Quality of life for up to 18 months after low-energy hip, vertebral, and distal forearm fractures-results from the ICUROS.
This study used data from the International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) to estimate the quality of life (QoL) impact of fracture. Hip, vertebral, and distal forearm fractures incur substantial QoL losses. Hip and vertebral fracture results in markedly impaired QoL for at least 18 months. The International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) is a multinational observational study that aims to describe costs and quality of life (QoL) consequences of osteoporotic fractures. To date, 11 countries have participated in the study: Australia, Austria, Estonia, France, Italy, Lithuania, Mexico, Russia, Spain, the UK, and the USA. The objective of this paper is to describe the QoL impact of hip, vertebral, and distal forearm fracture. Data were collected at four time-points for five QoL point estimates: within 2 weeks after fracture (including pre-fracture recall) and at 4, 12, and 18 months after fracture. Quality of life was measured as health state utility values (HSUVs) derived from the EQ-5D-3L. Complete case analysis was conducted as the base case with available case and multiple imputation performed as sensitivity analyses. Multivariate analysis was performed to explore predictors of QoL impact of fracture. Among 5456 patients enrolled using convenience sampling, 3021 patients were eligible for the base case analysis (1415 hip, 1047 distal forearm, and 559 vertebral fractures). The mean (SD) difference between HSUV before and after fracture for hip, vertebral, and distal forearm fracture was estimated at 0.89 (0.40), 0.67 (0.45), and 0.48 (0.34), respectively (p < 0.001 for all fracture types). Eighteen months after fracture, mean HSUVs were lower than before the fracture in patients with hip fracture (0.66 vs. 0.77 p < 0.001) and vertebral fracture (0.70 vs. 0.83 p < 0.001). Hospitalization and higher recalled pre-fracture QoL were associated with increased QoL impact for all fracture types. Hip, vertebral, and distal forearm fractures incur substantial loss in QoL and for patients with hip or vertebral fracture, QoL is markedly impaired for at least 18 months.


Aryl hydrocarbon receptor signals attenuate lung fibrosis in the bleomycin-induced mouse model for pulmonary fibrosis through increase of regulatory T cells.
Interstitial lung disease (ILD) is a serious complication of connective tissue diseases (CTDs). Although immune dysregulation triggered by genetic and environmental factors is thought to provoke inflammation and subsequent fibrosis, precise mechanisms of these processes remain unclear. Recent reports suggest that activation of aryl hydrocarbon receptor (AhR) signals by various ligands such as tryptophan derivatives can induce hyper-immune responses and are involved in autoimmunity. We investigated the effects of AhR signals on the process of lung fibrosis and changes in immunological features using a bleomycin (BLM)-induced lung fibrosis mouse model. BLM was administered intratracheally to C57BL/6JJcl mice and either 5,11-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (FICZ), a natural AhR ligand, or vehicle was subsequently injected intraperitoneally on day 0, 1, and 2 from BLM administration. Mice were sacrificed at week 3, and lung fibrosis was quantified by the histological changes using the Ashcroft score and deposition of soluble collagen levels in the lung using Sircol assay. The population of immune cells infiltrated into the lungs was analyzed using flow cytometry. Both the Ashcroft score and soluble collagen level in FICZ-treated mice were significantly lower than those in the vehicle group. Moreover, the survival rate of FICZ-treated mice was significantly higher than that of control mice during the 3 weeks after treatment. Interestingly, flow cytometric analysis revealed that the number of CD4+Foxp3+ regulatory T cells (Tregs) was significantly increased and CD4+IFNγ+ and γδ+IL-17A+ T cells were decreased in the lungs of FICZ-treated mice, while the total number of T, B, and NK cells were unaffected by FICZ treatment. Our findings suggest that stimulation of AhR signals attenuated lung fibrosis by increasing Tregs and suppressing inflammatory T cell subsets in a BLM-induced fibrosis model. AhR signaling pathways may therefore be useful therapeutic targets for connective tissue disease-associated ILD.


Salicylic Acid Induces Resistance to Alternaria solani in Hydroponically Grown Tomato.
ABSTRACT Alternaria solani is the causal agent of early blight disease in tomato and is responsible for significant economic losses sustained by tomato producers each year. Because salicylic acid (SA) is an important signal molecule that plays a critical role in plant defense against pathogen invasion, we investigated if the exogenous application of SA would activate systemic acquired resistance (SAR) against A. solani in tomato leaves. The addition of 200 muM SA to the root system significantly increased the endogenous SA content of leaves. Free SA levels increased 65-fold over basal levels to 5.85 mug g(-1) fresh weight (FW) after 48 h. This level of SA had no visible phytotoxic effects. Total SA content (free SA + SA-glucose conjugate) increased to 108 mug g(-1) FW after 48 h. Concomitant with elevated SA levels, expression of the tomato pathogenesis-related (PR)-1B gene was strongly induced within 24 h of the addition of 200 muM SA. PR-1B expression was still evident after 48 h; however, PR-1B induction was not observed in plants not receiving SA treatment. Challenge inoculation of SA-treated tomato plants using conidia of A. solani resulted in 83% fewer lesions per leaf and a 77% reduction in blighted leaf area as compared with control plants not receiving SA. Our data indicate that root feeding 200 muM SA to tomato plants can (i) significantly elevate foliar SA levels, (ii) induce PR-1B gene expression, and (iii) activate SAR that is effective against A. solani.


Comparative analysis of sorghum (C4) and rice (C3) plant headspace volatiles induced by artificial herbivory.
Acute stress responses include release of defensive volatiles from herbivore-attacked plants. Here we used two closely related monocot species, rice as a representative C3 plant, and sorghum as a representative C4 plant, and compared their basal and stress-induced headspace volatile organic compounds (VOCs). Although both plants emitted similar types of constitutive and induced VOCs, in agreement with the close phylogenetic relationship of the species, several mono- and sesquiterpenes have been significantly less abundant in headspace of sorghum relative to rice. Furthermore, in spite of generally lower VOC levels, some compounds, such as the green leaf volatile (Z)-3-hexenyl acetate and homoterpene DMNT, remained relatively high in the sorghum headspace, suggesting that a separate mechanism for dispersal of these compounds may have evolved in this plant. Finally, a variable amount of several VOCs among three sorghum cultivars of different geographical origins suggested that release of VOCs could be used as a valuable resource for the increase of sorghum resistance against herbivores.


Tendon tissue engineering: progress, challenges, and translation to the clinic.
The tissue engineering field has made great strides in understanding how different aspects of tissue engineered constructs (TECs) and the culture process affect final tendon repair. However, there remain significant challenges in developing strategies that will lead to a clinically effective and commercially successful product. In an effort to increase repair quality, a better understanding of normal development, and how it differs from adult tendon healing, may provide strategies to improve tissue engineering. As tendon tissue engineering continues to improve, the field needs to employ more clinically relevant models of tendon injury such as degenerative tendons. We need to translate successes to larger animal models to begin exploring the clinical implications of our treatments. By advancing the models used to validate our TECs, we can help convince our toughest customer, the surgeon, that our products will be clinically efficacious. As we address these challenges in musculoskeletal tissue engineering, the field still needs to address the commercialization of products developed in the laboratory. TEC commercialization faces numerous challenges because each injury and patient is unique. This review aims to provide tissue engineers with a summary of important issues related to engineering tendon repairs and potential strategies for producing clinically successful products.


Feedback inhibition of catecholamine release by two different alpha2-adrenoceptor subtypes prevents progression of heart failure.
Elevated plasma norepinephrine levels are associated with increased mortality in patients and in animal models with chronic heart failure. To test which alpha2-adrenoceptor subtypes operate as presynaptic inhibitory receptors to control norepinephrine release in heart failure, we investigated the response of gene-targeted mice lacking alpha2-adrenoceptor subtypes (alpha2-KO) to chronic left ventricular pressure overload. In addition, we determined the functional consequences of genetic variants of alpha2-adrenoceptors in human patients with chronic heart failure. Cardiac pressure overload was induced by transverse aortic constriction. Three months after aortic banding, survival was dramatically reduced in alpha2A-KO (52%) and alpha2C-KO (47%) mice compared with wild-type and alpha2B-deficient (86%) animals. Excess mortality in alpha2A- and alpha2C-KO strains was attributable to heart failure with enhanced left ventricular hypertrophy and fibrosis and elevated circulating catecholamines. The clinical importance of this finding is emphasized by the fact that heart failure patients with a dysfunctional variant of the alpha2C-adrenoceptor had a worse clinical status and decreased cardiac function as determined by invasive catheterization and by echocardiography. Our results indicate an essential function of alpha2A- and alpha2C-adrenoceptors in the prevention of heart failure progression in mice and human patients. Identification of heart failure patients with genetic alpha2-adrenoceptor variants as well as new alpha2-receptor subtype-selective drugs may represent novel therapeutic strategies in chronic heart failure and other diseases with enhanced sympathetic activation.


Sedentary time in children: influence of accelerometer processing on health relations.
Accelerometry is increasingly being used to assess sedentary time in epidemiological studies, yet the most appropriate means of processing these data remains uncertain. This cross-sectional study examined the influence of selected accelerometer cut points and nonwear criteria on associations of sedentary time with adiposity and clustered metabolic risk. Data were from the European Youth Heart Study, which included assessment of sedentary time by accelerometer. Sixteen sedentary time variables were constructed based on combinations of frequently used cut points (100, 500, 800, and 1100 counts per minute) and nonwear criteria (10-, 20-, 60-, and 100-min consecutive zeros). Adiposity was assessed by sum of four skinfold thickness measures. A clustered metabolic risk score was calculated as the mean of standardized metabolic syndrome components, including blood pressure, insulin resistance, and inverted fasting HDL-cholesterol. Analyses were conducted using multilevel cross-sectional time series regression, adjusted for overall physical activity (accelerometer counts per minute). Meta-analysis was used to obtain pooled estimates of the exposure-outcome association over all processing protocols; meta-regression was used to determine the influence of nonwear and cut point protocol on observed associations. Sedentary time follows a power law with cut point (exponent = 0.27) and zero string (exponent = 0.03), and it was positively associated with clustered metabolic risk (β = 0.0051; 95% confidence interval = 0.0018-0.0085). The association was moderated by cut point, with higher cut points typically producing stronger associations. No significant association between sedentary time and adiposity was observed. The choice of accelerometer cut point may moderate the association between sedentary time and clustered metabolic risk, suggesting that direct comparisons of associations between studies using different cut points must be made with caution.


A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors.
The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric CNS and solid tumors. This was a standard 3+3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m2/day for 28 days per cycle. Twenty-three patients (median age 10 years, range 4-18 years) with CNS tumors (DIPG [n = 3], high-grade glioma [n = 5], medulloblastoma [n = 2], ependymoma [n = 3]), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter-related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m2/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with high-grade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (≥11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m2/day.


The molecular basis of alpha-thalassaemia in Thailand.
The molecular basis of alpha-thalassaemia has been established in 48 Thai subjects with Hb H disease and 15 with the Hb Bart's hydrops fetalis syndrome. This study has shown that in this population there are at least 18 different types of chromosome carrying seven independent alpha-thalassaemia mutations one of which is a novel deletion removing the entire alpha-globin gene complex. Although there are a limited number of alpha-thalassaemia determinants in the Thai population, there is a remarkable degree of variation in the genetic markers which flank them. These markers may be of value in establishing the evolutionary history of the alpha-thalassaemias.


Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer.
Sensory hair cells in the mammalian cochlea convert mechanical stimuli into electrical impulses that subserve audition. Loss of hair cells and their innervating neurons is the most frequent cause of hearing impairment. Atonal homologue 1 (encoded by Atoh1, also known as Math1) is a basic helix-loop-helix transcription factor required for hair-cell development, and its misexpression in vitro and in vivo generates hair-cell-like cells. Atoh1-based gene therapy to ameliorate auditory and vestibular dysfunction has been proposed. However, the biophysical properties of putative hair cells induced by Atoh1 misexpression have not been characterized. Here we show that in utero gene transfer of Atoh1 produces functional supernumerary hair cells in the mouse cochlea. The induced hair cells display stereociliary bundles, attract neuronal processes and express the ribbon synapse marker carboxy-terminal binding protein 2 (refs 12,13). Moreover, the hair cells are capable of mechanoelectrical transduction and show basolateral conductances with age-appropriate specializations. Our results demonstrate that manipulation of cell fate by transcription factor misexpression produces functional sensory cells in the postnatal mammalian cochlea. We expect that our in utero gene transfer paradigm will enable the design and validation of gene therapies to ameliorate hearing loss in mouse models of human deafness.


Rapid Quantification of the Binocular Visual Field for Clinical Trials: Performance of a Modified Esterman Supra-Threshold Test Implemented with the Open Perimetry Interface.
We aimed to assess the performance of the modified-Esterman test (mET) as a rapid suprathreshold binocular quantification tool for the assessment of peripheral visual fields. The mET consists of an even spread of test points across the visual field. The mET was implemented on the Octopus 0900 perimeter using the Open Perimetry Interface (OPI) and consisted of 160 points. Patients with choroideremia, a rod-cone dystrophy, Stargardt disease, a cone-rod dystrophy, and healthy volunteers underwent both the mET and the standard Esterman tests twice. Disease severity (mild/moderate/severe) was graded on both tests independently. Voronoi tessellation was utilised to compare the tests. The Voronoi visualisation was able to demonstrate that the mET was able to provide more information about the disease state at all stages of diseases. This was confirmed by the agreement statistic, which showed that the mET detected 27% more points of visual field loss compared to the Esterman test, being most useful in patients with rod-cone dystrophies. The mET provides a speedy quantitative measure of the peripheral visual field loss, which can be used in clinical trials to monitor longitudinal assessment of peripheral visual function. The mET provides a more even coverage across the visual field compared to the Esterman test points, making it more suitable for this purpose. This is a key part of safety monitoring in retinal clinical trials. The mET can easily be implemented on commercially available perimeters that allow Open Perimetry.


Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis.
In recent years it has become clear that multiple sclerosis (MS) patients benefit from physical exercise as performed in aerobic training but little is known about the effect on functional domains and physiological factors mediating these effects. We studied immunological, endocrine and neurotrophic factors as well as coordinative function and quality of life during an 8-week aerobic bicycle training in a waitlist control design. In the immune-endocrine study (1) 28 patients were included, the coordinative extension study (2) included 39 patients. Training was performed at 60% VO(2)max after determining individual exertion levels through step-by-step ergometry. Metabolic (lactate), endocrine (cortisol, adrendocortico-releasing hormone, epinephrine, norepinephrine), immune (IL-6, soluble IL-6 receptor), and neurotrophic (brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF)) parameters were compared from a prestudy and a poststudy endurance test at 60% VO(2)max for 30 min. In study (1), lowered lactate levels despite higher workload levels indicated a training effect. Disease-specific quality of life (as measured by the Hamburg Quality of Life Questionnaire for Multiple Sclerosis, HAQUAMS) significantly increased in the training group. No significant training effects were seen for endocrine and immune parameters or neurotrophins. In study (2), two out of three coordinative parameters of the lower extremities were significantly improved. In summary, low-level aerobic training in MS improves not only quality of life but also coordinative function and physical fitness.


A fully automated conversational agent for promoting mental well-being: A pilot RCT using mixed methods.
Fully automated self-help interventions can serve as highly cost-effective mental health promotion tools for massive amounts of people. However, these interventions are often characterised by poor adherence. One way to address this problem is to mimic therapy support by a conversational agent. The objectives of this study were to assess the effectiveness and adherence of a smartphone app, delivering strategies used in positive psychology and CBT interventions via an automated chatbot (Shim) for a non-clinical population - as well as to explore participants' views and experiences of interacting with this chatbot. A total of 28 participants were randomized to either receive the chatbot intervention (n = 14) or to a wait-list control group (n = 14). Findings revealed that participants who adhered to the intervention (n = 13) showed significant interaction effects of group and time on psychological well-being (FS) and perceived stress (PSS-10) compared to the wait-list control group, with small to large between effect sizes (Cohen's d range 0.14-1.06). Also, the participants showed high engagement during the 2-week long intervention, with an average open app ratio of 17.71 times for the whole period. This is higher compared to other studies on fully automated interventions claiming to be highly engaging, such as Woebot and the Panoply app. The qualitative data revealed sub-themes which, to our knowledge, have not been found previously, such as the moderating format of the chatbot. The results of this study, in particular the good adherence rate, validated the usefulness of replicating this study in the future with a larger sample size and an active control group. This is important, as the search for fully automated, yet highly engaging and effective digital self-help interventions for promoting mental health is crucial for the public health.


Autologous osteochondral mosaicplasty for osteochondritis dissecans of the elbow in teenage athletes.
Although autologous osteochondral mosaicplasty is widely used as a procedure for osteochondritis dissecans lesions, the effectiveness of this procedure in elbow lesions remains unclear. Our aim was to clarify the surgical efficacy of mosaicplasty for teenage athletes with advanced lesions of capitellar osteochondritis dissecans. From 2001 to 2006, nineteen teenage male patients who were competitive athletes and had advanced lesions of capitellar osteochondritis dissecans underwent mosaicplasties. The mean age of the patients was 14.2 years. The surgical technique involved obtaining small-sized cylindrical osteochondral grafts with a mean diameter of 3.5 mm from the lateral periphery of the femoral condyle at the level of the patellofemoral joint and transplanting the grafts (mean, 3.3 grafts) to prepared osteochondral defects. The patients were evaluated clinically and radiographically at a mean of forty-five months after surgery. Eighteen patients were free from elbow pain, and one had mild pain occasionally. The mean total arc of elbow motion and standard deviation increased significantly from 112 degrees +/- 17 degrees preoperatively to 128 degrees +/- 12 degrees postoperatively (p < 0.005). The mean clinical score described by Timmerman and Andrews (with a maximum of 200 points) improved significantly from 131 +/- 23 points preoperatively to 191 +/- 15 points postoperatively (p < 0.0001). All patients except one had an excellent or good clinical result. All donor knees were graded as excellent on the basis of the Lysholm knee scoring system. All patients except two returned to a competitive level of the sport they had previously played. Neither loose-body formation nor secondary osteoarthritic changes were found in any patient. The current midterm results indicate that mosaicplasty can provide satisfactory clinical outcomes for teenage athletes with advanced capitellar osteochondritis dissecans lesions.


An investigation of antibiotic prophylaxis in implant practice in the UK.
There is increasing evidence of the inappropriate use of antimicrobials in dentistry and this may contribute to the problem of antimicrobial resistance. The research to date with regard to efficacy of antimicrobial prophylaxis in reducing failure of integration and postoperative complications when placing dental implants remains equivocal. The aim of this study was to investigate how dentists in the UK use antimicrobials prophylactically in implant practice. An e-mail link was provided in 2011 to an anonymous online (Smart-Survey) questionnaire using three databases of dentists who, by being on them, had registered an interest in placing dental implants. Absolute frequencies were used to describe the study sample demographics and examine the distribution of responses for all the variables investigated. One hundred and nine completed questionnaires were received. Seventy-two percent (n = 76) routinely prescribed prophylactic antibiotics for all procedures. There was a wide variation in the pre-operative and postoperative prescription regimens with the majority (84%) stating that it was to prevent infection at the site of surgery or to reduce a bacteraemia. Although this was a small study with a low response rate, wide variations in antibiotic prescribing regimens with respect to drug, dose and duration were found. Further research is needed and guidelines developed to prevent antibiotic overprescribing and misuse.


Plant-based solutions for veterinary immunotherapeutics and prophylactics.
An alarming increase in emergence of antibiotic resistance among pathogens worldwide has become a serious threat to our ability to treat infectious diseases according to the World Health Organization. Extensive use of antibiotics by livestock producers promotes the spread of new resistant strains, some of zoonotic concern, which increases food-borne illness in humans and causes significant economic burden on healthcare systems. Furthermore, consumer preferences for meat/poultry/fish produced without the use of antibiotics shape today's market demand. So, it is viewed as inevitable by the One Health Initiative that humans need to reduce the use of antibiotics and turn to alternative, improved means to control disease: vaccination and prophylactics. Besides the intense research focused on novel therapeutic molecules, both these strategies rely heavily on the availability of cost-effective, efficient and scalable production platforms which will allow large-volume manufacturing for vaccines, antibodies and other biopharmaceuticals. Within this context, plant-based platforms for production of recombinant therapeutic proteins offer significant advantages over conventional expression systems, including lack of animal pathogens, low production costs, fast turnaround and response times and rapid, nearly-unlimited scalability. Also, because dried leaves and seeds can be stored at room temperature for lengthy periods without loss of recombinant proteins, plant expression systems have the potential to offer lucrative benefits from the development of edible vaccines and prophylactics, as these would not require "cold chain" storage and transportation, and could be administered in mass volumes with minimal processing. Several biotechnology companies currently have developed and adopted plant-based platforms for commercial production of recombinant protein therapeutics. In this manuscript, we outline the challenges in the process of livestock immunization as well as the current plant biotechnology developments aimed to address these challenges.


Influence of interior packing and hydrophobicity on the stability of a protein.
Protein interiors contain many tightly packed apolar atoms in a nearly crystalline state. Both shielding of apolar atoms from solvent and efficient interior packing arrangements affect protein stability, but their relative importance is unclear. To separate these effects, the stabilities of wild-type and mutant gene V proteins from bacteriophage fl were studied by measuring resistance to denaturation. The effects of subtle interior packing changes, both separate from and combined with changes in buried side chain hydrophobicity, were measured. For the interior apolar-to-apolar substitutions studied, the two effects were of the same magnitude and alteration of packing without accompanying hydrophobicity changes substantially destabilized the protein.


Molecular structure of endotoxins from Gram-negative marine bacteria: an update.
Marine bacteria are microrganisms that have adapted, through millions of years, to survival in environments often characterized by one or more extreme physical or chemical parameters, namely pressure, temperature and salinity. The main interest in the research on marine bacteria is due to their ability to produce several biologically active molecules, such as antibiotics, toxins and antitoxins, antitumor and antimicrobial agents. Nonetheless, lipopolysaccharides (LPSs), or their portions, from Gram-negative marine bacteria, have often shown low virulence, and represent potential candidates in the development of drugs to prevent septic shock. Besides, the molecular architecture of such molecules is related to the possibility of thriving in marine habitats, shielding the cell from the disrupting action of natural stress factors. Over the last few years, the depiction of a variety of structures of lipids A, core oligosaccharides and O-specific polysaccharides from LPSs of marine microrganisms has been given. In particular, here we will examine the most recently encountered structures for bacteria belonging to the genera Shewanella, Pseudoalteromonas and Alteromonas, of the gamma-Proteobacteria phylum, and to the genera Flavobacterium, Cellulophaga, Arenibacter and Chryseobacterium, of the Cytophaga-Flavobacterium-Bacteroides phylum. Particular attention will be paid to the chemical features expressed by these structures (characteristic monosaccharides, non-glycidic appendages, phosphate groups), to the typifying traits of LPSs from marine bacteria and to the possible correlation existing between such features and the adaptation, over years, of bacteria to marine environments.


The Slothful Claw: Osteology and Taphonomy of Nothronychus mckinleyi and N. graffami (Dinosauria: Theropoda) and Anatomical Considerations for Derived Therizinosaurids.
Nothronychus was the first definitive therizinosaurian discovered in North America and currently represents the most specialized North American therizinosaurian genus. It is known from two species, No. mckinleyi from the Moreno Hill Formation (middle Turonian) in west-central New Mexico, and No. graffami from the Tropic Shale (early Turonian) in south-central Utah. Both species are represented by partial to nearly complete skeletons that have helped elucidate evolutionary trends in Therizinosauria. In spite of the biogeographical and evolutionary importance of these two taxa, neither has received a detailed description. Here, we present comprehensive descriptions of No. mckinleyi and No. graffami, the latter of which represents the most complete therizinosaurid skeleton known to date. We amend previous preliminary descriptions of No. mckinleyi and No. graffami based on these new data and modify previous character states based on an in-depth morphological analysis. Additionally, we review the depositional history of both specimens of Nothronychus and compare their taphonomic modes. We demonstrate that the species were not only separated geographically, but also temporally. Based on ammonoid biozones, the species appear to have been separated by at least 1.5 million years and up to 3 million years. We then discuss the impacts of diagenetic deformation on morphology and reevaluate potentially diagnostic characters in light of these new data. For example, the ulna of No. mckinleyi is curved whereas the ulna of No. graffami was considered straight, a character originally separating the two species. However, here we present the difference as much more likely related to diagenetic compression in No. graffami rather than as a true biologic difference. Finally, we include copies of three-dimensional surface scans of all major bones for both taxa for reference.


Strigolactones Improve Plant Growth, Photosynthesis, and Alleviate Oxidative Stress under Salinity in Rapeseed (Brassica napus L.) by Regulating Gene Expression.
Rapeseed (Brassica napus L.) is a very important edible oil crop in the world, and the production is inhibited by abiotic stresses, such as salinity. Plant hormones can alleviate the stress by regulating the physiological processes and gene expression. To study the plant responses to salinity in combination with GR24, a synthesized strigolactone, the oilseed rape variety (Zhongshuang 11) replications were grown in the pots in a controlled growth chamber under three levels of salinity (0, 100, and 200 mM NaCl) and 0.18 μM GR24 treatments at the seedling stage for 7 days. The results showed that salinity depressed the shoots and roots growth, whereas GR24 improved the growth under salt stress. Leaf chlorophyll contents and gas exchange parameters (net photosynthetic rates, stomatal conductance, intercellular CO2 concentration, and transpiration rate) were also reduced significantly with increasing salinity, and these effects could be partially reversed by GR24 application. Additionally, GR24 treatment significantly increased and decreased the photosystem II quantum yield and non-photochemical quenching, respectively, under salinity stress conditions. The activities of peroxidase and superoxide dismutase increased, and lipid peroxidation measured by the level of malondialdehyde reduced due to GR24 application. The transcriptome analysis of root and shoot was conducted. Three hundred and forty-two common differentially expressed genes (DEGs) after GR24 treatment and 166 special DEGs after GR24 treatment under salinity stress were identified in root and shoot. The DEGs in root were significantly more than that in shoot. Quantitative PCR validated that the stress alleviation was mainly related to the gene expression of tryptophan metabolism, plant hormone signal transduction, and photosynthesis.


Stimulation of lens cell differentiation by gap junction protein connexin 45.6.
The present study was undertaken to explore the roles gap junctions play in lens epithelial cell differentiation. Recombinant retroviruses expressing three chick lens connexins (Cx)-Cx43, Cx45.6, and Cx56-were prepared and used to infect isolated chick lens primary cultures. The expression and distribution of proteins was determined using immunoblots and confocal immunofluorescence microscopy. Intercellular couplings were assessed by single cell microinjection and scrape-loading dye transfer, and cell proliferation was evaluated by [(3)H]thymidine labeling. Of the three lens connexins, only the cultures overexpressing exogenous Cx45.6 displayed the advancement of lens epithelial-fiber cell differentiation. The lentoids, a unique morphologic structure that is an indicative of lens fiber formation, were formed earlier in Cx45.6 overexpressed cultures; however, the rate of lens cell proliferation was not affected. The expression of the lens differentiation marker proteins, major intrinsic protein (MIP) and delta-crystallin, was also increased in Cx45.6-overexpressing cells. The cells overexpressing Cx45.6 displayed similar levels of intercellular couplings as did the controls. Moreover, exogenously expressed connexins were mostly colocalized with their endogenous counterparts and the overexpression of Cx45.6 had no impact on the expression of endogenous Cx43 and Cx56. These results suggest that Cx45.6 plays an important role in stimulating lens cell differentiation and fiber formation, which is different from the other lens connexins, Cx43 and Cx56. This stimulatory effect is independent of gap junction-mediated intercellular communication and lens cell proliferation.


Glycemic Control and Urinary Tract Infections in Women with Type 1 Diabetes: Results from the DCCT/EDIC.
We examined the relationship between glycemic control and urinary tract infections in women with type 1 diabetes mellitus. Women enrolled in the Epidemiology of Diabetes Interventions and Complications study, the observational followup of the Diabetes Control and Complications Trial, were surveyed to assess the rate of physician diagnosed urinary tract infections in the preceding 12 months. The relationship between glycated hemoglobin levels and number of urinary tract infections in the previous 12 months was assessed using a multivariable Poisson regression model. A total of 572 women were evaluated at year 17. Mean age was 50.7 ± 7.2 years, mean body mass index was 28.6 ± 5.9 kg/m(2), mean type 1 diabetes duration was 29.8 ± 5.0 years and mean glycated hemoglobin was 8.0% ± 0.9%. Of these women 86 (15.0%) reported at least 1 physician diagnosed urinary tract infection during the last 12 months. Higher glycated hemoglobin levels were significantly associated with number of urinary tract infections such that for every unit increase (1%) in recent glycated hemoglobin level, there was a 21% (p=0.02) increase in urinary tract infection frequency in the previous 12 months after adjusting for race, hysterectomy status, urinary incontinence, sexual activity in the last 12 months, peripheral and autonomic neuropathy, and nephropathy. The frequency of urinary tract infections increases with poor glycemic control in women with type 1 diabetes. This relationship is independent of other well described predictors of urinary tract infections and suggests that factors directly related to glycemic control may influence the risk of lower urinary tract infections.


Fluctuation tests: how reliable are the estimates of mutation rates?
Fifty one years ago, Luria and Delbrück published in Genetics a paper that was to become a classic. In it they proved, beyond all reasonable doubt, that bacteria were mutating to phage resistance long before they could have encountered any bacteriophage. Luria and Delbrück also showed how the same experimental data could be used to estimate bacterial mutation rates. Since that time and in many different contexts the methods that they introduced have been used to estimate mutation rates. However, little seems to be known about the errors to be expected in such estimates. In what follows I examine how much uncertainty in the estimates is to be expected merely on the basis of the stochastic variability inherent in the sampling process. On the basis of this examination I question a few traditional ideas and conclude with some practical suggestions. The results were obtained by stimulation. It is my hope that they may inspire others to provide a rigorous theoretical basis for such calculations.


Pax6 associates with H3K4-specific histone methyltransferases Mll1, Mll2, and Set1a and regulates H3K4 methylation at promoters and enhancers.
Pax6 is a key regulator of the entire cascade of ocular lens formation through specific binding to promoters and enhancers of batteries of target genes. The promoters and enhancers communicate with each other through DNA looping mediated by multiple protein-DNA and protein-protein interactions and are marked by specific combinations of histone posttranslational modifications (PTMs). Enhancers are distinguished from bulk chromatin by specific modifications of core histone H3, including H3K4me1 and H3K27ac, while promoters show increased H3K4me3 PTM. Previous studies have shown the presence of Pax6 in as much as 1/8 of lens-specific enhancers but a much smaller fraction of tissue-specific promoters. Although Pax6 is known to interact with EP300/p300 histone acetyltransferase responsible for generation of H3K27ac, a potential link between Pax6 and histone H3K4 methylation remains to be established. Here we show that Pax6 co-purifies with H3K4 methyltransferase activity in lens cell nuclear extracts. Proteomic studies show that Pax6 immunoprecipitates with Set1a, Mll1, and Mll2 enzymes, and their associated proteins, i.e., Wdr5, Rbbp5, Ash2l, and Dpy30. ChIP-seq studies using chromatin prepared from mouse lens and cultured lens cells demonstrate that Pax6-bound regions are mostly enriched with H3K4me2 and H3K4me1 in enhancers and promoters, though H3K4me3 marks only Pax6-containing promoters. The shRNA-mediated knockdown of Pax6 revealed down-regulation of a set of direct target genes, including Cap2, Farp1, Pax6, Plekha1, Prox1, Tshz2, and Zfp536. Pax6 knockdown was accompanied by reduced H3K4me1 at enhancers and H3K4me3 at promoters, with little or no changes of the H3K4me2 modifications. These changes were prominent in Plekha1, a gene regulated by Pax6 in both lens and retinal pigmented epithelium. Our study supports a general model of Pax6-mediated recruitment of histone methyltransferases Mll1 and Mll2 to lens chromatin, especially at distal enhancers. Genome-wide data in lens show that Pax6 binding correlates with H3K4me2, consistent with the idea that H3K4me2 PTMs correlate with the binding of transcription factors. Importantly, partial reduction of Pax6 induces prominent changes in local H3K4me1 and H3K4me3 modification. Together, these data open the field to mechanistic studies of Pax6, Mll1, Mll2, and H3K4me1/2/3 dynamics at distal enhancers and promoters of developmentally controlled genes.


Mirnovo: genome-free prediction of microRNAs from small RNA sequencing data and single-cells using decision forests.
The discovery of microRNAs (miRNAs) remains an important problem, particularly given the growth of high-throughput sequencing, cell sorting and single cell biology. While a large number of miRNAs have already been annotated, there may well be large numbers of miRNAs that are expressed in very particular cell types and remain elusive. Sequencing allows us to quickly and accurately identify the expression of known miRNAs from small RNA-Seq data. The biogenesis of miRNAs leads to very specific characteristics observed in their sequences. In brief, miRNAs usually have a well-defined 5' end and a more flexible 3' end with the possibility of 3' tailing events, such as uridylation. Previous approaches to the prediction of novel miRNAs usually involve the analysis of structural features of miRNA precursor hairpin sequences obtained from genome sequence. We surmised that it may be possible to identify miRNAs by using these biogenesis features observed directly from sequenced reads, solely or in addition to structural analysis from genome data. To this end, we have developed mirnovo, a machine learning based algorithm, which is able to identify known and novel miRNAs in animals and plants directly from small RNA-Seq data, with or without a reference genome. This method performs comparably to existing tools, however is simpler to use with reduced run time. Its performance and accuracy has been tested on multiple datasets, including species with poorly assembled genomes, RNaseIII (Drosha and/or Dicer) deficient samples and single cells (at both embryonic and adult stage).


Population pharmacokinetics of olprinone in healthy male volunteers.
Olprinone decreases the cardiac preload and/or afterload because of its vasodilatory effect and increases myocardial contractility by inhibiting phosphodiesterase III. The objective of this study was to characterize the population pharmacokinetics of olprinone after a single continuous infusion in healthy male volunteers. We used 500 plasma concentration data points collected from nine healthy male volunteers for the study. The population pharmacokinetic analysis was performed using the nonlinear mixed effect model (NONMEM®) software. The time course of plasma concentration of olprinone was best described using a two-compartment model. The final pharmacokinetic parameters were total clearance (7.37 mL/minute/kg), distribution volume of the central compartment (134 mL/kg), intercompartmental clearance (7.75 mL/minute/kg), and distribution volume of the peripheral compartment (275 mL/kg). The interindividual variability in the total clearance was 12.4%, and the residual error variability (exponential and additive) were 22.2% and 0.129 (standard deviation). The final pharmacokinetic model was assessed using a bootstrap method and visual predictive check. We developed a population pharmacokinetic model of olprinone in healthy male adults. The bootstrap method and visual predictive check showed that this model was appropriate. Our results might be used to develop the population pharmacokinetic model in patients.


Dlx1 and Dlx2 control neuronal versus oligodendroglial cell fate acquisition in the developing forebrain.
Progenitors within the ventral telencephalon can generate GABAergic neurons and oligodendrocytes, but regulation of the neuron-glial switch is poorly understood. We investigated the combinatorial expression and function of Dlx1&2, Olig2, and Mash1 transcription factors in the ventral telencephalon. We show that Dlx homeobox transcription factors, required for GABAergic interneuron production, repress oligodendrocyte precursor cell (OPC) formation by acting on a common progenitor to determine neuronal versus oligodendroglial cell fate acquisition. We demonstrate that Dlx1&2 negatively regulate Olig2-dependant OPC formation and that Mash1 promotes OPC formation by restricting the number of Dlx+ progenitors. Progenitors transplanted from Dlx1&2 mutant ventral telencephalon into newborn wild-type mice do not produce neurons but differentiate into myelinating oligodendrocytes that survive into adulthood. Our results identify another role for Dlx genes as modulators of neuron versus oligodendrocyte development in the ventral embryonic forebrain.


Vultures respond to challenges of near-ground thermal soaring by varying bank angle.
Many large birds rely on thermal soaring flight to travel cross-country. As such, they are under selective pressure to minimise the time spent gaining altitude in thermal updrafts. Birds should be able to maximise their climb rates by maintaining a position close to the thermal core through careful selection of bank angle and airspeed; however, there have been few direct measurements of either parameter. Here, we apply a novel methodology to quantify the bank angles selected by soaring birds using on-board magnetometers. We couple these data with airspeed measurements to parameterise the soaring envelope of two species of Gyps vulture, from which it is possible to predict 'optimal' bank angles. Our results show that these large birds respond to the challenges of gaining altitude in the initial phase of the climb, where thermal updrafts are weak and narrow, by adopting relatively high, and conserved, bank angles (25-35 deg). The bank angle decreased with increasing altitude, in a manner that was broadly consistent with a strategy of maximising the rate of climb. However, the lift coefficients estimated in our study were lower than those predicted by theoretical models and wind-tunnel studies. Overall, our results highlight how the relevant currency for soaring performance changes within individual climbs: when thermal radius is limiting, birds vary bank angle and maintain a constant airspeed, but speed increases later in the climb in order to respond to decreasing air density.


The relationship of hand abnormalities to diabetes and diabetic retinopathy.
The hands of 299 diabetic patients with and 161 without retinopathy were examined for abnormalities. Almost all abnormalities were finger joint contractures resulting in limited joint mobility (LJM) and/or Dupuytren's contractures (DC). Both LJM and DC occurred not only in insulin-dependent diabetes (IDDM) but also in non-insulin-dependent diabetes (NIDDM). In retinopathy patients LJM and DC occurred in 48% and 36% of patients, respectively, compared with 24% and 16% in those without retinopathy. These differences were statistically significant (P less than 0.001). The higher prevalence of LJM in the retinopathy group affected mainly those with severe retinopathy, there being no difference between background and nonretinopathy patients. DC was less clearly related to severe retinopathy. LJM was more severe in those with than without retinopathy. LJM and DC were also related to age and duration of known diabetes. Subgroups matched for age and duration of known diabetes showed that the main relationship of hand abnormalities was to retinopathy in IDDM, but more to age and duration of known diabetes in NIDDM.


Polyarginine Interacts More Strongly and Cooperatively than Polylysine with Phospholipid Bilayers.
The interactions of two highly positively charged short peptide sequences with negatively charged lipid bilayers were explored by fluorescence binding assays and all-atom molecular dynamics simulations. The bilayers consisted of mixtures of phosphatidylglycerol (PG) and phosphatidylcholine (PC) lipids as well as a fluorescence probe that was sensitive to the interfacial potential. The first peptide contained nine arginine repeats (Arg9), and the second one had nine lysine repeats (Lys9). The experimentally determined apparent dissociation constants and Hill cooperativity coefficients demonstrated that the Arg9 peptides exhibited weakly anticooperative binding behavior at the bilayer interface at lower PG concentrations, but this anticooperative effect vanished once the bilayers contained at least 20 mol % PG. By contrast, Lys9 peptides showed strongly anticooperative binding behavior at all PG concentrations, and the dissociation constants with Lys9 were approximately 2 orders of magnitude higher than with Arg9. Moreover, only arginine-rich peptides could bind to the phospholipid bilayers containing just PC lipids. These results along with the corresponding molecular dynamics simulations suggested two important distinctions between the behavior of Arg9 and Lys9 that led to these striking differences in binding and cooperativity. First, the interactions of the guanidinium moieties on the Arg side chains with the phospholipid head groups were stronger than for the amino group. This helped facilitate stronger Arg9 binding at all PG concentrations that were tested. However, at PG concentrations of 20 mol % or greater, the Arg9 peptides came into sufficiently close proximity with each other so that favorable like-charge pairing between the guanidinium moieties could just offset the long-range electrostatic repulsions. This led to Arg9 aggregation at the bilayer surface. By contrast, Lys9 molecules experienced electrostatic repulsion from each other at all PG concentrations. These insights may help explain the propensity for cell penetrating peptides containing arginine to more effectively cross cell membranes in comparison with lysine-rich peptides.


Functional properties of mesothelial cells after prolonged exposure to dialysate effluent.
The authors tested in vitro the effect of glucose-based and amino acid-based dialysate effluent on the function of human peritoneal mesothelial cells. After 9 days of exposure to the tested effluents with medium (1:1 v/v) or to a medium supplemented with 10% fetal calf serum (FCS) (control), several functional properties of the cells were studied. The synthesis of DNA measured by incorporation of 3H-methyl-thymidine was higher in mesothelial-cell monolayers exposed to the dialysates than in the controls. Synthesis of hyaluronic acid was similar in all three groups, but after stimulation with Il-1 the cells exposed to the dialysates produced more hyaluronic acid. Synthesis of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) was higher in the control cells. However, after stimulation with IL-1, the cells exposed to the dialysate showed greater synthesis of PAI-1 than of t-PA. Also, procoagulant activity of the control cells was higher than that of the cells exposed to the dialysates. We have concluded that the functional properties of the mesothelial cells may be altered in vitro during prolonged exposure to the dialysate, something that may also occur in vivo.


Teratopharmacological and behavioral effects of coffee in mice.
The possible relationship between coffee exposure during pregnancy and the teratopharmacological effects on the developing neonates was evaluated in albino mice. The body weight of pups of treated dams was significantly affected after birth and as the pups grew, their weight gains were lower compared to controls. This effect was time- and dose-dependent and the perinatal treatment was more effective (F(6) = 5.06, p < 0.02) than the prepartum treatment (F(6) = 3.12, p < 0.05). Body hair appearance and eye opening were delayed in all treated groups and again, the perinatal treatment was more effective and dose-dependent. Almost all indices for "locomotor behavior" were affected by all doses of coffee but only in the perinatally treated groups and the effects were neither time- nor dose-dependent. In the "tube restraint test", the latency to the first bite was decreased and the number of bites was increased in the offspring, while in female offspring the effect was opposite. The body weight of female offspring remained low even in young adult animals (F(6) = 9.89, p < 0.005). The brain weight in males was unaffected but in females it was decreased but only at the dose of 2 mg/kg. The liver and kidney weights of both sexes decreased at the lower doses. The protein content of these organs was also significantly affected by coffee treatment. These results suggest that coffee intake during pregnancy should be limited since it produces significant and long-lasting teratopharmacological and behavioral alterations in the offspring.


Cardiopulmonary Exercise Testing: What Is its Value?
Compared with traditional exercise tests, cardiopulmonary exercise testing (CPET) provides a thorough assessment of exercise integrative physiology involving the pulmonary, cardiovascular, muscular, and cellular oxidative systems. Due to the prognostic ability of key variables, CPET applications in cardiology have grown impressively to include all forms of exercise intolerance, with a predominant focus on heart failure with reduced or with preserved ejection fraction. As impaired cardiac output and peripheral oxygen diffusion are the main determinants of the abnormal functional response in cardiac patients, invasive CPET has gained new popularity, especially for diagnosing early heart failure with preserved ejection fraction and exercise-induced pulmonary hypertension. The most impactful advance has recently come from the introduction of CPET combined with echocardiography or CPET imaging, which provides basic information regarding cardiac and valve morphology and function. This review highlights modern CPET use as a single or combined test that allows the pathophysiological bases of exercise limitation to be translated, quite easily, into clinical practice.


Forensic expectations: Investigating a crime scene with prior information.
In a large body of research the influence of contextual information on decisions made in a broad range of disciplines has been studied. To date, the influence of these expectancy effects on the crime scene investigation has not been studied. In the present study we explored the effect of prior information given to crime scene investigators on their perception and interpretation of an ambiguous crime scene. Participants (N=58) were experienced crime scene investigators who were provided with a panoramic photograph of an ambiguous mock crime scene. The victim may have committed suicide or was murdered. Participants either received prior information indicating suicide, prior information indicating a violent death, or they received no prior information. Participants were asked about what they thought had happened at the scene of the crime, both at the initial assessment of the scene and at the end of the investigation when they were asked to describe the most likely scenario. They were also asked which traces they wanted to secure and why. Results showed that participants interpreted the crime scene differently dependent on how it was presented to them. Both the initial assessment of the scene and the most likely scenario that was described after the investigation were influenced by the prior information the participants were provided with, even though roughly the same traces were secured by all, independent of the prior information. Results demonstrate that prior information indeed influences the interpretation of the crime scene, but since the present study was exploratory further research is needed.


A cellular hierarchy in melanoma uncouples growth and metastasis.
Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.


Use of Indwelling Urinary Catheters in Nursing Homes: Implications for Quality Improvement Efforts.
To describe the epidemiology of indwelling urinary catheter use in nursing homes (NHs). Observational cohort study. A purposeful sampling strategy was used to identify a diverse sample of 28 Connecticut NHs, defined in terms of ownership, quality ratings, and bed size. Long-stay (>100 days) residents of study NHs with an indwelling urinary catheter present at any time over a 1-year period. Duration of catheter use was determined, and indications for catheter placement were documented. Indications considered appropriate included urinary retention or outlet obstruction, pressure ulcer (Stage 3 or 4 with risk of contamination by urine), hospice care, and need for accurate measurement of input and output. During quarterly follow-up assessments, whether the catheter was still in place or had been removed for any reason other than routine maintenance was determined. The overall rate of any urinary catheter use per 100 resident-beds over a 1-year period was 4.8 (range 1.0-9.9, median 5.1). Of the 228 residents meeting eligibility criteria, a documented indication for the catheter was present in the NH record for 195 (86%). Of those with a documented indication, 99% (n = 193) had one or more indications deemed appropriate, including urinary retention (83%), pressure ulcer (21%), hospice care (10%), and need for accurate measurement of input and output (6%). The urinary catheter was removed at some point during the period of observation in 49% (n = 111) of participants; those with a shorter duration of catheter use before study enrollment were more likely to have the catheter removed during the follow-up period. Of the 111 residents who had the catheter removed, 58 (52.3%) had it reinserted at some point during follow-up. These findings suggest that indwelling urinary catheter use in long-stay NH residents is uncommon and generally appropriate and that efforts to improve catheter care and outcomes should extend beyond a singular focus on reducing use.


Epistemologies of evidence-based medicine: a plea for corpus-based conceptual research in the medical humanities.
Evidence-based medicine has been the subject of much controversy within and outside the field of medicine, with its detractors characterizing it as reductionist and authoritarian, and its proponents rejecting such characterization as a caricature of the actual practice. At the heart of this controversy is a complex linguistic and social process that cannot be illuminated by appealing to the semantics of the modifier evidence-based. The complexity lies in the nature of evidence as a basic concept that circulates in both expert and non-expert spheres of communication, supports different interpretations in different contexts, and is inherently open to contestation. We outline a new methodology that combines a social epistemological perspective with advanced methods of corpus linguistics and elements of conceptual history to investigate this and other basic concepts that underpin the practice and ethos of modern medicine. The potential of this methodology to offer new insights into controversies such as those surrounding EBM is demonstrated through a case study of the various meanings supported by evidence and based, as attested in a large electronic corpus of online material written by non-experts as well as a variety of experts in different fields, including medicine.


In situ Fabrication of α-Bi2O3/(BiO)2CO3 Nanoplate Heterojunctions with Tunable Optical Property and Photocatalytic Activity.
Exploring the full potential use of heterojunction photocatalysts containing bismuth has attracted considerable interest in recent years. Fabrication of well-defined heterojunction photocatalysts with precise modulation of their chemical composition is crucial for tuning their optical properties and photocatalytic activity. In this study, we fabricated nanoplate α-Bi2O3/(BiO)2CO3 heterojunctions through in situ thermal treatment of (BiO)2CO3 nanoplates synthesized using a facile hydrothermal process. Characterization results showed that the as-prepared Bi2O3/(BiO)2CO3 heterojunctions possessed distinct crystal interface and exhibited pronounced structural and optical modulation, resulting in significant improvement of their photocatalytic activity for NO removal under simulated solar light irradiation compared with pristine (BiO)2CO3. Electron spin resonance spectroscopy showed that ⋅OH radicals were the major reactive species involved in NO degradation, which is consistent with the theoretical analysis. The heterojunction formation can not only broaden the light absorption range but also improve the charge separation of photo-induced electron-hole pairs. This study is an important advancement in the development of semiconductor heterojunctions towards achieving functional photocatalysts.


Serum response factor: toggling between disparate programs of gene expression.
Serum response factor (SRF) is a widely expressed transcription factor involved in orchestrating disparate programs of gene expression linked to muscle differentiation and cellular growth. Vascular smooth muscle cell (SMC) differentiation, for example, is marked by the coordinate expression of several contractile and cytoskeletal genes regulated directly by SRF through one or more CArG-box elements in the immediate vicinity of transcription start sites. In vascular disease, this CArG-dependent program of SMC differentiation is compromised and numerous CArG-dependent early growth-response genes are activated. Thus, SRF must toggle between programs of SMC differentiation and growth depending on local environmental cues. Moreover, SRF must distinguish between a course of SMC differentiation and programs of cardiac and skeletal muscle differentiation. Several mechanisms exist to ensure context- and cell-specific programs of SRF-dependent gene expression. These include regulated expression, DNA binding, and alternative splicing of SRF, flanking sequences adjacent to and chromatin remodeling of CArG boxes, RhoA-mediated alterations in the cytoskeleton, and association of SRF with a variety of cell-restricted cofactors including the recently discovered myocardin coactivator. Although many SMC-differentiation genes require critical evolutionarily conserved CArG boxes for SMC-restricted promoter activity in cultured cells and transgenic mice, the expression of a growing number of similarly restricted genes appears to be independent of SRF. Thus, parallel circuits of gene transcription have evolved for the appropriate expression of all genes that define mammalian SMC lineages. The purpose of this review is to summarize the history and progress made in SRF research with emphasis on the role this transcription factor plays in facilitating a program of SMC-restricted gene expression.


Correlation study between molecular structure of sesquiterpene lactones and the selective adsorption performance of molecularly imprinted polymers.
We preliminarily report that the structure of template molecules and target components correlates with the selective adsorption performance of molecularly imprinted polymer (MIPs) in sesquiterpene lactones. Template molecules involved three categories of sesquiterpene lactones with distinct ring systems: 5-mem lactone ring atractylenolide III, 7-mem lactone ring dehydrocostus lactone, and 10-mem lactone ring costunolide lactone, of which the conformations were verified by variable-temperature (1)H NMR spectroscopy. Reciprocal MIPs were prepared by precipitation polymerization and employed as selective sorbents in the columns of solid phase extraction (SPE). These columns were further used for enriching the mixed adsorption solution of sesquiterpene lactone ingredients and reference components. Finally, the extract of Radix Aucklandiae, a Chinese medicine herb, was used to verify the efficiency of this method. Our results demonstrate that the steric conformational stability of molecules is associated with the selective adsorption of their corresponding MIPs. We have further observed that the maximum adsorption capacity occurs when the target molecule conformation is consistent with that of the template molecule. The addition of more hydrophilic groups correlates with weaker adsorption of MIPs. Our findings provide important information to help guide the selection of appropriate template molecules for synthesis of MIPs with specific adsorption.


Peroxisome proliferator-activated receptor-gamma: too much of a good thing causes harm.
The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) helps to translate 'what you eat' into 'what you are' because it allows dietary fatty acids (PPARgamma ligands) to modulate gene transcription. Treatments for diabetes include PPARgamma activators, as they sensitize the body to insulin. Our understanding of PPARgamma function has recently been enhanced by a flurry of human and mouse genetic studies, and the characterization of new PPARgamma ligands. This insight has led us to propose that modulating PPARgamma activity, rather than activating it, might be the most effective strategy for treating metabolic disorders, as this will improve glucose homeostasis while preventing adipogenesis.


An overview of adenocarcinoma of the small intestine.
Even though the small intestine contains 90% of the gastrointestinal tract mucosa and is located between the stomach and large intestine, two organs with a high cancer incidence, adenocarcinoma of the small intestine is 1/50th as common as adenocarcinoma of the large bowel. In several other respects, small-intestinal adenocarcinoma resembles large bowel adenocarcinoma; eg, it arises from adenomatous polyps, co-occurs in the same individuals, and has a similar pattern of incidence rates by country. Small-intestinal adenocarcinoma is diagnosed prior to surgery in only about 50% of cases and often occurs in conjunction with small bowel obstruction. The mainstay of treatment is surgery; prognosis depends on stage at presentation. Little is known about the use of radiotherapy and chemotherapy in this malignancy, but most physicians utilize therapeutic strategies modeled on the management of large-intestinal adenocarcinoma. Clarification of the reason for the low incidence of small-intestinal adenocarcinoma could lead to new interventions for the prevention of colorectal cancer.


CD56 expression in acute promyelocytic leukemia: a possible indicator of poor treatment outcome?
Blast expression of CD56 is frequent in patients with t(8;21)(q22;q22) acute myeloid leukemia and is associated with an inferior outcome. The expression of CD56 has rarely been reported in acute promyelocytic leukemia (APL) and has not been clinically characterized. Therefore, we examined the prognostic significance of CD56 expression in APL. We identified all reported cases of CD56+ APL in the medical literature and collected clinical, biologic, and therapeutic details. Data were obtained for 12 patients with CD56+ APL (> 20% blast expression of CD56), including four cases from a single institution with a total of 42 APL patients. All of the CD56+ APL patients had documented cytogenetic presence of t(15;17), and of the nine reported isotypes, eight (89%) were S-isoform. Only six CD56+ patients (50%) attained complete remission (CR); the other six individuals died within 35 days of presentation. Of the six patients who attained a CR, three (50%) relapsed at 111, 121, and 155 weeks, whereas three remained in continuous CR at 19, 90, and 109 weeks. Comparison of the control CD56- to CD56+ APL patients demonstrated that the latter group had a significantly lower fibrinogen level (P = .007), and among patients for whom data were available, there was a higher frequency of the S-isoform (P = .006). Additionally, the CR rate (50% v 84%, P = .025) and overall median survival (5 v 232 weeks; P = .019) were significantly inferior for CD56+ APL patients. CD56+ acute promyelocytic leukemia is infrequent, seems to occur more frequently with the S-isoform subtype, and may be associated with a lower CR rate and inferior overall survival.


Traveling to a High-volume Center is Associated With Improved Survival for Patients With Esophageal Cancer.
An association between volume and outcomes has been observed for esophagectomy, though little is known about why or how patients choose low- or high-volume centers. The purpose of this study was to evaluate how travel burden and hospital volume influence treatment and outcomes of patients with locally advanced esophageal cancer. Predictors of receiving esophagectomy for patients with T1-3N1M0 mid or distal esophageal cancer in the National Cancer Data Base from 2006 to 2011 were identified using multivariable logistic regression. Survival was compared using propensity score-matched groups: patients in the bottom quartile of travel distance who underwent treatment at low-volume facilities (Local) and patients in the top quartile of travel distance who underwent treatment at high-volume facilities (Travel). Of 4979 patients who met inclusion criteria, we identified 867 Local patients who traveled 2.7 [interquartile range (IQR): 1.6-4 miles] miles to centers that treated 2.6 (IQR: 1.9-3.3) esophageal cancers per year, and 317 Travel patients who traveled 107.1 (IQR: 65-247) miles to centers treating 31.9 (IQR: 30.9-38.5) cases. Travel patients were more likely to undergo esophagectomy (67.8% vs 42.9%, P < 0.001) and had significantly better 5-year survival (39.8% vs 20.6%, P < 0.001) than Local patients. Patients who travel longer distances to high-volume centers have significantly different treatment and better outcomes than patients who stay close to home at low-volume centers. Strategies that support patient travel for treatment at high-volume centers may improve esophageal cancer outcomes.


Adherence to Oral Therapy for Urgency Urinary Incontinence: Results from the Anticholinergic Versus Botox Comparison (ABC) Trial.
Medication adherence with urgency urinary incontinence (UUI) treatment is challenging and the best assessment methodology is uncertain. We sought to describe adherence with anticholinergic (AC) versus placebo (P) by comparing pill counts and MEMSCAP event data and to identify factors associated with adherence. The randomized controlled AC versus Botox Comparison trial of women with moderate to severe idiopathic UUI included 126 participants initiating AC plus P bladder injection and 121 receiving P pills plus Botox injection. Adherence data on 243 participants (124 AC and 119 P) were calculated by pill count and MEMSCAP data for each 2-month interval during the 6-month study that allowed for dose escalation/drug change. Overall composite adherence estimates were calculated using the average of both methods and weighted by the duration of each 2-month interval. Treatment groups had no significant differences in dosing duration (P = 0.76) or mean adherence (AC, 83.3% [16.8] vs. P, 84.8% [13.8]). Only 53% of women met the dichotomous outcome of more than 80% adherence during all intervals. Correlation between adherence by pill counts versus MEMSCAP decreased over time with pill counts demonstrating higher adherence than MEMSCAP (r = 0.53, 0.50, and 0.36 for each 2-month interval). Lower adherence was associated with higher baseline incontinence severity and better UUI quality of life for the AC group and with current smoking status in both groups. Adherence using pill counts and MEMSCAP was reasonably correlated and similar in both the AC and P groups. In the AC group, higher baseline incontinence severity and better UUI Quality of Life were associated with decreased adherence. Smokers were less adherent.


Organic anion-transporting polypeptides.
Organic anion-transporting polypeptides or OATPs are central transporters in the disposition of drugs and other xenobiotics. In addition, they mediate transport of a wide variety of endogenous substrates. The critical role of OATPs in drug disposition has spurred research both in academia and in the pharmaceutical industry. Translational aspects with clinical questions are the focus in academia, while the pharmaceutical industry tries to define and understand the role these transporters play in pharmacotherapy. The present overview summarizes our knowledge on the interaction of food constituents with OATPs and on the OATP transport mechanisms. Further, it gives an update on the available information on the structure-function relationship of the OATPs and, finally, covers the transcriptional and posttranscriptional regulation of OATPs.


Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial.
Whether concomitant therapy is superior to bismuth quadruple therapy or 14-day triple therapy for the first-line treatment of Helicobacter pylori infection remains poorly understood. We aimed to compare the efficacy and safety of 10-day concomitant therapy, 10-day bismuth quadruple therapy, and 14-day triple therapy in the first-line treatment of H pylori. In this multicentre, open-label, randomised trial, we recruited adult patients (aged >20 years) with H pylori infection from nine medical centres in Taiwan. Patients who had at least two positive tests from the rapid urease test, histology, culture, or serology or who had a single positive 13C-urea breath test for gastric cancer screening were eligible for enrolment. Patients were randomly assigned (1:1:1) to either concomitant therapy (lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily) for 10 days; bismuth quadruple therapy (bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day) for 10 days; or triple therapy (lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily) for 14 days. A computer-generated permuted block randomisation sequence with a block size of 6 was used for randomisation, and the sequence was concealed in an opaque envelope until the intervention was assigned. Investigators were masked to treatment allocation. The primary outcome was the eradication frequency of H pylori with first-line therapy assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01906879. Between July 17, 2013, and April 20, 2016, 5454 patients were screened for eligibility. Of these, 1620 patients were randomly assigned in this study. The eradication frequencies were 90·4% (488/540 [95% CI 87·6-92·6]) for 10-day bismuth quadruple therapy, 85·9% (464/540 [82·7-88·6]) for 10-day concomitant therapy, and 83·7% (452/540 [80·4-86·6]) for 14-day triple therapy in the intention-to-treat analysis. 10-day bismuth quadruple therapy was superior to 14-day triple therapy (difference 6·7% [95% CI 2·7-10·7, p=0·001), but not 10-day concomitant therapy. 10-day concomitant therapy was not superior to 14-day triple therapy. The frequency of adverse events was 67% (358/533) in patients treated with 10-day bismuth quadruple therapy, 58% (309/535) in patients treated with 10-day concomitant therapy, and 47% (252/535) in patients treated with 14-day triple therapy. Bismuth quadruple therapy is preferable to 14-day triple therapy in the first-line treatment in the face of rising prevalence of clarithromycin resistance. Concomitant therapy given for 10 days might not be optimum and a longer treatment length should be considered. National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.


Protein C activity in dogs: adaptation of a commercial human colorimetric assay and evaluation of effects of storage time and temperature.
Objectives of this study were to adapt a commercial human protein C (PC) colorimetric assay for use in dogs and to investigate effects of various storage conditions. The human assay was modified by using pooled canine plasma for calibration and by increasing the activation time. PC activity was measured in fresh canine plasma and in plasma stored under various conditions. PC activity of some stored samples was significantly different from that of fresh plasma; however, differences were small. No difference was detected in samples stored under similar conditions but analyzed in different laboratories using similar methodology. Results of this study indicate that the human colorimetric assay is suitable for canine samples if pooled canine plasma is used for calibration, that Clinical and Laboratory Standards Institute sample storage guidelines developed for testing in humans are appropriate for dogs, and that comparisons of results from laboratories using similar methodology are legitimate.


Gap junction coupling and islet delta-cell function in health and disease.
The pancreatic islets contain beta-cells and alpha-cells, which are responsible for secreting two principal gluco-regulatory hormones; insulin and glucagon, respectively. However, they also contain delta-cells, a relatively sparse cell type that secretes somatostatin (SST). These cells have a complex morphology allowing them to establish an extensive communication network throughout the islet, despite their scarcity. Delta-cells are electrically excitable cells, and SST secretion is released in a glucose- and KATP-dependent manner. SST hyperpolarises the alpha-cell membrane and suppresses exocytosis. In this way, islet SST potently inhibits glucagon release. Recent studies investigating the activity of delta-cells have revealed they are electrically coupled to beta-cells via gap junctions, suggesting the delta-cell is more than just a paracrine inhibitor. In this Review, we summarize delta-cell morphology, function, and the role of SST signalling for regulating islet hormonal output. A distinguishing feature of this Review is that we attempt to use the discovery of this gap junction pathway, together with what is already known about delta-cells, to reframe the role of these cells in both health and disease. In particular, we argue that the discovery of gap junction communication between delta-cells and beta-cells provides new insights into the contribution of delta-cells to the islet hormonal defects observed in both type 1 and type 2 diabetes. This reappraisal of the delta-cell is important as it may offer novel insights into how the physiology of this cell can be utilised to restore islet function in diabetes.


SMURF1 promotes the proliferation, migration and invasion of gastric cancer cells.
Smad ubiquitin regulatory factor 1 (SMURF1), a well-known E3 ubiquitin ligase, targets substrate proteins for ubiquitination and proteasomal degradation. Accumulating studies have shown that SMURF1 acts as an oncogenic factor in human malignancies. However, the clinical significance of SMURF1 and its role in gastric cancer (GC) remain unclear. The expression of SMURF1 was detected in 68 cases of GC and corresponding tumor-adjacent specimens. Our results revealed that SMURF1 was prominently overexpressed in GC specimens compared to corresponding tumor-adjacent tissues. Furthermore, increased levels of SMURF1 mRNA were also observed in GC cell lines. Clinicopathological detection ascertained that SMURF1-positive expression was associated with large tumor size, more lymph nodes and distant metastasis as well as advanced tumor-node-metastasis (TNM) stage of GC. Notably, GC patients with SMURF1 positive‑expressing tumors exhibited a significant decreased survival. Further experiments illustrated that SMURF1 knockdown significantly inhibited proliferation, migration and invasion of MGC-803 cells, while SMURF1 overexpression prominently promoted these behaviors in SGC-7901 cells. In vivo studies revealed that SMURF1 knockdown markedly inhibited tumor growth and liver metastasis of GC. Mechanically, SMURF1 inversely regulated the expression of DOC-2/DAB2 interactive protein (DAB2IP) in GC tissues and cells. Furthermore, DAB2IP restoration revealed similar effects to SMURF1 knockdown on MGC-803 cells with decreased proliferation, migration and invasion. In addition, the PI3K/Akt pathway and its downstream targets including c-Myc and ZEB1 were potentially involved in the oncogenic role of the SMURF1/DABIP axis. Collectively, the present study revealed the first evidence that SMURF1 can be potentially used as a clinical biomarker and target for novel treatment of human GC.


Carbon- and crack-free growth of hexagonal boron nitride nanosheets and their uncommon stacking order.
The quality of hexagonal boron nitride nanosheets (h-BNNS) is often associated with the most visible aspects such as lateral size and thickness. Less obvious factors such as sheet stacking order could also have a dramatic impact on the properties of BNNS and therefore its applications. The stacking order can be affected by contamination, cracks, and growth temperatures. In view of the significance of chemical-vapour-decomposition (CVD) assisted growth of BNNS, this paper reports on strategies to grow carbon- and crack-free BNNS by CVD and describes the stacking order of the resultant BNNS. Pretreatment of the most commonly used precursor, ammonia borane, is necessary to remove carbon contamination caused by residual hydrocarbons. Flattening the Cu and W substrates prior to growth and slow cooling around the Cu melting point effectively facilitate the uniform growth of h-BNNS, as a result of a minimal temperature gradient across the Cu substrate. Confining the growth inside alumina boats effectively minimizes etching of the nanosheet by silica nanoparticles originating from the commonly used quartz reactor tube. h-BNNS grown on solid Cu surfaces using this method adopt AB, ABA, AC', and AC'B stacking orders, which are known to have higher energies than the most stable AA' configuration. These findings identify a pathway for the fabrication of high-quality h-BNNS via CVD and should spur studies on stacking order-dependent properties of h-BNNS.


Disorders of breathing and continence have a stronger association with back pain than obesity and physical activity.
Although obesity and physical activity have been argued to predict back pain, these factors are also related to incontinence and breathing difficulties. Breathing and continence mechanisms may interfere with the physiology of spinal control, and may provide a link to back pain. The aim of this study was to establish the association between back pain and disorders of continence and respiration in women. We conducted a cross-sectional analysis of self-report, postal survey data from the Australian Longitudinal Study on Women's Health. We used multinomial logistic regression to model four levels of back pain in relation to both the traditional risk factors of body mass index and activity level, and the potential risk factors of incontinence, breathing difficulties, and allergy. A total of 38,050 women were included from three age-cohorts. When incontinence and breathing difficulties were considered, obesity and physical activity were not consistently associated with back pain. In contrast, odds ratios (OR) for often having back pain were higher for women often having incontinence compared to women without incontinence (OR were 2.5, 2.3 and 2.3 for young, mid-age and older women, respectively). Similarly, mid-aged and older women had higher odds of having back pain often when they experienced breathing difficulties often compared to women with no breathing problems (OR of 2.0 and 1.9, respectively). Unlike obesity and physical activity, disorders of continence and respiration were strongly related to frequent back pain. This relationship may be explained by physiological limitations of co-ordination of postural, respiratory and continence functions of trunk muscles.


Speeding towards individualized treatment for pancreatic cancer by taking an alternative road.
Accumulation of genetic mutations drives the development of pancreatic ductal adenocarcinoma (PDAC). Contrary to what it is expected, however, genetic analyses, no matter how precise or detailed, do not allow the identification of patient groups with different clinical outcomes or the selection of specific treatments. In fact, clinical outcome and sensitivity to treatments are associated with a given phenotype and are therefore associated at a transcriptomic level. In practical terms, therefore, the most appropriate readout for phenotypically stratifying PDACs should be transcriptomic and not genetic analysis. Recently data indicate that studying the expression of a selected gene set could inform selection of the most appropriate treatment for patients, moving towards an individualized medicine approach for this dismal disease. We are optimizing this approach by developing a platform based on obtaining organoids directly from surgical as well as endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsies of tumors, which serve as a source of RNA, allowing determination of the transcription level of some informative genes. We are convinced that in the near future, the treatment of cancers will be preceded by an extensive molecular characterization of cancer cells in order to select the most appropriate treatments.


Protective Efficacy of the Caterpillar Mushroom, Ophiocordyceps sinensis (Ascomycetes), from India in Neuronal Hippocampal Cells against Hypoxia.
This study demonstrated the protective efficiency of extracts of the Indian variety of Ophiocordyceps sinensis (=Cordyceps sinensis) (CSEs) in HT22 (murine hippocampal) cells under hypoxic conditions. Various parameters such as cell viability, reactive oxygen species, levels of endogenous antioxidants, inflammatory cytokines, transcription factors, and oxidation of macromolecules were analyzed. In addition, the radical scavenging abilities of hydroxyl radicals, nitric oxide, and superoxide radicals were also studied. Antioxidant compounds, ascorbic acid, hesperidin, and rutin were quantified by high-performance thin-layer chromatography. The information acquired from high-performance thin-layer chromatography profiling was subjected to principal component analysis for data clustering. Findings of this research revealed that ascorbic acid and rutin were highest in aqueous CSE, whereas the maximum amount of hesperidin was found in 25% alcoholic CSE. In vitro studies showed that all the CSEs protected HT22 cells well by upregulating the level of endogenous antioxidants and preventing the oxidation of lipids and proteins. These extracts also reduced the amount of hypoxia-induced inflammatory cytokines and transcription factors on par with the normoxic control with more or less equal protection in the cells under hypoxia, and indicated significant radical scavenging potential.


Can groundwater sampling techniques used in monitoring wells influence methane concentrations and isotopes?
Methane concentrations and isotopic composition in groundwater are the focus of a growing number of studies. However, concerns are often expressed regarding the integrity of samples, as methane is very volatile and may partially exsolve during sample lifting in the well and transfer to sampling containers. While issues concerning bottle-filling techniques have already been documented, this paper documents a comparison of methane concentration and isotopic composition obtained with three devices commonly used to retrieve water samples from dedicated observation wells. This work lies within the framework of a larger project carried out in the Saint-Édouard area (southern Québec, Canada), whose objective was to assess the risk to shallow groundwater quality related to potential shale gas exploitation. The selected sampling devices, which were tested on ten wells during three sampling campaigns, consist of an impeller pump, a bladder pump, and disposable sampling bags (HydraSleeve). The sampling bags were used both before and after pumping, to verify the appropriateness of a no-purge approach, compared to the low-flow approach involving pumping until stabilization of field physicochemical parameters. Results show that methane concentrations obtained with the selected sampling techniques are usually similar and that there is no systematic bias related to a specific technique. Nonetheless, concentrations can sometimes vary quite significantly (up to 3.5 times) for a given well and sampling event. Methane isotopic composition obtained with all sampling techniques is very similar, except in some cases where sampling bags were used before pumping (no-purge approach), in wells where multiple groundwater sources enter the borehole.


The complete Ac/Ds transposon family of maize.
The nonautonomous maize Ds transposons can only move in the presence of the autonomous element Ac. They comprise a heterogeneous group that share 11-bp terminal inverted repeats (TIRs) and some subterminal repeats, but vary greatly in size and composition. Three classes of Ds elements can cause mutations: Ds-del, internal deletions of the 4.6-kb Ac element; Ds1, ~400-bp in size and sharing little homology with Ac, and Ds2, variably-sized elements containing about 0.5 kb from the Ac termini and unrelated internal sequences. Here, we analyze the entire complement of Ds-related sequences in the genome of the inbred B73 and ask whether additional classes of Ds-like (Ds-l) elements, not uncovered genetically, are mobilized by Ac. We also compare the makeup of Ds-related sequences in two maize inbreds of different origin. We found 903 elements with 11-bp Ac/Ds TIRs flanked by 8-bp target site duplications. Three resemble Ac, but carry small rearrangements. The others are much shorter, once extraneous insertions are removed. There are 331 Ds1 and 39 Ds2 elements, many of which are likely mobilized by Ac, and two novel classes of Ds-l elements. Ds-l3 elements lack subterminal homology with Ac, but carry transposase gene fragments, and represent decaying Ac elements. There are 44 such elements in B73. Ds-l4 elements share little similarity with Ac outside of the 11-bp TIR, have a modal length of ~1 kb, and carry filler DNA which, in a few cases, could be matched to gene fragments. Most Ds-related elements in B73 (486/903) fall in this class. None of the Ds-l elements tested responded to Ac. Only half of Ds insertion sites examined are shared between the inbreds B73 and W22. The majority of Ds-related sequences in maize correspond to Ds-l elements that do not transpose in the presence of Ac. Unlike actively transposing elements, many Ds-l elements are inserted in repetitive DNA, where they probably become methylated and begin to decay. The filler DNA present in most elements is occasionally captured from genes, a rare feature in transposons of the hAT superfamily to which Ds belongs. Maize inbreds of different origin are highly polymorphic in their DNA transposon makeup.


Sex-specific effects of wind on the flight decisions of a sexually dimorphic soaring bird.
In a highly dynamic airspace, flying animals are predicted to adjust foraging behaviour to variable wind conditions to minimize movement costs. Sexual size dimorphism is widespread in wild animal populations, and for large soaring birds which rely on favourable winds for energy-efficient flight, differences in morphology, wing loading and associated flight capabilities may lead males and females to respond differently to wind. However, the interaction between wind and sex has not been comprehensively tested. We investigated, in a large sexually dimorphic seabird which predominantly uses dynamic soaring flight, whether flight decisions are modulated to variation in winds over extended foraging trips, and whether males and females differ. Using GPS loggers we tracked 385 incubation foraging trips of wandering albatrosses Diomedea exulans, for which males are c. 20% larger than females, from two major populations (Crozet and South Georgia). Hidden Markov models were used to characterize behavioural states-directed flight, area-restricted search (ARS) and resting-and model the probability of transitioning between states in response to wind speed and relative direction, and sex. Wind speed and relative direction were important predictors of state transitioning. Birds were much more likely to take off (i.e. switch from rest to flight) in stronger headwinds, and as wind speeds increased, to be in directed flight rather than ARS. Males from Crozet but not South Georgia experienced stronger winds than females, and males from both populations were more likely to take-off in windier conditions. Albatrosses appear to deploy an energy-saving strategy by modulating taking-off, their most energetically expensive behaviour, to favourable wind conditions. The behaviour of males, which have higher wing loading requiring faster speeds for gliding flight, was influenced to a greater degree by wind than females. As such, our results indicate that variation in flight performance drives sex differences in time-activity budgets and may lead the sexes to exploit regions with different wind regimes.


Immunotoxins: magic bullets or misguided missiles?
Thirteen years have passed since specific in vitro and in vivo killing of tumor cells by immunotoxins was first described. Why, then, has it taken so long to determine whether these pharmaceuticals will have a major impact on the treatment of cancer, AIDS and autoimmune disease? The answer is that the transfer of basic discoveries to the clinic is a slow, multistep, interdisciplinary process. Thus, immunotoxin molecules must be designed and redesigned by the basic scientist depending on the efficacy and toxicity shown in vitro and in relevant experimental models. Next, each version must be evaluated by clinicians in humans through a lengthy process (1-3 years) in which the dose regimen is optimized and in which new problems and issues frequently emerge. These problems must again be modeled and studied in animals before additional clinical trials are initiated. In this article, Ellen Vitetta and colleagues discuss both basic and clinical aspects of the development of immunotoxin therapy.


A comparison of blindpulling and blindwalking as measures of perceived absolute distance.
Blindwalking has become a common measure of perceived absolute distance and location, but it requires a relatively large testing space and cannot be used with people for whom walking is difficult or impossible. In the present article, we describe an alternative response type that is closely matched to blindwalking in several important respects but is less resource intensive. In the blindpulling technique, participants view a target, then close their eyes and pull a length of tape or rope between the hands to indicate the remembered target distance. As with blindwalking, this response requires integration of cyclical, bilateral limb movements over time. Blind-pulling and blindwalking responses are tightly linked across a range of viewing conditions, and blindpulling is accurate when prior exposure to visually guided pulling is provided. Thus, blindpulling shows promise as a measure of perceived distance that may be used in nonambulatory populations and when the space available for testing is limited.


Glyoxalase-I is a novel prognosis factor associated with gastric cancer progression.
Glyoxalase I (GLO1), a methylglyoxal detoxification enzyme, is implicated in the progression of human malignancies. The role of GLO1 in gastric cancer development or progression is currently unclear. The expression of GLO1 was determined in primary gastric cancer specimens using quantitative polymerase chain reaction, immunohistochemistry (IHC), and western blotting analyses. GLO1 expression was higher in gastric cancer tissues, compared with that in adjacent noncancerous tissues. Elevated expression of GLO1 was significantly associated with gastric wall invasion, lymph node metastasis, and pathological stage, suggesting a novel role of GLO1 in gastric cancer development and progression. The 5-year survival rate of the lower GLO1 expression groups was significantly greater than that of the higher expression groups (log rank P = 0.0373) in IHC experiments. Over-expression of GLO1 in gastric cancer cell lines increases cell proliferation, migration and invasiveness. Conversely, down-regulation of GLO1 with shRNA led to a marked reduction in the migration and invasion abilities. Our data strongly suggest that high expression of GLO1 in gastric cancer enhances the metastasis ability of tumor cells in vitro and in vivo, and support its efficacy as a potential marker for the detection and prognosis of gastric cancer.