA) now in clinical trials. These drugs are selective inhibitors of Hsp90, a molecular chaperone vital for many of the activities that drive cancer progression. Mutational changes to their interaction site, the extremely conserved ATP binding site of Hsp90, would mostly be predicted to inactivate die chaperone. As a result, drug resistance should not arise readily this way. Nevertheless, Streptomyces hygroscopicus, the actinomycete that produces GdA, has evolved an Hsp90 family protein (HtpG) that lacks GdA binding. It is altered in certain of die highly conserved ammo acids making contacts to this antibiotic in crystal structures of GdA bound to eukaryotic forms of Hsp90. Two of these amino acid changes, located on one side of die nucleotide-binding cleft, weakened GdA/Hsp90 binding and conferred partial GdA resistance when inserted into die endogenous Hsp90 of yeast cells. Crystal structures revealed their main effect to be a weakening of interactions with the C-12 medioxy group of die GdA ansamycin ring. This is the first study to demonstrate that partial GdA resistance is possible by mutation within the ATP binding pocket of Hsp90. [ABSTRACT FROM AUTHOR]