Blood autotransfusion outcomes compared with Ringer lactate infusion in dogs with hemorrhagic shock induced by controlled bleeding.
The most common cause of shock in the surgical or trauma patient is hemorrhage. Crystalloid solutions and blood transfusion are the mainstays of treatment of hemorrhagic shock. Considering the disadvantages of allogeneic blood transfusion, such as risk of transmission of infectious diseases, and access and maintenance limitations, treatment of shock with autologous blood seems to be a decent solution. Autologous blood accumulated in body cavities in traumatic bleeding (such hemothorax), and bloodshed in operation field during open heart or vascular surgeries, and similar situations, can be utilized again. In this study, autotransfusion effects compared with crystalloid fluid in the treatment of hemorrhagic shock was investigated. After induction of hemorrhagic shock in dogs by Wiggers type controlled bleeding, treating them in a group with autologous blood and another group with Ringer lactate were performed, and the results of treatment were studied. There was no mortality in both treatment approaches. Immediately after treatment, crystalloid positive effects such as renormalized vital signs and appropriate consciousness were more noticeable than autotransfusion, while twenty-four hours after, the desired effects of autologous blood were more pronounced like decreased metabolic acidosis and improvement of diuresis. Crystalloid during the first hours after treatment of hemorrhagic shock may be better than autologous blood as preferred treatment, while autotransfusion showed its benefits some hours after. This finding can be used to develop better strategies for treatment of hemorrhagic shock.


Morphological adaptation of a planktonic diatom to growth in Antarctic sea ice.
Chaetoceros dichaeta Ehrenberg is one of the most important planktonic diatom species in the Southern Ocean, making a significant contribution to the total biomass in the region. Our observations on both field and culture material have revealed the existence of a specialized form of C. dichaeta adapted to living in sea ice. This sea ice form differs from the planktonic form by the shape and orientation of the setae and the aperture length between sibling cells. Thus, the diameter of the chain is equivalent to the apical axes of the cells and is accompanied by a two order of magnitude decrease in minimal space requirement. Here, we report for the first time on the extraordinary overwintering strategy of a planktonic diatom in sea ice facilitated by its rapid morphological adaptation to changing environmental conditions. This morphological plasticity enables it to thrive in the confined space of the sea ice brine matrix and retain its numerical dominance in recurrent growing seasons and has likely evolved to optimally exploit the dynamic ecosystem of the seasonally ice-covered seas of the Southern Ocean.


[Validation of the functional independence scale].
To assess the psychometric quality of an instrument designed to measure functional independence (Functional Independence Scale [FIS]) in several activities of daily living domains and to be applied by trained non-health-related interviewers. The study was carried out in the autonomous region of Madrid in community-dwelling elders. We performed a cross-sectional validation study. In addition to the FIS, Pfeiffer's questionnaire, the Depression Subscale of the Hospital Anxiety and Depression Scale, the Comorbidity Index, the Barthel Index, and EQ-5D were used. These measures were cross-sectionally applied to community-dwelling elders (n=500) and outpatients in a general hospital (n=100) aged 65 years. The following FIS psychometric attributes were analyzed: acceptability, scaling assumptions, internal consistency, construct validity, and precision. A fully computable FIS total score was obtained in 94.3% of the subjects. A ceiling effect (60.65%), but no floor effect (0.22%) was evident in the community-dwelling elders. No floor or ceiling effects were detected in the hospital sample. Scaling assumptions and internal consistency were satisfactory (item-total correlations: 0.57-0.91; Cronbach's alpha: 0.94). Factor analysis identified three factors that explained 74.3% of the variance. Indexes of convergent, internal, and known-groups validity were satisfactory. The scale's precision, determined by the standard error of measurement (2.49; 95%CI=4.88), was also satisfactory. The FIS is an easy-to-use instrument with appropriate metric attributes. This scale can be usefully applied in broad samples of non-institutionalized elders by non-health related personnel.


Cost effectiveness of nurse led secondary prevention clinics for coronary heart disease in primary care: follow up of a randomised controlled trial.
To establish the cost effectiveness of nurse led secondary prevention clinics for coronary heart disease based on four years' follow up of a randomised controlled trial. Cost effectiveness analysis. 19 general practices in north east Scotland. 1343 patients (673 in intervention group and 670 in control group, as originally randomised) aged under 80 years with a diagnosis of coronary heart disease but without terminal illness or dementia and not housebound. Nurse led clinics to promote medical and lifestyle components of secondary prevention. Costs of clinics; overall costs to health service; and cost per life year and per quality adjusted life year (QALY) gained, expressed as incremental gain in intervention group compared with control group. The cost of the intervention (clinics and drugs) was 136 pounds sterling (254 dollars; 195 euros) per patient higher (1998-9 prices) in the intervention group, but the difference in other NHS costs, although lower for the intervention group, was not statistically significant. Overall, 28 fewer deaths occurred in the intervention group leading to a gain in mean life years per patient of 0.110 and of 0.124 QALYs. The incremental cost per life year saved was 1236 pounds sterling and that per QALY was 1097 pounds sterling. Nurse led clinics for the secondary prevention of coronary heart disease in primary care seem to be cost effective compared with most interventions in health care, with the main gains in life years saved.


Using Avida to test the effects of natural selection on phylogenetic reconstruction methods.
Phylogenetic trees group organisms by their ancestral relationships. There are a number of distinct algorithms used to reconstruct these trees from molecular sequence data, but different methods sometimes give conflicting results. Since there are few precisely known phylogenies, simulations are typically used to test the quality of reconstruction algorithms. These simulations randomly evolve strings of symbols to produce a tree, and then the algorithms are run with the tree leaves as inputs. Here we use Avida to test two widely used reconstruction methods, which gives us the chance to observe the effect of natural selection on tree reconstruction. We find that if the organisms undergo natural selection between branch points, the methods will be successful even on very large time scales. However, these algorithms often falter when selection is absent.


Automated Vision-Based High Intraocular Pressure Detection Using Frontal Eye Images.
Glaucoma, the silent thief of vision, is mostly caused by the gradual increase of pressure in the eye which is known as intraocular pressure (IOP). An effective way to prevent the rise in eye pressure is by early detection. Prior computer vision-based work regarding IOP relies on fundus images of the optic nerves. This paper provides a novel vision-based framework to help in the initial IOP screening using only frontal eye images. The framework first introduces the utilization of a fully convolutional neural (FCN) network on frontal eye images for sclera and iris segmentation. Using these extracted areas, six features that include mean redness level of the sclera, red area percentage, Pupil/Iris diameter ratio, and three sclera contour features (distance, area, and angle) are computed. A database of images from the Princess Basma Hospital is used in this work, containing 400 facial images; 200 cases with normal IOP; and 200 cases with high IOP. Once the features are extracted, two classifiers (support vector machine and decision tree) are applied to obtain the status of the patients in terms of IOP (normal or high). The overall accuracy of the proposed framework is over 97.75% using the decision tree. The novelties and contributions of this work include introducing a fully convolutional network architecture for eye sclera segmentation, in addition to scientifically correlating the frontal eye view (image) with IOP by introducing new sclera contour features that have not been previously introduced in the literature from frontal eye images for IOP status determination.


In vivo footprinting of the human alpha-globin locus upstream regulatory element by guanine and adenine ligation-mediated polymerase chain reaction.
A major regulatory element required for expression of the human alpha-globin genes is located 40 kb upstream of the embryonic zeta-globin gene. To understand how this and other locus control region (LCR) elements contribute to high-level expression in erythroid cells, we have performed high-resolution, in vivo dimethyl sulfate footprinting. In addition, we have modified the dimethyl sulfate-based ligation-mediated polymerase chain reaction in vivo footprinting procedure to permit the assessment of interactions at guanine and adenine residues, rather than guanines alone. In vivo footprinting of the human alpha-LCR element carried on chromosome 16 in a mouse erythroleukemia cell environment revealed protein occupancy at GATA-1, AP-1/NF-E2, and CACC/GGTGG motifs, specific differences compared with in vitro protein binding, and distinct changes in one region upon dimethyl sulfoxide-induced cellular maturation. No protein contacts were detected in nonexpressing hepatoma cells. In addition, we have demonstrated that two AP-1 motifs in the alpha-LCR element which are occupied in vivo bind purified mouse NF-E2 protein in vitro. Our data suggest that three proteins, GATA-1, NF-E2, and unknown CACC/GGTGG factors, are minimally required as DNA-binding proteins for the function of LCR-like elements. The juxtaposition and interaction of these factors with each other, and with accessory proteins not directly in contact with DNA, are likely to account for the relative position independence of the upstream globin regulatory elements.


Life values before versus after a breast cancer diagnosis.
The main aim of this study was to investigate whether women's life values change with a breast cancer diagnosis. In addition, associations between life values and anxiety/depression ratings were investigated. Life value changes were prospectively studied in 517 women recalled for further examination after attending mammographic screening, 38 of whom were diagnosed with primary breast cancer. Life values were assessed by a study-specific version of a life value questionnaire, including ratings of the perceived attainment and importance of seven life value dimensions. Three months after being recalled, women diagnosed with primary breast cancer reported a reduction of the attainment and the importance of Health. In addition, these women reported changes in the perceived importance of Responsibility and Involvement. High levels of anxiety and depression in particular were associated with large discrepancies between attainment and importance for some life values. This suggests that changes in the perceived importance of some life values may constitute one part of women's psychological adaptation to a breast cancer diagnosis.


Sexual conflict and antagonistic coevolution across water strider populations.
Microevolutionary studies have demonstrated sexually antagonistic selection on sexual traits, and existing evidence supports a macroevolutionary pattern of sexually antagonistic coevolution. Two current questions are how antagonistic selection within-populations scales to divergence among populations, and to what extent intraspecific divergence matches species-level patterns. To address these questions, we conducted an intraspecific comparative study of sexual armaments and mating behaviors in a water strider (Gerris incognitus) in which male genitals grasp resistant females and female abdominal structures help ward off males. The degree of exaggeration of these armaments coevolves across species. We found a similar strong pattern of antagonistic coevolution among populations, suggesting that sexual conflict drives population differentiation in morphology. Furthermore, relative exaggeration in armaments was closely related to mating outcomes in a common environment. Interestingly, the effect of armaments on mating was mediated by population sexual size dimorphism. When females had a large size advantage, mating activity was low and independent of armaments, but when males had a relative size advantage, mating activity depended on which sex had relatively exaggerated armaments. Thus, a strong signal of sexually antagonistic coevolution is apparent even among populations. These results open opportunities to understand links between sexual arms races, ecological variation, and reproductive isolation.


Coupling of Single Molecule, Long Read Sequencing with IMGT/HighV-QUEST Analysis Expedites Identification of SIV gp140-Specific Antibodies from scFv Phage Display Libraries.
The simian immunodeficiency virus (SIV)/macaque model of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome pathogenesis is critical for furthering our understanding of the role of antibody responses in the prevention of HIV infection, and will only increase in importance as macaque immunoglobulin (IG) gene databases are expanded. We have previously reported the construction of a phage display library from a SIV-infected rhesus macaque (Macaca mulatta) using oligonucleotide primers based on human IG gene sequences. Our previous screening relied on Sanger sequencing, which was inefficient and generated only a few dozen sequences. Here, we re-analyzed this library using single molecule, real-time (SMRT) sequencing on the Pacific Biosciences (PacBio) platform to generate thousands of highly accurate circular consensus sequencing (CCS) reads corresponding to full length single chain fragment variable. CCS data were then analyzed through the international ImMunoGeneTics information system® (IMGT®)/HighV-QUEST (www.imgt.org) to identify variable genes and perform statistical analyses. Overall the library was very diverse, with 2,569 different IMGT clonotypes called for the 5,238 IGHV sequences assigned to an IMGT clonotype. Within the library, SIV-specific antibodies represented a relatively limited number of clones, with only 135 different IMGT clonotypes called from 4,594 IGHV-assigned sequences. Our data did confirm that the IGHV4 and IGHV3 gene usage was the most abundant within the rhesus antibodies screened, and that these genes were even more enriched among SIV gp140-specific antibodies. Although a broad range of VH CDR3 amino acid (AA) lengths was observed in the unpanned library, the vast majority of SIV gp140-specific antibodies demonstrated a more uniform VH CDR3 length (20 AA). This uniformity was far less apparent when VH CDR3 were classified according to their clonotype (range: 9-25 AA), which we believe is more relevant for specific antibody identification. Only 174 IGKV and 588 IGLV clonotypes were identified within the VL sequences associated with SIV gp140-specific VH. Together, these data strongly suggest that the combination of SMRT sequencing with the IMGT/HighV-QUEST querying tool will facilitate and expedite our understanding of polyclonal antibody responses during SIV infection and may serve to rapidly expand the known scope of macaque V genes utilized during these responses.


Elderly patients in acute medical wards: factors predicting length of stay in hospital.
A prospective study of 419 patients aged 70 and over admitted to acute medical wards was carried out by medical staff from a geriatric unit. Data, including presenting problem, housing, social support, mental state, continence, and degree of independence before and after admission, were recorded. Of the 419 patients, 143 remained in hospital after 14 days and 65 after 28 days. The major factors associated with prolonged stay in hospital included advanced age, stroke, confusion and falls as reasons for admission to hospital, incontinence, and loss of independence for everyday activities. Social circumstances did not predict length of stay. Although these factors are interrelated, the most important influence on length of stay was the medical reason for admission. Early contact with the geriatric medical unit in these patients may speed up the recovery or result in more appropriate placement.


Arcanobacterium bovis sp. nov., isolated from the milk of a cow with mastitis.
A polyphasic taxonomic study was performed on an unidentified Arcanobacterium-like Gram-stain-positive bacterium designated strain C605018/01/1T isolated from a milk sample collected from the udder of a cow at post mortem. Comparative 16S rRNA gene sequencing showed that the bacterium belonged to the genus Arcanobacterium and was most closely related to the type strain of Arcanobacterium pluranimalium (99.76 %); sequence similarities to all other Arcanobacterium species were below 97 %. The wet-lab DNA-DNA hybridization values among strain C605018/01/1T and A. pluranimalium DSM 13483ᵀ were low, 16.9 % (reciprocal, 49.8 %). Pertaining to the whole genome sequence with a total length of 2.02 Mb and 1654 protein counts, the novel strain C605018/01/01T displayed a G+C content of 51.6 % mol%. The presence of the major menaquinone MK-9(H4) supported the affiliation of this strain to the genus Arcanobacterium. The polar lipid profile consisted of the major components diphosphatidylglycerol, phosphatidylcholine, phosphatidylinositol, phosphatidylinositol-mannoside and unidentified glycolipid and aminophospholipids. Based on these results it is proposed that strain C605018/01/1T should be classified as representing a novel species, Arcanbacterium bovis sp. nov. The type strain C605018/01/1T (CCUG 45425T=DSM 107286T=BCCM/LMG 30783T).


Massive rectal bleeding after prostate biopsy controlled by endoclipping in a patient using acetylsalicylic acid.
A case of severe rectal bleeding following transurethral ultrasound (TRUS)-guided prostate biopsy is reported. Rectal bleeding is considered a minor, transient complication of this standard diagnostic procedure that can usually be controlled successfully by conservative measures. In this case where the patient had been taking acetylsalicylic acid (ASA), massive bleeding required hospitalization and blood transfusions. Conservative treatment attempts were not succesful, and profuse rectal bleeding was eventually treated by colonoscopy and endoclipping of the bleeding vessel. Although generally regarded as a less significant complication, rectal bleeding may rarely be encountered as a life-threatening situation. Furthermore, conservative therapeutic approach to this minor complication may be ineffective in patients taking ASA. Early endoscopic intervention may be necessary to prevent blood transfusion and prolonged hospitalization in severe rectal bleeding after TRUS biopsy.


13C-Urea breath test for the diagnosis of Helicobacter pylori infection.
Helicobacter pylori (H. pylori) is a Gram-negative bacterium able to colonize the gastric mucosa as well as gastric metaplastic areas of the duodenum, producing inflammation. The clinical outcome depends on sophisticated interactions between bacterial factors, such as the expression of determinants of virulence and pathogenicity, and host characteristics. The severity of inflammation, may then vary among different subjects, leading to the occurrence of different gastroduodenal diseases, ranging from chronic gastritis to gastric cancer and MALT-lymphoma, to some defined extragastric manifestations. Many diagnostic tests are available for the detection of H. pylori infection including noninvasive methods, such as serology, (13)C-urea breath test (UBT), and fecal antigen tests and invasive techniques, including a combined use of endoscopic biopsy-based methods, such as rapid urease testing, histology, culture, and molecular methods. UBT is a highly sensitive and specific and allows to diagnose the presence or absence of infection of H. pylori, through the oral administration of a solution containing urea labelled with the non-radioactive natural carbon 13. This review article analyzes microbiological and clinical features of H. pylori as well as the different diagnostic tests able to detect this bacterium with a special focus on UBT.


Formation of recent martian debris flows by melting of near-surface ground ice at high obliquity.
The observation of small gullies associated with recent surface runoff on Mars has renewed the question of liquid water stability at the surface of Mars. The gullies could be formed by groundwater seepage from underground aquifers; however, observations of gullies originating from isolated peaks and dune crests question this scenario. We show that these landforms may result from the melting of water ice in the top few meters of the martian subsurface at high obliquity. Our conclusions are based on the analogy between the martian gullies and terrestrial debris flows observed in Greenland and numerical simulations that show that above-freezing temperatures can occur at high obliquities in the near surface of Mars, and that such temperatures are only predicted at latitudes and for slope orientations corresponding to where the gullies have been observed on Mars.


Evanescent-wave scattering by electrophoretic microparticles: a mechanism for optical switching.
The total internal reflection of light occurring at the interface between glass and a low-index liquid containing suspended microparticles can be electrically controlled. The particles are charged and the glass is coated with a thin, transparent conductor. When the conductor is biased to attract the particles, they scatter and absorb light from the evanescent optical field near the interface, thus reducing the reflectivity. When the conductor is biased to repel the particles, total internal reflection is achieved. Experimental results are given for the time, voltage, and angle-of-incidence dependence of the reflectivity at the interface between an In-Sn-oxide-coated glass surface and a suspension of 0.47-µm-diameter silica particles in acetonitrile. The switching is found to be fast (~ 100 ms) and reproducible. In certain conditions the on/off ratio for a single reflection can be as large as 2:1. A simple theoretical model is developed to interpret these experiments. The model gives a reasonable fit to the data and allows one to extract information such as the particle mobility and the particle density in the evanescent-wave region.


Current Status and Future Directions of mHealth Interventions for Health System Strengthening in India: Systematic Review.
With the exponential increase in mobile phone users in India, a large number of public health initiatives are leveraging information technology and mobile devices for health care delivery. Given the considerable financial and human resources being invested in these initiatives, it is important to ascertain their role in strengthening health care systems. We undertook this review to identify the published mobile health (mHealth) or telemedicine initiatives in India in terms of their current role in health systems strengthening. The review classifies these initiatives based on the disease areas, geographical distribution, and target users and assesses the quality of the available literature. A search of the literature was done to identify mHealth or telemedicine articles published between January 1997 and June 2017 from India. The electronic bibliographic databases and registries searched included MEDLINE, EMBASE, Joanna Briggs Institute Database, and Clinical Trial Registry of India. The World Health Organization health system building block framework was used to categorize the published initiatives as per their role in the health system. Quality assessment of the selected articles was done using the Cochrane risk of bias assessment and National Institutes of Health, US tools. The combined search strategies yielded 2150 citations out of which 318 articles were included (primary research articles=125; reviews and system architectural, case studies, and opinion articles=193). A sharp increase was seen after 2012, driven primarily by noncommunicable disease-focused articles. Majority of the primary studies had their sites in the south Indian states, with no published articles from Jammu and Kashmir and north-eastern parts of India. Service delivery was the primary focus of 57.6% (72/125) of the selected articles. A majority of these articles had their focus on 1 (36.0%, 45/125) or 2 (45.6%, 57/125) domains of health system, most frequently service delivery and health workforce. Initiatives commonly used client education as a tool for improving the health system. More than 91.2% (114/125) of the studies, which lacked a sample size justification, had used convenience sampling. Methodological rigor of the selected trials (n=11) was assessed to be poor as majority of the studies had a high risk for bias in at least 2 categories. In conclusion, mHealth initiatives are being increasingly tested to improve health care delivery in India. Our review highlights the poor quality of the current evidence base and an urgent need for focused research aimed at generating high-quality evidence on the efficacy, user acceptability, and cost-effectiveness of mHealth interventions aimed toward health systems strengthening. A pragmatic approach would be to include an implementation research component into the existing and proposed digital health initiatives to support the generation of evidence for health systems strengthening on strategically important outcomes.


Several dystrophin-glycoprotein complex members are present in crude surface membranes but they are sodium dodecyl sulphate invisible in KCl-washed microsomes from mdx mouse muscle.
The dystrophin-glycoprotein complex (DGC) is a large trans-sarcolemmal complex that provides a linkage between the subsarcolemmal cytoskeleton and the extracellular matrix. In skeletal muscle, it consists of the dystroglycan, sarcoglycan and cytoplasmic complexes, with dystrophin forming the core protein. The DGC has been described as being absent or greatly reduced in dystrophin-deficient muscles, and this lack is considered to be involved in the dystrophic phenotype. Such a decrease in the DGC content was observed in dystrophin-deficient muscle from humans with muscular dystrophy and in mice with X-linked muscular dystrophy (mdx mice). These deficits were observed in total muscle homogenates and in partially membrane-purified muscle fractions, the so-called KCl-washed microsomes. Here, we report that most of the proteins of the DGC are actually present at normal levels in the mdx mouse muscle plasma membrane. The proteins are detected in dystrophic animal muscles when the immunoblot assay is performed with crude surface membrane fractions instead of the usually employed KCl-washed microsomes. We propose that these proteins form SDS-insoluble membrane complexes when dystrophin is absent.


Map positions of yeast genes SIR1, SIR3 and SIR4.
The HML and HMR loci in the yeast Saccharomyces cerevisiae each contain a complete copy of mating-type information. HML and HMR normally are transcriptionally inactive due to four unlinked genes, known as MAR or SIR or CMT. The map position of MAR1 (SIR2) has been reported previously; it is located on the left arm of chromosome IV, 27 cM from the centromere. Using conventional meiotic and mitotic mapping combined with recombinant DNA techniques, we have mapped three other SIR genes. SIR1 maps near the telomere of the right arm of chromosome XI; SIR3 (MAR2) maps to the right arm of chromosome XII, 31 cM distal to URA4; and SIR4 maps to the right arm of chromosome IV, 16 cM proximal to LYS4.


Analysis of the acrolein-modified sites of apolipoprotein B-100 in LDL.
We have reported that acrolein-conjugated low-density lipoprotein (Acro-LDL) uptake by scavenger receptor class A type 1 (SR-A1) can mediate macrophage foam cell formation. The purpose of this study was to determine which amino acid residues of apoB protein in LDL are conjugated with acrolein. Acro-apoB was prepared by incubation of LDL with acrolein (10 to 60 μM) at 37 °C for 7 days. Identification of acrolein-conjugated amino acid residues in apoB was performed using LC-MS/MS. The levels of acrolein-conjugated amino acid residues of apoB as well as crosslinking apoB increased in proportion to acrolein concentration. The level of LDL uptake by macrophages was parallel with the acrolein-conjugated monomer apoB. Acrolein-conjugated amino acid residues in apoB were C212, K327, K742, K949, K1087, H1923, K2634, K3237 and K3846. The NH2-teriminal four amino acid residues (C212, K327, K742 and K949) were located at the scavenger receptor SR-A1 recognition site, suggesting that these four acrolein-conjugated amino acids are involved in the rapid uptake of Acro-LDL by macrophages. It is proposed that the rapid uptake of LDL by macrophages is dependent on acrolein conjugation of four amino acids residues at the scavenger receptor recognition site of apoB in LDL.


The 2009 Retirement Confidence Survey: economy drives confidence to record lows; many looking to work longer.
RECORD LOW CONFIDENCE LEVELS: Workers who say they are very confident about having enough money for a comfortable retirement this year hit the lowest level in 2009 (13 percent) since the Retirement Confidence Survey started asking the question in 1993, continuing a two-year decline. Retirees also posted a new low in confidence about having a financially secure retirement, with only 20 percent now saying they are very confident (down from 41 percent in 2007). THE ECONOMY, INFLATION, COST OF LIVING ARE THE BIG CONCERNS: Not surprisingly, workers overall who have lost confidence over the past year about affording a comfortable retirement most often cite the recent economic uncertainty, inflation, and the cost of living as primary factors. In addition, certain negative experiences, such as job loss or a pay cut, loss of retirement savings, or an increase in debt, almost always contribute to loss of confidence among those who experience them. RETIREMENT EXPECTATIONS DELAYED: Workers apparently expect to work longer because of the economic downturn: 28 percent of workers in the 2009 RCS say the age at which they expect to retire has changed in the past year. Of those, the vast majority (89 percent) say that they have postponed retirement with the intention of increasing their financial security. Nevertheless, the median (mid-point) worker expects to retire at age 65, with 21 percent planning to push on into their 70s. The median retiree actually retired at age 62, and 47 percent of retirees say they retired sooner than planned. WORKING IN RETIREMENT: More workers are also planning to supplement their income in retirement by working for pay. The percentage of workers planning to work after they retire has increased to 72 percent in 2009 (up from 66 percent in 2007). This compares with 34 percent of retirees who report they actually worked for pay at some time during their retirement. GREATER WORRY ABOUT BASIC AND HEALTH EXPENSES: Workers who say they very confident in having enough money to take care of basic expenses in retirement dropped to 25 percent in 2009 (down from 40 percent in 2007), while only 13 percent feel very confident about having enough to pay for medical expenses (down from 20 percent in 2007. Among retirees, only a quarter (25 percent, down from 41 percent in 2007) feel very confident about covering their health expenses. HOW WORKERS ARE RESPONDING: Among workers who have lost confidence in their ability to secure a comfortable retirement, most (81 percent) say they have reduced their expenses, while others are changing the way they invest their money (43 percent), working more hours or a second job (38 percent), saving more money (25 percent), and seeking advice from a financial professional (25 percent). Among all workers, 75 percent say they and/or their spouse have saved money for retirement, one of the highest levels ever measured by the RCS. IGNORANCE STILL A MAJOR FACTOR: Many workers still do not have a good idea of how much they need to save for retirement. Only 44 percent of workers report they and/or their spouse have tried to calculate how much money they will need to have saved by the time they retire--and an equal proportion (44 percent) simply guess at how much they will need for a comfortable retirement.


Divalent metal transporter, DMT1: a novel MRI reporter protein.
Manganese (Mn)-enhanced MRI (MEMRI) has found a growing number of applications in anatomical and functional imaging in small animals, based on the cellular uptake of Mn ions in the brain, heart, and other organs. Previous studies have relied on endogenous mechanisms of paramagnetic Mn ion uptake and enhancement. To genetically control MEMRI signals, we reverse engineered a major component of the molecular machinery involved in Mn uptake, the divalent metal transporter, DMT1. DMT1 provides positive cellular enhancement in a manner that is highly sensitive and dynamic, allowing greater spatial and temporal resolution for MRI compared to previously proposed MRI reporters such as ferritin. We characterized the MEMRI signal enhancement properties of DMT1-expressing cells, both in vitro and in vivo in mouse models of cancer and brain development. Our results show that DMT1 provides an effective genetic MRI reporter for a wide range of biological and preclinical imaging applications.


The chronology of the earliest Upper Palaeolithic in northern Iberia: New insights from L'Arbreda, Labeko Koba and La Viña.
Since the late 1980s, northern Iberia has yielded some of the earliest radiocarbon dated Aurignacian assemblages in Western Europe, probably produced by anatomically modern humans (AMHs). This is at odds with its location furthest from the likely eastern entry point of AMHs, and has also suggested to some that the Châtelperronian resulted from cultural transfer from AMHs to Neanderthals. However, the accuracy of the early chronology has been extensively disputed, primarily because of the poor association between the dated samples and human activity. Here, we test the chronology of three sites in northern Iberia, L'Arbreda, Labeko Koba and La Viña, by radiocarbon dating ultrafiltered collagen from anthropogenically modified bones. The published dates from Labeko Koba are shown to be significant underestimates due to the insufficient removal of young contaminants. The early (c.44 ka cal BP [thousands of calibrated years before present]) Aurignacian chronology at L'Arbreda cannot be reproduced, but the reason for this is difficult to ascertain. The existing chronology of La Viña is found to be approximately correct. Together, the evidence suggests that major changes in technocomplexes occurred contemporaneously between the Mediterranean and Atlantic regions of northern Iberia, with the Aurignacian appearing around 42 ka cal BP, a date broadly consistent with the appearance of this industry elsewhere in Western Europe.


Quantification of local matrix deformations and mechanical properties during capillary morphogenesis in 3D.
Reciprocal mechanical interactions between cells and the extracellular matrix (ECM) are thought to play important instructive roles in branching morphogenesis. However, most studies to date have failed to characterize these interactions on a length scale relevant to cells, especially in three-dimensional (3D) matrices. Here we utilized two complementary methods, spatio-temporal image correlation spectroscopy (STICS) and laser optical tweezers-based active microrheology (AMR), to quantify endothelial cell (EC)-mediated deformations of individual ECM elements and the local ECM mechanical properties, respectively, during the process of capillary morphogenesis in a 3D cell culture model. In experiments in which the ECM density was systematically varied, STICS revealed that the rate at which ECs deformed individual ECM fibers on the microscale positively correlated with capillary sprouting on the macroscale. ECs expressing constitutively active V14-RhoA displaced individual matrix fibers at significantly faster rates and displayed enhanced capillary sprouting relative to wild-type cells, while those expressing dominant-negative N19-RhoA behaved in an opposite fashion. In parallel, AMR revealed a local stiffening of the ECM proximal to the tips of sprouting ECs. By quantifying the dynamic physical properties of the cell-ECM interface in both space and time, we identified a correlation linking ECM deformation rates and local ECM stiffening at the microscale with capillary morphogenesis at the macroscale.


The striking and unexpected cytogenetic diversity of genus Tanacetum L. (Asteraceae): a cytometric and fluorescent in situ hybridisation study of Iranian taxa.
Although karyologically well studied, the genus Tanacetum (Asteraceae) is poorly known from the perspective of molecular cytogenetics. The prevalence of polyploidy, including odd ploidy warranted an extensive cytogenetic study. We studied several species native to Iran, one of the most important centres of diversity of the genus. We aimed to characterise Tanacetum genomes through fluorochrome banding, fluorescent in situ hybridisation (FISH) of rRNA genes and the assessment of genome size by flow cytometry. We appraise the effect of polyploidy and evaluate the existence of intraspecific variation based on the number and distribution of GC-rich bands and rDNA loci. Finally, we infer ancestral genome size and other cytogenetic traits considering phylogenetic relationships within the genus. We report first genome size (2C) estimates ranging from 3.84 to 24.87 pg representing about 11 % of those recognised for the genus. We found striking cytogenetic diversity both in the number of GC-rich bands and rDNA loci. There is variation even at the population level and some species have undergone massive heterochromatic or rDNA amplification. Certain morphometric data, such as pollen size or inflorescence architecture, bear some relationship with genome size. Reconstruction of ancestral genome size, number of CMA+ bands and number of rDNA loci show that ups and downs have occurred during the evolution of these traits, although genome size has mostly increased and the number of CMA+ bands and rDNA loci have decreased in present-day taxa compared with ancestral values. Tanacetum genomes are highly unstable in the number of GC-rich bands and rDNA loci, although some patterns can be established at the diploid and tetraploid levels. In particular, aneuploid taxa and some odd ploidy species show greater cytogenetic instability than the rest of the genus. We have also confirmed a linked rDNA arrangement for all the studied Tanacetum species. The labile scenario found in Tanacetum proves that some cytogenetic features previously regarded as relatively constant, or even diagnostic, can display high variability, which is better interpreted within a phylogenetic context.


Living on the edge: transfer and traffic of E. coli in a confined flow.
We quantitatively study the transport of E. coli near the walls of confined microfluidic channels, and in more detail along the edges formed by the interception of two perpendicular walls. Our experiments establish the connection between bacterial motion at the flat surface and at the edges and demonstrate the robustness of the upstream motion at the edges. Upstream migration of E. coli at the edges is possible at much larger flow rates compared to motion at the flat surfaces. Interestingly, the speed of bacteria at the edges mainly results from collisions between bacteria moving along this single line. We show that upstream motion not only takes place at the edge but also in an "edge boundary layer" whose size varies with the applied flow rate. We quantify the bacterial fluxes along the bottom walls and the edges and show that they result from both the transport velocity of bacteria and the decrease of surface concentration with increasing flow rate due to erosion processes. We rationalize our findings as a function of local variations in the shear rate in the rectangular channels and hydrodynamic attractive forces between bacteria and walls.


The inhibitory effect of an arginine bicarbonate/calcium carbonate CaviStat-containing dentifrice on the development of dental caries in Venezuelan school children.
This study assessed the effect of an arginine bicarbonate/calcium carbonate (CaviStat)-containing dentifrice on caries development, mainly in 11- to 12-year-old Venezuelan children over a two-year period. Children (726) with a DMFT between 3 and 6 were examined at baseline, six months, and one and two years using a mirror, probe, and DMFS scoring. Subjects who completed the study consisted of two groups; 304 test and 297 control. The test group received a CaviStat-containing dentifrice, and the controls used a commercially available 1100 ppm fluoride toothpaste. All subjects were instructed to brush three times a day for 1 minute followed by swishing for 30 seconds. After six months, the mean DMFS scores increased only slightly from baseline in both groups, 6.93 +/- 0.22 in the control and 6.59 +/- 0.22 in the test subjects. After one year, the mean DMFS score in the control group rose to 8.00 +/- 0.24 and leveled off at 7.92 +/- 0.30 at two years. In contrast, the mean DMFS score in the test group decreased to 5.50 +/- 0.24 after one year before rising to 6.99 +/- 0.28 at two years. DMFS difference between the two groups was highly significant (p < 0.001), but mainly due to the large difference seen at one year. Dissection of the data showed that the erupted first molars dominated the overall DMFS changes. At the beginning of this study, first molar scores started at high values and showed a pattern thereafter like that seen for the total data. In contrast, premolars/molars, which erupt 4-6 years later (and at the start of the study had a mean DMFS score slightly above zero), showed a clear rise in the DMFS score in the control group during the first year of the study, which continued to rise until the end of the investigation. In contrast, the CaviStat group showed no change in the premolar/second molar DMFS score from baseline during the first year (giving the impression of 100% inhibition at one year), but showed a delayed rise thereafter that paralleled that seen in the controls between one and two years (58.3% inhibition at two years). Reversal of the development of early dental caries lesions in the CaviStat subjects and limitations of the diagnosis of very early caries lesions with standard dental explorers was suggested for the interesting first molar, first year data. Inhibition of caries initiation and caries progression in the CaviStat group was also observed and easier to see in the premolar/second molar, second year data where the DMFS scores were very low at baseline and reversals are not a significant issue. The results were subjected to statistical analysis including analysis of covariance. Largely because of the first year and first molar data, the difference between control and experimental groups was highly significant (p < 0.001). Similar comparison with the later-erupting premolar/molar teeth showed the CaviStat effect was also significant but at a lower level (p < 0.05). The differences could not be due to examiner error since the Kappa for 10% of the subjects randomly selected and re-examined was 0.898 overall and 0.914 for the first molar data. The data also suggested CaviStat inhibition of caries progression because of a slower rate of rise of missing+filled teeth in the CaviStat vs. the control group (p < 0.05). A CaviStat-containing toothpaste was more effective both clinically and statistically in inhibiting caries initiation and progression than the fluoride toothpaste control, and manifested its effects differently in the already-erupted first molars than in the later-erupting premolars and second molars.


Novel derivatives of 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with improved fluorescent and σ receptors binding properties.
Despite the promising potentials of σ2 receptors in cancer therapy and diagnosis, there are still ambiguities related to the nature and physiological role of the σ2 protein. With the aim of providing potent and reliable tools to be used in σ2 receptor research, we developed a novel series of fluorescent σ2 ligands on the basis of our previous work, where high-affinity σ2 ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (1, PB28) was used as the pharmacophore. Compared to the previous compounds, these novel ligands displayed improved fluorescence and σ2 binding properties, were σ2-specifically taken up by breast tumor cells, and were successfully employed in confocal microscopy. Compound 14, which was the best compromise between pharmacological and fluorescent properties, was successfully employed in flow cytometry, demonstrating its potential to be used as a tool in nonradioactive binding assays for studying the affinity of putative σ2 receptor ligands.


The anti-proliferative effects of 1alpha,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression.
The anti-proliferative action of the seco-steroid hormone 1alpha, 25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] extends to some, but not all breast and prostate cancer cell lines. By elucidating the molecular mechanisms mediating the sensitivity of these cells, we can identify critical target genes regulated directly or indirectly by 1alpha,25(OH)2D3 and pathways potentially disrupted during transformation. In this study, we demonstrated the induction of expression of BRCA1 mRNA and protein as well as transcriptional activation from the BRCA1-promoter by 1alpha,25(OH)2D3 in the sensitive breast cancer cell line MCF-7. This was not observed in the 1alpha,25(OH)2D3-resistant breast cancer cell line MDA-MB-436. The induction of BRCA1 mRNA was blocked by cyclohexamide. This indicated that transcriptional activation was mediated indirectly by the vitamin D receptor (VDR). Inhibition of VDR protein levels by stable transformation of the anti-sense VDR in MCF-7 reduced the sensitivity of MCF-7 to 1alpha,25(OH)2D3 by 50-fold. In addition, the induction of BRCA1 protein and transcriptional activation of a BRCA1 promoter-luciferase reporter construct was abrogated in the stable transformant with the greatest reduction of VDR levels. Examination of other breast and prostate cancer cell lines revealed that sensitivity to the anti-proliferative effects of 1alpha, 25(OH)2D3 was strongly associated with an ability to modulate BRCA1 protein. Furthermore, the expression of the estrogen receptor in these cell lines strongly correlated with their sensitivity to 1alpha,25(OH)2D3 and their ability to modulate BRCA1 expression. Taken together, our data support a model whereby the anti-proliferative effects of 1alpha,25(OH)2D3 are mediated, in part, by the induction of BRCA1 gene expression via transcriptional activation by factors induced by the VDR and that this pathway is disrupted during the development of prostate and breast cancers.


Natural selection on PHYE by latitude in the Japanese archipelago: insight from locus specific phylogeographic structure in Arcterica nana (Ericaceae).
Phytochromes play a key role in allowing plants to monitor their surrounding environment and, conversely, adaptation to local environments has driven the evolutionary history of phytochromes. As a result of natural selection, polymorphisms in phytochrome genes would thus be expected to exhibit locus-specific phylogeographic structure. To evaluate this hypothesis, we conducted a phylogeographic investigation based on four nuclear genes, including two phytochrome genes (PHYB and PHYE) using 155 samples of Arcterica nana from the entire range of the Japanese archipelago. Bayesian clustering revealed geographic differentiation between northern and southern Japan when all four genes were included. However, this geographic differentiation is inconsistent with previously reported genetic structure of genome-wide polymorphisms based on amplified fragment length polymorphisms, as these did not show geographic differentiation throughout the Japanese archipelago. In contrast, the north-south differentiation was not apparent when PHYE was excluded. This indicates that PHYE alone could be responsible for the north-south differentiation (F(CT) = 0.15, P < 0.001). Furthermore, a single nonsynonymous polymorphism (C360T) strongly contributed to geographic differentiation (F(CT) = 0.57, P < 0.001) and its corresponding amino acid replacement (P120L) was significantly under positive selection based on maximum likelihood analysis (P = 0.98). Consequently, the locus-specific geographic differentiation in PHYE could be caused by natural selection, suggesting the involvement of PHYE in local adaptation between populations of A. nana in northern and southern Japan. This finding is consistent with a previous study on Cardamine nipponica, indicating the importance of PHYE for local adaptation in Japanese alpine plants.


Anti-tumor necrosis factor-alpha therapy during murine Klebsiella pneumoniae bacteremia: increased mortality in the absence of liver injury.
Klebsiella pneumoniae is a leading cause of gram-negative bacterial pneumonia, often resulting in bacteremia concurrent with the localized pulmonary infection. The beneficial role of tumor necrosis factor (TNF)-alpha during pulmonary infection has been well documented; however, consequences of TNF-alpha production during systemic bacterial infection are controversial. A murine model of K. pneumoniae was developed to address this important issue. Liver-associated TNF-alpha mRNA was induced within 30 min after intravenous bacterial inoculation and remained elevated through 6 h before returning to near-baseline at 24 h postinfection. Intravenous K. pneumoniae infection induced liver cellular injury that was completely ablated when mice were pretreated with a neutralizing anti-TNF-alpha antibody. Interestingly, this reduction in liver injury failed to translate into improved survival. Mice receiving anti-TNF-alpha continued to succumb to the infection even out to day 10 postinfection. Bacterial clearance after TNF-alpha neutralization was significantly impaired at later time points during infection. Correlating with impaired bacterial clearance was diminished production of liver-associated MIP-2, MIP-1alpha, MCP-1, and interferon-gamma. Further evidence of diminished antibacterial immune responses was noted when the activational status of splenic natural killer cells in anti-TNF-alpha-treated mice was examined 24 h postinfection. Natural killer cells displayed decreased CD69 expression. Combined, these data indicate that the beneficial effects of TNF-alpha during systemic K. pneumoniae infection outweigh the detrimental effects of TNF-alpha-mediated hepatocyte cellular injury. Anti-TNF-alpha therapy, although preventing liver injury during blood-borne bacterial infection, results in a dampened anti-bacterial host response, resulting in decreased bacterial clearance and overall survival.


Immediate effects of exposure to positive and negative emotional stimuli on visual search characteristics in patients with unilateral neglect.
The performance of patients with unilateral neglect (UN) in tasks demanding visual attention is characterized by contralesional disadvantage which is markedly unstable in magnitude. Such instability of the attentional system is seen very clearly in clinical practice and thus far has no satisfying explanation. Here we examined the immediate effect of exposure to non-lateralized emotional stimuli on UN patients' attentional bias and performance variability. We tested eight right-hemisphere damaged stroke patients with left-sided neglect and eight age-matched healthy subjects in a visual conjunction-search task, each trial performed immediately after viewing a centrally-presented picture, which was emotionally negative, positive or neutral. Both performance bias and variability in performing the search task was analyzed as a function of the valence of the picture, and a method for analyzing reaction time (RT) variance in a small sample is introduced. Overall, UN subjects, but not controls, were slower and more variable in their RT for left- compared to right-sided targets. In the UN group, detecting left-sided targets was significantly slower in trials that followed presentation of negative pictures as compared to positive pictures, regardless of the fact that both picture types were judged as equally arousing by the patients. Moreover, UN patients exhibited larger performance variance on the left then on the right, and negative emotional stimuli were associated with larger variance asymmetry than positive emotional stimuli. Examining the coefficient of variation pointed to a possible dissociation between the effects of emotional stimuli on the lateralized RT mean (reflecting attentional bias) and on the lateralized RT variance (reflecting system instability). We conclude that emotional stimuli affect the spatial imbalance of both performance speed and stability in UN patients.


Coach ratings of skills and their relations to practice, play and successful transitions from youth-elite to adult-professional status in soccer.
Elite soccer players (~15 yr) from professional academies in the UK were rated on technical, tactical, physical and creative skills by coaches at time 1 (T1). Players estimated accumulated hours in soccer practice (coach-led activities) and play (self-led activities) during childhood. Coach-ratings were again collected 2.5 yr later (T2) for players that received a professional contract (~17 yr). Adult-professional status was determined at T3 (~ 20 yr). Skill ratings distinguished across the three "future" groups (academy-only, youth-professional only and adult-professional), for all but creative skill. For players that transitioned to youth-professional, medium sized correlations were noted between childhood practice amounts and technical and creative skill ratings at T1, although practice amounts correlated more strongly with skill ratings at T2. Play amounts were not related to any skills. Within groups of youth elite athletes, domain-specific play in childhood, and to a lesser degree practice, were generally not good discriminators of specific-skills. The effects of sport-specific practice on the development (and discriminability) of skills takes time to emerge. We consider the implications for talent development models and purported links between play and creativity.


Curcumin suppresses doxorubicin-induced epithelial-mesenchymal transition via the inhibition of TGF-β and PI3K/AKT signaling pathways in triple-negative breast cancer cells.
Triple-negative breast cancer (TNBC) is defined by a lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER 2). Therefore, targeted therapy agents may not be used, and therapy is largely limited to chemotherapy. Doxorubicin treatment consequently acquires undesired malignance characteristics [i.e., epithelial-mesenchymal transition (EMT) and multi-drug resistance]. Our results illustrated that doxorubicin triggered EMT and resulted in the acquisition of a mesenchymal phenotype in TNBC cells. Moreover, we found that transforming growth factor-β (TGF-β) and PI3K/AKT signaling pathways were acquired for doxorubicin-induced EMT. Interestingly, we found that curcumin suppressed doxorubicin-induced EMT. Curcumin reversed doxorubicin-induced morphological changes, inhibited doxorubicin-induced downregulation of E-cadherin expressions, and inhibited doxorubicin-induced upregulation of vimentin expression. We also found that curcumin inhibited doxorubicin-induced EMT by inhibiting the TGF-β and PI3K/AKT signaling pathways. Moreover, curcumin enhanced the antiproliferative effects of doxorubicin in TNBC cells. In summary, our results suggest that doxorubicin in combination with curcumin may be a potential therapy for TNBC.


An assessment of the toxicity of phthalate esters to freshwater benthos. 2. Sediment exposures.
Seven phthalate esters were evaluated for their 10-d toxicity to the freshwater invertebrates Hyalella azteca and Chironomus tentans in sediment. The esters were diethyl phthalate (DEP), di-n-butyl phthalate (DBP), di-n-hexyl phthalate (DHP), di-(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), diisodecyl phthalate (DIDP), and a commercial mixture of C7, C9, and C11 isophthalate esters (711P). All seven esters were tested in a sediment containing 4.80% total organic carbon (TOC), and DBP alone was tested in two additional sediments with 2.45 and 14.1% TOC. Sediment spiking concentrations for DEP and DBP were based on LC50 (lethal concentration for 50% of the population) values from water-only toxicity tests, sediment organic carbon concentration, and equilibrium partitioning (EqP) theory. The five higher molecular weight phthalate esters (DHP, DEHP, DINP, DIDP, 711P), two of which were tested and found to be nontoxic in water-only tests (i.e., DHP and DEHP), were tested at single concentrations between 2,100 and 3,200 mg/kg dry weight. Preliminary spiking studies were performed to assess phthalate ester stability under test conditions. The five higher molecular weight phthalate esters in sediment had no effect on survival or growth of either C. tentans or H. azteca, consistent with predictions based on water-only tests and EqP theory. The 10-d LC50 values for DBP and H. azteca were >17,400, >29,500, and >71,900 mg/kg dry weight for the low, medium, and high TOC sediments, respectively. These values are more than 30x greater than predicted by EqP theory and may reflect the fact that H. azteca is an epibenthic species and not an obligative burrower. The 10-d LC50 values for DBP and C. tentans were 826, 1,664, and 4.730 mg/kg dry weight for the low, medium, and high TOC sediments, respectively. These values are within a factor of two of the values predicted by EqP theory. Pore-water 10-d LC50 values for DBP (dissolved fraction) and C. tentans in the three sediments were 0.65, 0.89, and 0.66 of the water-only LC50 value of 2.64 mg/L, thereby agreeing with EqP theory predictions to within a factor of 1.5. The LC50 value for DEP and C. tentans was >3,100 mg/kg dry weight, which is approximately 10x that predicted by EqP theory. It is postulated that test chemical loss and reduced organism exposure to pore water may have accounted for the observed discrepancies with EqP calculations for DEP


The objective burden in partners of heart failure patients; development and initial validation of the Dutch Objective Burden Inventory.
Measures on objective caregiver burden in partners of Heart Failure patients are hardly available and never include HF specific aspects. The main objective of our study was to develop an inventory that assesses the objective caregiver burden of partners of HF patients, including the full range of potential care giving demands. To develop the inventory, six domains of caregiving demands were identified. Items for the domains were generated from the literature, expert opinion and existing scales. The original 50-items self-report inventory was administered to 321 partners of HF patients. Demographic data of HF partners were collected by questionnaire. Clinical data of the HF patients were collected by chart review. Component analysis led to exclusion of 12 original items and to a meaningful four-factor solution with a total explained variance of 43%. The components reflected four different kinds of care giving tasks; personal care, emotional, motivational and practical (treatment related) support. They demonstrated good internal consistency and initial validity was supported by a pattern of meaningful associations with external variables. The Objective Burden Inventory is a promising inventory to assess objective care giving tasks performed by HF partners, including emotional and motivational support. It provides information on the caregiver situation that may help to develop effective interventions.


Air exposure assessment of TDI and biological monitoring of TDA in urine in workers in polyurethane foam industry.
Toluene diisocyanate (TDI) is used in the manufacturing process of polyurethane (PU) foams and is a potent inducer of occupational asthma. The objective of this study was to evaluate the correlation between the exposure to total TDI (2,4- and 2,6-TDI) in air and the corresponding biomarker concentration of total TDA (2,4- and 2,6-TDA) in hydrolysed urine. The aim was also to propose an appropriate biological exposure limit for total TDA in urine. 9 workers from two production lines in a PU foam producing plant were studied. Personal exposure to TDI during four representative production shifts was monitored by an active air sampling method (filter impregnated with 1-(2-methoxyphenyl)piperazine) and quantified by high-performance liquid chromatography and diode array detection (NIOSH n° 2535, 5521). In parallel, pre-shift and post-shift urinary samples were collected from the exposed workers, and TDA concentrations were determined by gas chromatography-mass spectrometry after alkaline hydrolysis. All samples were collected on four measuring days: two Fridays (end of workweek) and two Mondays (start of workweek) separated by a weekend without exposure. Strong correlations between the personal air concentrations of total TDI and the corresponding biomarker levels of total TDA in urine (r=0.816) were observed. An increase of 18.12 μg TDA/l (post-shift minus pre-shift concentration) corresponds to an exposure of 5 ppb (37 μg/m(3), the current American Conference of Governmental Industrial Hygienists threshold limit value) during the shift. The increase in TDA during the shift is a suitable biomarker for exposure to TDI during the same shift. Further research is needed to evaluate the use of start of week or end of week post-shift TDA in urine as biomarker since TDA was found to accumulate during the working week and thus the moment of sampling will clearly influence the result.


Polymerase chain reaction detection of Plasmodium vivax and Plasmodium falciparum DNA from stored serum samples: implications for retrospective diagnosis of malaria.
Polymerase chain reaction (PCR) detection of Plasmodium DNA is highly sensitive in diagnosing malaria. The specimen of choice for this assay has been whole blood samples from malaria patients. To retrospectively determine malaria infection rates in populations or cohorts for whom stored serum samples are available, we determined the ability of a nested PCR assay to detect Plasmodium DNA in stored serum samples. The PCR result was positive in 20 of 23 serum samples from patients with microscopy-confirmed malaria and negative in 8 of 8 healthy controls, resulting in a sensitivity of 87% and specificity of 100%. In all positive samples, species were correctly identified by PCR except for one case where a mixed infection was detected. The PCR is able to detect Plasmodium DNA in serum samples frozen up to 2.5 years and has the potential for the retrospective identification of malaria parasitemia in patient cohorts to determine potential interactions of malaria and other diseases such as human immunodeficiency virus/acquired immunodeficiency syndrome.


Microphysiological systems: analysis of the current status, challenges and commercial future.
The field of microphysiological systems (or organs-on-a-chip) experienced, in the past decade, a surge in publications and efforts towards commercialization. Such systems hold the promise to advance drug discovery, diagnostics, and many other areas. In this review we summarize and analyze the current status of the field, describe the commercial advances and discuss standing challenges and the commercial outlook of the field.


Comparison of genome sequencing technology and assembly methods for the analysis of a GC-rich bacterial genome.
Improvements in technology and decreases in price have made de novo bacterial genomic sequencing a reality for many researchers, but it has created a need to evaluate the methods for generating a complete and accurate genome assembly. We sequenced the GC-rich Caulobacter henricii genome using the Illumina MiSeq, Roche 454, and Pacific Biosciences RS II sequencing systems. To generate a complete genome sequence, we performed assemblies using eight readily available programs and found that builds using the Illumina MiSeq and the Roche 454 data produced accurate yet numerous contigs. SPAdes performed the best followed by PANDAseq. In contrast, the Celera assembler produced a single genomic contig using the Pacific Biosciences data after error correction with the Illumina MiSeq data. In addition, we duplicated this build using the Pacific Biosciences data with HGAP2.0. The accuracy of these builds was verified by pulsed-field gel electrophoresis of genomic DNA cut with restriction enzymes.


O6-Methylguanine DNA Methyltransferase Status Does Not Predict Response or Resistance to Alkylating Agents in Well-Differentiated Pancreatic Neuroendocrine Tumors.
Alkylating agents have activity in well-differentiated pancreatic neuroendocrine tumors (WD panNETs). In glioblastoma multiforme, decreased activity of O-methylguanine DNA methyltransferase (MGMT) predicts response; in panNETs, MGMT relevance is unknown. We identified patients with WD panNETs treated with alkylating agents, determined best overall response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, and performed MGMT activity testing. Fifty-six patients were identified; 26 (46%) of the 56 patients experienced partial response, 24 (43%) of 56 experienced stable disease, and 6 (11%) of 56 experienced progression of disease. O-methylguanine DNA methyltransferase status was available for 36 tumors. For tumors with partial response, 10 (67%) of 15 were MGMT deficient, and 5 (33%) of 15 were MGMT intact. For tumors with stable disease, 7 (47%) of 15 were MGMT deficient, and 8 (53%) of 15 were MGMT intact. For tumors with progression of disease, 3 (50%) of 6 were MGMT deficient, and 3 (50%) of 6 were MGMT intact. We observed response and resistance to alkylating agents in MGMT-deficient and MGMT-intact tumors. O-methylguanine DNA methyltransferase status should not guide alkylating agent therapy in WD panNETs.


Modification of experimental nephrotoxicity with fish oil as the vehicle for cyclosporine.
Cyclosporine-associated renal dysfunction is well recognized. While renal vasoconstriction appears to be a major pathogenic factor, the precise mechanism responsible for the altered hemodynamics is unclear. To investigate whether alterations in renal eicosanoid metabolism could be involved, we substituted fish oil rich in eicosapentaenoic acid (EPA), an inhibitor of cyclooxygenase metabolites, for the conventional olive oil cyclosporine vehicle. Male rats were pretreated with 1.0 cc fish oil or olive oil by gavage. After 14 days, cyclosporine (12.5 mg/cc vehicle) was added to the oil and animals received cyclosporine 50 mg/kg for an additional 14 days. Pair-fed control animals received fish oil or olive oil alone. Glomerular filtration rate (GFR) was severely reduced in the cyclosporine-in-olive-oil (CSA + OO) group (0.28 +/- .05 ml/min/100 g) vs. olive oil (OO) controls (0.70 +/- .04) (P less than 0.001). While GFR was reduced in the cyclosporine-in-fish oil group (CSA + FO) vs. fish oil (FO) controls (0.47 +/- .07 vs. 0.74 +/- .04), it was significantly higher than in the CSA + OO group (P less than 0.05). Trough whole-blood cyclosporine levels were not significantly different in the two groups. While CSA + OO appeared to elevate renal cortical content of thromboxane B2 (65.7 +/- 7.3 pg/mg tissue vs. 46.9 +/- 5.3 for OO), both the CSA + FO and FO groups had reduced levels (31.1 +/- 2.7 and 29.5 +/- 2.3, respectively). In addition, there was a striking reduction in proximal tubular vacuolar changes in the CSA +/- FO vs. CSA + OO group. We conclude that the use of EPA-rich fish oil as the vehicle for cyclosporine results in improved renal function and morphology and is associated with depressed renal cortical levels of vasoconstrictor thromboxane B2.


In-situ observations of catalytic surface reactions with soft x-rays under working conditions.
Catalytic chemical reactions proceeding on solid surfaces are an important topic in fundamental science and industrial technologies such as energy conversion, pollution control and chemical synthesis. Complete understanding of the heterogeneous catalysis and improving its efficiency to an ultimate level are the eventual goals for many surface scientists. Soft x-ray is one of the prime probes to observe electronic and structural information of the target materials. Most studies in surface science using soft x-rays have been performed under ultra-high vacuum conditions due to the technical limitation, though the practical catalytic reactions proceed under ambient pressure conditions. However, recent developments of soft x-ray based techniques operating under ambient pressure conditions have opened a door to the in-situ observation of materials under realistic environments. The near-ambient-pressure x-ray photoelectron spectroscopy (NAP-XPS) using synchrotron radiation enables us to observe the chemical states of surfaces of condensed matters under the presence of gas(es) at elevated pressures, which has been hardly conducted with the conventional XPS technique. Furthermore, not only the NAP-XPS but also ambient-pressure compatible soft x-ray core-level spectroscopies, such as near-edge absorption fine structure (NEXAFS) and x-ray emission spectroscopy (XES), have been significantly contributing to the in-situ observations. In this review, first we introduce recent developments of in-situ observations using soft x-ray techniques and current status. Then we present recent new findings on catalytically active surfaces using soft x-ray techniques, particularly focusing on the NAP-XPS technique. Finally we give a perspective on the future direction of this emerging technique.


A multicenter, open study of the non-sedating antihistamine, terfenadine (Seldane), in the maintenance therapy of seasonal allergic rhinitis.
A multicenter open study was conducted throughout the 1984 fall pollen season to assess the possible development of tolerance or loss of efficacy to terfenadine in the maintenance therapy of patients with seasonal pollinosis. Patients with proven allergic pollinosis were entered into a 1-week initial treatment period taking terfenadine 60 mg bid and only those who responded to the initial treatment with "moderate" to "complete" relief continued on terfenadine throughout a 4 to 11-week pollen season for evaluation of continued efficacy. A total of 179 patients from five study centers were enrolled in the initial treatment period and 154 (86%) responded to terfenadine with "moderate" to "complete" relief of symptoms. Of these 154 patients who continued terfenadine treatment, approximately 90% of the patients maintained the same degree of relief throughout the pollen season. All symptoms of seasonal pollinosis including nasal congestion improved significantly the first day of treatment. This improvement in symptoms continued during the first week and remained unabated throughout the pollen season. The incidence of adverse events was low with sedation being reported by only 2.8% of patients at some time point during the study. It is concluded that terfenadine is a safe and effective non-sedating antihistamine in the maintenance therapy of seasonal allergic pollinosis and that tolerance is not noted during continued administration.


The influence of environmental variables on the density of larval lampreys in different seasons.
The objective of the study was to identify a subset of a set of twenty environmental variables which could explain variations in the density of larval lampreys (Geotria australis) in a south-western Australian stream. Generalised linear modelling, assuming Poisson distributions for the larval counts, led to a different model for each of the four seasons, with variations in larval density being explained in each season by a combination of between five and eight environmental variables. The influence of stream region also had to be taken into account in the model for winter.Four environmental variables (substrate organic material and chlorophyll a, macrophyte roots and low-angle shading) were present in three of the four seasonal models. A further six variables (water depth, substrate depth and profile, medium-sized sands, light intensity, and the presence of an eddy) were each found useful for two models. Two variables (current velocity and substrate profile) were each retained in one model. Eight of the twenty variables were not required for any of the seasonal models. The importance of organic material, shade, eddies, current velocity substrate particle size and a sufficient depth of substrate in our models agree with the largely subjective assessments of larval lamprey habitats made in the field by many previous workers for other lamprey species in diverse geographical localities.Our finding that larval density increased with increases in organic material and unicellular algae in the substrate and with shade, contrasts with the results of a different model based on data collected in a northern European stream. These differences can be related to our use of a more rigorous and comprehensive sampling regime and a more appropriate form of statistical analysis.


Optimising the management of vaginal discharge syndrome in Bulgaria: cost effectiveness of four clinical algorithms with risk assessment.
To evaluate the performance and cost effectiveness of the WHO recommendations of incorporating risk-assessment scores and population prevalence of Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) into vaginal discharge syndrome (VDS) algorithms. Non-pregnant women presenting with VDS were recruited at a non-governmental sexual health clinic in Sofia, Bulgaria. NG and CT were diagnosed by PCR and vaginal infections by microscopy. Risk factors for NG/CT were identified in multivariable analysis. Four algorithms based on different combinations of behavioural factors, clinical findings and vaginal microscopy were developed. Performance of each algorithm was evaluated for detecting vaginal and cervical infections separately. Cost effectiveness was based on cost per patient treated and cost per case correctly treated. Sensitivity analysis explored the influence of NG/CT prevalence on cost effectiveness. 60% (252/420) of women had genital infections, with 9.5% (40/423) having NG/CT. Factors associated with NG/CT included new and multiple sexual partners in the past 3 months, symptomatic partner, childlessness and >or=10 polymorphonuclear cells per field on vaginal microscopy. For NG/CT detection, the algorithm that relied solely on behavioural risk factors was less sensitive but more specific than those that included speculum examination or microscopy but had higher correct-treatment rate and lower over-treatment rates. The cost per true case treated using a combination of risk factors, speculum examination and microscopy was euro 24.08. A halving and tripling of NG/CT prevalence would have approximately the inverse impact on the cost-effectiveness estimates. Management of NG/CT in Bulgaria was improved by the use of a syndromic approach that included risk scores. Approaches that did not rely on microscopy lost sensitivity but were more cost effective.


Real-world treatment practice in patients with advanced melanoma in the era before ipilimumab: results from the IMAGE study.
The therapeutic landscape for advanced melanoma has recently been transformed by several novel agents (immune checkpoint inhibitors and molecular-targeted agents). The prospective, multi-site, observational study IMAGE (ipilimumab: management of advanced melanoma in real practice) included a retrospective cohort to describe real-world treatment prior to approval of the immune checkpoint inhibitor ipilimumab. This retrospective cohort of patients, who started second-line/subsequent treatment (index therapy) for advanced melanoma within 3 years before ipilimumab approval, was selected randomly by chart review. Collected data included treatment history, patient outcomes, and healthcare resource utilization. All patients had ≥1 year of follow-up data. This analysis included 177 patients from Europe (69%) and North America (31%). The most common index therapies (used alone or in combination) were fotemustine (23%), dacarbazine (21%), temozolomide (14%), and platinum-based chemotherapy (14%). Most patients (89%) discontinued index treatment during the study period; the most common reason was disease progression (59%). Among patients with tumor assessment (153/177; 86%), 2% had complete response, 5% had partial response, and 12% had stable disease on last tumor assessment. At 1-year study follow-up, median progression-free survival was 2.6 months (95% confidence interval [CI], 2.1-2.9) and median overall survival was 8.8 months (95% CI, 6.5-9.7). During follow-up, 95% of the patients had healthcare visits for advanced melanoma, 74% of whom were hospitalized or admitted to a hospice facility. These results provide insights into patient care with advanced melanoma in the era before ipilimumab and may serve as a benchmark for new agents in future real-world studies.


Effects of a chronic treatment by nisoldipine, a calcium antagonistic dihydropyridine, on arteries of spontaneously hypertensive rats.
Earlier studies have shown that relaxation in response to several agents is impaired in arteries from spontaneously hypertensive rats (SHR). We had previously reported that SHR aortas present a delayed relaxation when first exposed for 35 minutes to a 100 mM KCl solution and then transferred into physiological solution. The first phase of relaxation appeared similar in SHR and Wistar-Kyoto rat arteries, but the second phase was markedly slowed down in SHR arteries, giving rise to a postcontraction tone. In this study, we found that this postcontraction tone could be demonstrated not only in the aorta but also in the mesenteric artery, was independent of the presence of endothelium, increased with the age of SHR, and disappeared progressively when arterial segments were submitted to successive cycles of KCl depolarization followed by reimmersion in physiological solution. Chronic treatment of SHR with nisoldipine at doses that blocked the development of hypertension and attenuated the concomitant hypertrophy of heart and aorta, or in vitro pretreatment of SHR arteries with nisoldipine, decreased the contractile force developed by arteries in response to KCl depolarization and normalized the subsequent relaxation. [3H] (+)-PN200-110 binding studies on heart and brain homogenates indicated an increase in apparent Kd in nisoldipine-fed rats without significant change in Bmax. Binding data were compatible with the view that occupation of dihydropyridine receptors by nisoldipine after chronic oral administration was responsible for the modifications observed ex vivo in the mechanical activity of arteries. We conclude that the postcontraction tone of SHR arteries was mainly due to an abnormally prolonged activation of calcium channels after transfer of depolarized arteries into the physiological solution and that a labile or slowly releasable factor was probably involved in this phenomenon. We suggest that the antihypertensive action of nisoldipine might be related to the mechanisms involved in the suppression of the postcontraction tone as observed in vitro and that this mode of action could be more important than the vasodilating effect of this drug.


Treatment efficacy of ribociclib or palbociclib plus letrozole in hormone receptor-positive/HER2-negative metastatic breast cancer.
Background: Ribociclib, palbociclib and abemaciclib are currently approved CDK4/6 inhibitors along with aromatase inhibitors as the first-line standard-of-care for patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Methods: The authors report retrospective real-life data for 600 patients with estrogen receptor- and/or progesterone receptor-positive and HER2-negative metastatic breast cancer who were treated with ribociclib and palbociclib in combination with letrozole. Results & conclusion: The results demonstrated that the combination of palbociclib or ribociclib with letrozole has similar progression-free survival and overall survival benefit in real life for the patient group with similar clinical features. Specifically, endocrine sensitivity may be a factor to be considered in the treatment preference.


Structural and dynamic properties of some aqueous salt solutions.
Aqueous salt solutions are utilized and encountered in wide-ranging technological applications and natural settings. Towards improved understanding of the effect of salts on the dynamic properties of such systems, dilute aqueous salt solutions (up to 1 molar concentration) are investigated here, via experiments and molecular simulations. Four salts are considered: sodium chloride, for which published results are readily available for comparison, ammonium acetate, barium acetate and barium nitrate, for which published data are scarce. In the present work, molecular dynamics (MD) simulations are conducted to quantify viscosity and water self-diffusion coefficients, together with rheometry and Pulsed Field Gradient Spin Echo (PFGSE)-NMR experiments for validation. Simulation predictions are consistent with experimental observations in terms of trend and magnitude of salt-specific effects. Combining insights from the approaches considered, an interpretation of the results is proposed whereby the capacity of salts to influence bulk dynamics arises from their molecular interfacial area and strength of interaction with first hydration-shell water molecules. For the concentration range investigated, the interpretation could be useful in formulating aqueous systems for applications including the manufacturing of advanced catalysts.


Differences in the characteristics of responders and non-responders in a prevalence survey of vertebral osteoporosis. European Vertebral Osteoporosis Study Group.
Men and women aged 50 years and over were recruited for participation in a population-based prevalence survey of vertebral osteoporosis from 36 centres in 19 European countries. All subjects were invited to attend by letter of invitation for a "lifestyle" interview and lateral spinal radiograph. The aim of this analysis was to investigate how far those who agreed to attend were representative of the target population and thus whether any important level of non-response bias existed. To address this a second invitation was sent to all non-responders and, in 20 centres, a sample of ultimate non-responders was contacted by mail, telephone or home visit and given a shortened version of the lifestyle questionnaire. Compared with the sample of non-responders, responders might be considered less at risk from osteoporosis in that as a group they took more exercise and were less likely to be current smokers. Other factors suggested the contrary in that they consumed less calcium and were more likely to have suffered a previous fracture. Amongst responders, these factors appeared also to be related to the timing of response. Thus compared with delayed responders, those who participated after a first letter of invitation took more exercise, were less likely to be smokers and more likely to have suffered a previous fracture. However, in contrast to the results suggested by the non-response survey early responders consumed more calcium than late responders. The magnitude of the differences between responders and non-responders was small (less than 10% for most of the categorical variables) and the differences were not consistently in the direction of an increased or decreased risk of osteoporosis. Additionally the size or direction of these differences was not consistently influenced by the response rate based on classifying centres into those with a high, medium or low response rate. This suggests that in this multicentre study response bias probably does not have a major influence on the prevalence estimates of vertebral fracture. In epidemiological studies of osteoporosis comparison of the lifestyle differences between early and late responders provides useful information concerning response characteristics.


Health seeking behaviour and challenges in utilising health facilities in Wakiso district, Uganda.
The health seeking behaviour of a community determines how they use health services. Utilisation of health facilities can be influenced by the cost of services, distance to health facilities, cultural beliefs, level of education and health facility inadequacies such as stock-out of drugs. To assess the health seeking practices and challenges in utilising health facilities in a rural community in Wakiso district, Uganda. The study was a cross sectional survey that used a structured questionnaire to collect quantitative data among 234 participants. The sample size was obtained using the formula by Leslie Kish. While 89% of the participants were aware that mobile clinics existed in their community, only 28% had received such services in the past month. The majority of participants (84%) did not know whether community health workers existed in their community. The participants' health seeking behaviour the last time they were sick was associated with age (p = 0.028) and occupation (p = 0.009). The most significant challenges in utilising health services were regular stock-out of drugs, high cost of services and long distance to health facilities. There is potential to increase access to health care in rural areas by increasing the frequency of mobile clinic services and strengthening the community health worker strategy.


Biotic and abiotic drivers of intraspecific trait variation within plant populations of three herbaceous plant species along a latitudinal gradient.
The importance of intraspecific trait variation (ITV) is increasingly acknowledged among plant ecologists. However, our understanding of what drives ITV between individual plants (ITVBI) at the population level is still limited. Contrasting theoretical hypotheses state that ITVBI can be either suppressed (stress-reduced plasticity hypothesis) or enhanced (stress-induced variability hypothesis) under high abiotic stress. Similarly, other hypotheses predict either suppressed (niche packing hypothesis) or enhanced ITVBI (individual variation hypothesis) under high niche packing in species rich communities. In this study we assess the relative effects of both abiotic and biotic niche effects on ITVBI of four functional traits (leaf area, specific leaf area, plant height and seed mass), for three herbaceous plant species across a 2300 km long gradient in Europe. The study species were the slow colonizing Anemone nemorosa, a species with intermediate colonization rates, Milium effusum, and the fast colonizing, non-native Impatiens glandulifera. Climatic stress consistently increased ITVBI across species and traits. Soil nutrient stress, on the other hand, reduced ITVBI for A. nemorosa and I. glandulifera, but had a reversed effect for M. effusum. We furthermore observed a reversed effect of high niche packing on ITVBI for the fast colonizing non-native I. glandulifera (increased ITVBI), as compared to the slow colonizing native A. nemorosa and M. effusum (reduced ITVBI). Additionally, ITVBI in the fast colonizing species tended to be highest for the vegetative traits plant height and leaf area, but lowest for the measured generative trait seed mass. This study shows that stress can both reduce and increase ITVBI, seemingly supporting both the stress-reduced plasticity and stress-induced variability hypotheses. Similarly, niche packing effects on ITVBI supported both the niche packing hypothesis and the individual variation hypothesis. These results clearly illustrates the importance of simultaneously evaluating both abiotic and biotic factors on ITVBI. This study adds to the growing realization that within-population trait variation should not be ignored and can provide valuable ecological insights.


Dead regions in the cochlea: implications for speech recognition and applicability of articulation index theory.
Dead regions in the cochlea have been suggested to be responsible for failure by hearing aid users to benefit from apparently increased audibility in terms of speech intelligibility. As an alternative to the more cumbersome psychoacoustic tuning curve measurement, threshold-equalizing noise (TEN) has been reported to enable diagnosis of dead regions. The purpose of the present study was first to assess the feasibility of the TEN test protocol, and second, to assess the ability of the procedure to reveal related functional impairment. The latter was done by a test for the recognition of low-pass-filtered speech items. Data were collected from 22 hearing-impaired subjects with moderate-to-profound sensorineural hearing losses. The results showed that 11 subjects exhibited abnormal psychoacoustic behaviour in the TEN test, indicative of a possible dead region. Estimates of audibility were used to assess the possible connection between dead-region candidacy and ability to recognize low-pass-filtered speech. Large variability was observed with regard to the ability of audibility to predict recognition scores for both dead-region and no-dead-region subjects. Furthermore, the results indicate that dead-region subjects might be better than no-dead-region subjects at recognizing speech of marginal audibility.


ADAR-Mediated RNA Editing Predicts Progression and Prognosis of Gastric Cancer.
Gastric cancer (GC) is the third leading cause of global cancer mortality. Adenosine-to-inosine RNA editing is a recently described novel epigenetic mechanism involving sequence alterations at the RNA but not DNA level, primarily mediated by ADAR (adenosine deaminase that act on RNA) enzymes. Emerging evidence suggests a role for RNA editing and ADARs in cancer, however, the relationship between RNA editing and GC development and progression remains unknown. In this study, we leveraged on the next-generation sequencing transcriptomics to demarcate the GC RNA editing landscape and the role of ADARs in this deadly malignancy. Relative to normal gastric tissues, almost all GCs displayed a clear RNA misediting phenotype with ADAR1/2 dysregulation arising from the genomic gain and loss of the ADAR1 and ADAR2 gene in primary GCs, respectively. Clinically, patients with GCs exhibiting ADAR1/2 imbalance demonstrated extremely poor prognoses in multiple independent cohorts. Functionally, we demonstrate in vitro and in vivo that ADAR-mediated RNA misediting is closely associated with GC pathogenesis, with ADAR1 and ADAR2 playing reciprocal oncogenic and tumor suppressive roles through their catalytic deaminase domains, respectively. Using an exemplary target gene PODXL (podocalyxin-like), we demonstrate that the ADAR2-regulated recoding editing at codon 241 (His to Arg) confers a loss-of-function phenotype that neutralizes the tumorigenic ability of the unedited PODXL. Our study highlights a major role for RNA editing in GC disease and progression, an observation potentially missed by previous next-generation sequencing analyses of GC focused on DNA alterations alone. Our findings also suggest new GC therapeutic opportunities through ADAR1 enzymatic inhibition or the potential restoration of ADAR2 activity.


Characterising neural plasticity at the single patient level using connectivity fingerprints.
The occurrence of wide-scale neuroplasticity in the injured human brain raises hopes for biomarkers to guide personalised treatment. At the individual level, functional reorganisation has proven challenging to quantify using current techniques that are optimised for population-based analyses. In this cross-sectional study, we acquired functional MRI scans in 44 patients (22 men, 22 women, mean age: 39.4 ± 14 years) with a language-dominant hemisphere brain tumour prior to surgery and 23 healthy volunteers (11 men, 12 women, mean age: 36.3 ± 10.9 years) during performance of a verbal fluency task. We applied a recently developed approach to characterise the normal range of functional connectivity patterns during task performance in healthy controls. Next, we statistically quantified differences from the normal in individual patients and evaluated factors driving these differences. We show that the functional connectivity of brain regions involved in language fluency identifies "fingerprints" of brain plasticity in individual patients, not detected using standard task-evoked analyses. In contrast to healthy controls, patients with a tumour in their language dominant hemisphere showed highly variable fingerprints that uniquely distinguished individuals. Atypical fingerprints were influenced by tumour grade and tumour location relative to the typical fluency-activated network. Our findings show how alterations in brain networks can be visualised and statistically quantified from connectivity fingerprints in individual brains. We propose that connectivity fingerprints offer a statistical metric of individually-specific network organisation through which behaviourally-relevant adaptations could be formally quantified and monitored across individuals, treatments and time.


Assessing and prioritizing ecological communities for monitoring in a regional habitat conservation plan.
In nature reserves and habitat conservation areas, monitoring is required to determine if reserves are meeting their goals for preserving species, ecological communities, and ecosystems. Increasingly, reserves are established to protect multiple species and communities, each with their own conservation goals and objectives. As resources are always inadequate to monitor all components, criteria must be applied to prioritize both species and communities for monitoring and management. While methods for prioritizing species based on endangerment or risk have been established, approaches to prioritizing ecological communities for monitoring are not well developed, despite a long-standing emphasis on communities as target elements in reserve design. We established guidelines based on four criteria derived from basic principles of conservation and landscape ecology--extent, representativeness, fragmentation, and endangerment--to prioritize communities in the San Diego Multiple Species Conservation Plan (MSCP). The MSCP was one of the first multiple-species habitat conservation areas established in California, USA, and it has a complex spatial configuration because of the patterns of surrounding land use, which are largely urbanized. In this case study, high priority communities for monitoring include coastal sage scrub (high endangerment, underrepresented within the reserve relative to the region, and moderately fragmented), freshwater wetlands, and coastal habitats (both have high fragmentation, moderate endangerment and representativeness, and low areal extent). This framework may be useful to other conservation planners and land managers for prioritizing the most significant and at-risk communities for monitoring.


Potentiation of taste and extract stimuli in conditioned flavor preference learning.
In these experiments, we investigated the nature of potentiation in the conditioned flavor preference paradigm. Almond and banana extracts, which have strong odor components, were combined with salt and saccharin (liked tastes; Experiment 1) or quinine and citric acid (disliked tastes; Experiment 2) in a flavor preference procedure that mixed these solutions with a caloric reinforcer (polycose). The results showed that liked tastes potentiated preference conditioning to extracts (Experiment 1), whereas extracts potentiated preference conditioning to disliked tastes (Experiment 2). In both experiments, the presumably less liked stimulus (i.e., the extract in Experiment 1 and the disliked taste in Experiment 2) was the potentiated cue.


A single gene affects both ecological divergence and mate choice in Drosophila.
Evolutionary changes in traits involved in both ecological divergence and mate choice may produce reproductive isolation and speciation. However, there are few examples of such dual traits, and the genetic and molecular bases of their evolution have not been identified. We show that methyl-branched cuticular hydrocarbons (mbCHCs) are a dual trait that affects both desiccation resistance and mate choice in Drosophila serrata. We identify a fatty acid synthase mFAS (CG3524) responsible for mbCHC production in Drosophila and find that expression of mFAS is undetectable in oenocytes (cells that produce CHCs) of a closely related, desiccation-sensitive species, D. birchii, due in part to multiple changes in cis-regulatory sequences of mFAS. We suggest that ecologically influenced changes in the production of mbCHCs have contributed to reproductive isolation between the two species.