Determination of Arabidopsis floral meristem identity by AGAMOUS.
Determinate growth of floral meristems in Arabidopsis requires the function of the floral regulatory gene AGAMOUS (AG). Expression of AG mRNA in the central region of floral meristems relies on the partially overlapping functions of the LEAFY (LFY) and APETALA1 (AP1) genes, which promote initial floral meristem identity. Here, we provide evidence that AG function is required for the final definition of floral meristem identity and that constitutive AG function can promote, independent of LFY and AP1 functions, the determinate floral state in the center of reproductive meristems. Loss-of-function analysis showed that the indeterminate central region of the ag mutant floral meristem undergoes conversion to an inflorescence meristem when long-day-dependent flowering stimulus is removed. Furthermore, gain-of-function analysis demonstrated that ectopic AG function results in precocious flowering and the formation of terminal flowers at apices of both the primary inflorescence and axillary branches of transgenic Arabidopsis plants in which AG expression is under the control of the 35S promoter from cauliflower mosaic virus. Similar phenotypes were also observed in lfy ap1 double mutants carrying a 35S-AG transgene. Together, these results indicate that AG is a principal developmental switch that controls the transition of meristem activity from indeterminate to determinate.


Gate-controlled heat generation in ZnO nanowire FETs.
Nanoscale heating production using nanowires has been shown to be particularly attractive for a number of applications including nanostructure growth, localized doping, transparent heating and sensing. However, all proof-of-concept devices proposed so far relied on the use of highly conductive nanomaterials, typically metals or highly doped semiconductors. In this article, we demonstrate a novel nanoheater architecture based on a single semiconductor nanowire field-effect transistor (NW-FET). Nominally undoped ZnO nanowires were incorporated into three-terminal devices whereby control of the nanowire temperature at a given source-drain bias was achieved by additional charge carriers capacitatively induced via the third gate electrode. Joule-heating selective ablation of poly(methyl methacrylate) deposited on ZnO nanowires was shown, demonstrating the ability of the proposed NW-FET configuration to enhance by more than one order of magnitude the temperature of a ZnO nanowire, compared to traditional two-terminal configurations. These findings demonstrate the potential of field-effect architectures to improve Joule heating power in nanowires, thus vastly expanding the range of suitable materials and applications for nanowire-based nanoheaters.


Double, Rydberg and charge transfer excitations from pairing matrix fluctuation and particle-particle random phase approximation.
Double, Rydberg, and charge transfer (CT) excitations have been great challenges for time-dependent density functional theory (TDDFT). Starting from an (N ± 2)-electron single-determinant reference, we investigate excitations for the N-electron system through the pairing matrix fluctuation, which contains information on two-electron addition/removal processes. We adopt the particle-particle random phase approximation (pp-RPA) and the particle-particle Tamm-Dancoff approximation (pp-TDA) to approximate the pairing matrix fluctuation and then determine excitation energies by the differences of two-electron addition/removal energies. This approach captures all types of interesting excitations: single and double excitations are described accurately, Rydberg excitations are in good agreement with experimental data and CT excitations display correct 1/R dependence. Furthermore, the pp-RPA and the pp-TDA have a computational cost similar to TDDFT and consequently are promising for practical calculations.


Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses.
Influenza remains a serious public health threat throughout the world. Vaccines and antivirals are available that can provide protection from infection. However, new viral strains emerge continuously because of the plasticity of the influenza genome, which necessitates annual reformulation of vaccine antigens, and resistance to antivirals can appear rapidly and become entrenched in circulating virus populations. In addition, the spread of new pandemic strains is difficult to contain because of the time required to engineer and manufacture effective vaccines. Monoclonal antibodies that target highly conserved viral epitopes might offer an alternative protection paradigm. Herein we describe the isolation of a panel of monoclonal antibodies derived from the IgG(+) memory B cells of healthy, human subjects that recognize a previously unknown conformational epitope within the ectodomain of the influenza matrix 2 protein, M2e. This antibody binding region is highly conserved in influenza A viruses, being present in nearly all strains detected to date, including highly pathogenic viruses that infect primarily birds and swine, and the current 2009 swine-origin H1N1 pandemic strain (S-OIV). Furthermore, these human anti-M2e monoclonal antibodies protect mice from lethal challenges with either H5N1 or H1N1 influenza viruses. These results suggest that viral M2e can elicit broadly cross-reactive and protective antibodies in humans. Accordingly, recombinant forms of these human antibodies may provide useful therapeutic agents to protect against infection from a broad spectrum of influenza A strains.


The impact of the 2008 financial crisis on food security and food expenditures in Mexico: a disproportionate effect on the vulnerable.
The present paper investigated the impact of the 2008 financial crisis on food security in Mexico and how it disproportionally affected vulnerable households. A generalized ordered logistic regression was estimated to assess the impact of the crisis on households' food security status. An ordinary least squares and a quantile regression were estimated to evaluate the effect of the financial crisis on a continuous proxy measure of food security defined as the share of a household's current income devoted to food expenditures. Setting Both analyses were performed using pooled cross-sectional data from the Mexican National Household Income and Expenditure Survey 2008 and 2010. The analytical sample included 29,468 households in 2008 and 27,654 in 2010. The generalized ordered logistic model showed that the financial crisis significantly (P<0·05) decreased the probability of being food secure, mildly or moderately food insecure, compared with being severely food insecure (OR=0·74). A similar but smaller effect was found when comparing severely and moderately food-insecure households with mildly food-insecure and food-secure households (OR=0·81). The ordinary least squares model showed that the crisis significantly (P<0·05) increased the share of total income spent on food (β coefficient of 0·02). The quantile regression confirmed the findings suggested by the generalized ordered logistic model, showing that the effects of the crisis were more profound among poorer households. The results suggest that households that were more vulnerable before the financial crisis saw a worsened effect in terms of food insecurity with the crisis. Findings were consistent with both measures of food security--one based on self-reported experience and the other based on food spending.


Randomized, double-blind, placebo-controlled clinical trial of sublingual immunotherapy in natural rubber latex allergic patients.
Natural rubber latex allergy is a common and unsolved health problem. Since the avoidance of exposure is very difficult, immunotherapy is strongly recommended, but before its use in patients, it is essential to prove the efficacy and safety of extracts.The aim of the present randomised, double-blind, placebo-controlled clinical trial was to assess the efficacy and tolerability of latex sublingual immunotherapy in adult patients undergoing permanent latex avoidance. Twenty-eight adult latex-allergic patients (5 males and 23 females), with mean age of 39 years (range 24-57) were randomized to receive a commercial latex-sublingual immunotherapy or placebo during one year, followed by another year of open, active therapy. The following outcomes were measured at baseline and at the end of first and second year of follow-up: skin prick test, gloves-use score, conjunctival challenge test, total and specific IgE, basophil activation test, and adverse reactions monitoring. No significant difference in any of the efficacy in vivo variables was observed between active and placebo groups at the end of the placebo-controlled phase, nor when each group was compared with their baseline values at the end of the two year-study. An improvement in the average percentage of basophils activated was observed. During the induction phase, 4 reactions in the active group and 5 in the placebo group were recorded. During the maintenance phase, two patients dropped out due to pruritus and to acute dermatitis respectively. Further studies are needed to evaluate latex-sublingual immunotherapy, since efficacy could not be demonstrated in adult patients with avoidance of the allergen. ACTRN12611000543987.


Cyclopentenyl cytosine induces senescence in breast cancer cells through the nucleolar stress response and activation of p53.
The induction of senescence has emerged as a potentially important contributor to the effects of chemotherapeutic agents against tumors. We have demonstrated that depletion of CTP induced by cyclopentenyl cytosine (CPEC; NSC 375575), a specific inhibitor of the enzyme CTP synthetase, induces irreversible growth arrest and senescence characterized by altered morphology and expression of senescence-associated β-galactosidase activity in MCF-7 breast cancer cells expressing wild-type p53. In contrast, differentiation in the absence of senescence resulted from CPEC treatment in MDA-MB-231 breast cancer cells that express a mutated p53. Both senescence of MCF-7 cells and differentiation of MDA-MB-231 cells were prevented by repletion of CTP through the cytidine salvage pathway. Senescence in MCF-7 cells was associated with a G(2)- and S-phase arrest, whereas differentiation in MDA-MB-231 cells was associated with arrest in G(1) phase at 5 days. Mechanistic studies revealed that CTP depletion induced a rapid translocation of nucleolar proteins, including nucleostemin and nucleolin into the nucleoplasm. This nucleolar stress response resulted in a sustained elevation of p53 and the p53 target genes, p21 and Mdm2, in cells with wild-type p53. Furthermore, short interfering RNA-induced knockdown of p53 in MCF-7 cells treated with CPEC prevented cellular senescence and increased apoptotic cell death. We conclude that CTP depletion and the resulting nucleolar stress response results in a senescence-like growth arrest through activation of p53, whereas cells with mutated p53 undergo differentiation or apoptotic cell death.


Intracranial pressure monitoring in patients with spontaneous intracerebral hemorrhage.
The utility of ICP monitoring and its benefit with respect to outcomes after ICH is unknown. The aim of this study was to compare intracerebral hemorrhage (ICH) outcomes in patients who underwent intracranial pressure (ICP) monitoring to those who were managed by care-guided imaging and/or clinical examination alone. This was a retrospective analysis of data from the Ethnic/Racial variations of Intracerebral Hemorrhage (ERICH) study between 2010 and 2015. ICH patients who underwent ICP monitoring were propensity-score matched, in a 1:1 ratio, to those who did not undergo ICP monitoring. The primary outcome was 90-day mortality. Secondary outcomes were in-hospital mortality, hyperosmolar therapy use, ICH evacuation, length of hospital stay, and 90-day modified Rankin Scale (mRS) score, excellent outcome (mRS score 0-1), good outcome (mRS score 0-2), Barthel Index, and health-related quality of life (HRQoL; measured by EQ-5D and EQ-5D visual analog scale [VAS] scores). A secondary analysis for patients without intraventricular hemorrhage was performed. The ICP and no ICP monitoring cohorts comprised 566 and 2434 patients, respectively. The matched cohorts comprised 420 patients each. The 90-day and in-hospital mortality rates were similar between the matched cohorts. Shift analysis of 90-day mRS favored no ICP monitoring (p < 0.001). The rates of excellent (p < 0.001) and good (p < 0.001) outcome, Barthel Index (p < 0.001), EQ-5D score (p = 0.026), and EQ-5D VAS score (p = 0.004) at 90 days were lower in the matched ICP monitoring cohort. Rates of mannitol use (p < 0.001), hypertonic saline use (p < 0.001), ICH evacuation (p < 0.001), and infection (p = 0.001) were higher, and length of hospital stay (p < 0.001) was longer in the matched ICP monitoring cohort. In the secondary analysis, the matched cohorts comprised 111 patients each. ICP monitoring had a lower rate of 90-day mortality (p = 0.041). Shift analysis of 90-day mRS, Barthel Index, and HRQoL metrics were comparable between the matched cohorts. The findings of this study do not support the routine utilization of ICP monitoring in patients with ICH.


An Increase in Mean Platelet Volume/Platelet Count Ratio Is Associated with Vascular Access Failure in Hemodialysis Patients.
After stenosis of arteriovenous vascular access in hemodialysis patients, platelets play a crucial role in subsequent thrombus formation, leading to access failure. In a previous study, the mean platelet volume (MPV)/platelet count ratio, but not MPV alone, was shown to be an independent predictor of 4-year mortality after myocardial infarction. However, little is known about the potential influence of MPV/platelet count ratio on vascular access patency in hemodialysis patients. A total of 143 patients undergoing routine hemodialysis were recruited between January 2013 and February 2016. Vascular access failure (VAF) was defined as thrombosis or a decrease of greater than 50% of normal vessel diameter, requiring either surgical revision or percutaneous transluminal angioplasty. Cox proportional hazards model analysis ascertained that the change of MPV/platelet count ratio between baseline and 3 months [Δ(MPV/platelet count ratio)3mo-baseline] had prognostic value for VAF. Additionally, the changes of MPV/platelet count ratio over time were compared in patients with and without VAF by using linear mixed model analysis. Of the 143 patients, 38 (26.6%) were diagnosed with VAF. During a median follow-up of 26.9 months (interquartile range 13.0-36.0 months), Δ(MPV/platelet count ratio)3mo-baseline significantly increased in patients with VAF compared to that in patients without VAF [11.6 (6.3-19.0) vs. 0.8 (-1.8-4.0), P< 0.001]. In multivariate analysis, Δ(MPV/platelet ratio count)3mo-baseline was an independent predictor of VAF, after adjusting for age, sex, diabetes, hypertension, coronary artery disease, cerebrovascular disease, vascular access type, the presence of previous VAF, and antiplatelet drug use (hazard ratio, 1.15; 95% confidence interval, 1.10-1.21; P< 0.001). Moreover, a liner mixed model revealed that there was a significant increase of MPV/platelet count ratio over time in patients with VAF compared to those without VAF (P< 0.001). An increase in MPV/platelet count ratio over time was an independent risk factor for VAF. Therefore, continuous monitoring of the MPV/platelet count ratio may be useful to screen the risk of VAF in patients undergoing routine hemodialysis.


Chest physical therapy for patients in the intensive care unit.
Chest physical therapy is used in the intensive care unit (ICU) to minimize pulmonary secretion retention, to maximize oxygenation, and to reexpand atelectatic lung segments. This article reviews how chest physical therapy is used with patients who are critically ill. A brief historical review of the literature is presented. Chest physical therapy treatments applicable to patients in the ICU are discussed. Postural drainage, percussion, vibration, breathing exercises, cough stimulation techniques, and airway suctioning are described in detail, with current references. The importance of patient mobilization is emphasized. The advantages of chest physical therapy over therapeutic bronchoscopy also are discussed. Two patient examples are used to demonstrate the beneficial effects that may be obtained with chest physical therapy. Following the removal of retained secretions, arterial oxygenation and partial pressure of arterial oxygen/fraction of inspired oxygen concentration ratios improved, and atelectasis resolved without the negative hemodynamic side effects of therapeutic bronchoscopy. Physical therapists trained in the ICU can safely perform chest physical therapy with the majority of patients who are critically ill.


Evidence of rodent-associated Bartonella and Rickettsia infections among intravenous drug users from Central and East Harlem, New York City.
We tested serum samples collected in 1997 and 1998 from a cohort of 204 injection drug users (IDUs) recruited from Central and East Harlem, New York City, New York, for antibodies reactive with seven rickettsial or Bartonella spp. antigens. Rodent-associated Bartonella elizabethae and Rickettsia akari were the primary etiologic agents of interest. The testing panel also included Bartonella henselae, Bartonella quintana, Rickettsia prowazekii, Rickettsia rickettsii, and Rickettsia typhi. The highest prevalence of seroreactive serum samples (46%) was found with B. elizabethae antigens; 10% of the samples reacted with B. henselae antigens, while 2% reacted with B. quintana antigens. Reactivity to the latter two antigens was likely due to cross-reactivity with B. elizabethae antigens in most instances. Among the spotted fever group rickettsiae, 18 (9%) samples reacted with R. akari, including 10 samples (5%) that also reacted with R. rickettsii. Cross-adsorption studies demonstrated that most of the spotted fever group rickettsiae antibodies were due to R. akari infections. Among the typhus group rickettsiae, 5 samples reacted weakly to R. prowazekii antigens, and no samples reacted with R. typhi antigens. These findings suggest that Harlem IDUs are commonly exposed to two rodent-associated zoonotic agents. Further study of IDU populations may help elucidate transmission cycles of these agents in inner cities where higher levels of transmission occur.


Distinct EEG amplitude suppression to facial gestures as evidence for a mirror mechanism in newborn monkeys.
At birth, human infants and newborns of other primate species demonstrate the capacity to attend and to respond to facial stimuli provided by a caregiver. Newborn infants are also capable of exhibiting a range of facial expressions. Identification of the neural underpinnings of these capacities represents a formidable challenge in understanding social development. One possible neuronal substrate is the mirror-neuron system assumed to activate shared motor cortical representations for both observation and production of actions. We tested this hypothesis by recording scalp EEG from 1- to 7-day-old newborn rhesus macaques who were observing and producing facial gestures. We found that 5-6 Hz EEG activity was suppressed both when the infants produced facial gestures and while they were observing facial gestures of a human experimenter, but not when they were observing nonbiological stimuli. These findings demonstrate the presence of neural reactivity for biological, communicatively relevant stimuli, which may be a likely signature of neuronal mirroring. The basic elements of the mirror-neuron system appear to operate from the very first days of life and contribute to the encoding of socially relevant stimuli.


Foodborne illness outbreak linked to a rural community kitchen in a rural area of Patiala District, Punjab, India, 2018.
In December 2018, an acute gastroenteritis outbreak was reported from Faridpur-Gujjran village, Patiala district, Punjab, India. The objective of this study was to describe the epidemiology and risk factors of the outbreak and recommend prevention measures. We conducted a descriptive study and a retrospective cohort study in the village. We defined a case as vomiting or ≥3 loose feces in 24 h plus abdominal pain and/or fever in a resident of the village during December 23-28, 2018. To find cases, we conducted a house-to-house survey; to identify risk factors, we conducted a retrospective cohort study. Fecal specimens were tested for enteric pathogens; water samples were tested for fecal contamination. We also interviewed food handlers. We compared attack rates by level of exposure. From the cohort study, we calculated risk ratios with 95% confidence intervals. From the 261 residents of the village, we identified 116 cases (attack rate 44%) and no deaths. The median age of affected persons was 27.5 years (range 0.5-80 years). The illness was associated with eating in a community kitchen of a temple during December 23-24, 2018. Eating mixed vegetables was associated with illness. We found no pathogens in fecal specimens. All three water samples showed coliform contamination. Cooked food had been left at room temperature before serving. Improper storage practices might have led to microbial proliferation of the food served. Our findings will help guide the enforcement of food safety policies for community kitchens.


N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase.
Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression. Recently generated data in the nur7 mouse model of Canavan disease suggests loss of aspartoacylase function results in compromised energetic integrity prior to oligodendrocyte death, abnormalities in myelin content, spongiform degeneration, and motor deficit. The present study utilized a next-generation "oligotropic" adeno-associated virus vector (AAV-Olig001) to quantitatively assess the impact of aspartoacylase reconstitution on developmental myelination. AAV-Olig001-aspartoacylase promoted normalization of NAA, increased bioavailable acetyl-CoA, and restored energetic balance within a window of postnatal development preceding gross histopathology and deteriorating motor function. Long-term effects included increased oligodendrocyte numbers, a global increase in myelination, reversal of vacuolation, and rescue of motor function. Effects on brain energy observed following AAV-Olig001-aspartoacylase gene therapy are shown to be consistent with a metabolic profile observed in mild cases of Canavan disease, implicating NAA in the maintenance of energetic integrity during myelination via oligodendroglial aspartoacylase.


An avian H7N1 gain-of-function experiment of great concern.
Inappropriately named gain-of-function influenza research seeks to confer airborne transmission on avian influenza A viruses that otherwise cause only dead-end infections in humans. A recent study has succeeded in doing this with a highly pathogenic ostrich H7N1 virus in a ferret model without loss of virulence. If transposable to humans, this would constitute a novel virus with a case fatality rate ~30 greater than that of Spanish flu. A commentary from three distinguished virologists considered the benefits of this work to outweigh potential risks. I beg to disagree with conclusions in both papers, for the underlying science is not as strong as it appears.


Important risk factors for death in adults: a 10-year follow-up of the Nutrition Canada survey cohort.
Data on mortality among over 8000 Canadians aged 35 to 79 years who participated in the Nutrition Canada survey are presented. The effects of various risk factors on mortality were assessed with a multivariate Poisson regression analysis. Factors associated with a significantly increased risk of death over a 10-year follow-up period ending in 1981 included cigarette smoking, hypertension and diabetes mellitus. A shallow U-shaped mortality pattern was observed for body mass index and for serum cholesterol level. No statistically significant increases in risk were associated with alcohol consumption. The population attributable risks for smoking, hypertension and diabetes were 39%, 8% and 6% respectively for men and 21%, 12% and 7% respectively for women.


Retest effects in working memory capacity tests: A meta-analysis.
The repeated administration of working memory capacity tests is common in clinical and research settings. For cognitive ability tests and different neuropsychological tests, meta-analyses have shown that they are prone to retest effects, which have to be accounted for when interpreting retest scores. Using a multilevel approach, this meta-analysis aims at showing the reproducibility of retest effects in working memory capacity tests for up to seven test administrations, and examines the impact of the length of the test-retest interval, test modality, equivalence of test forms and participant age on the size of retest effects. Furthermore, it is assessed whether the size of retest effects depends on the test paradigm. An extensive literature search revealed 234 effect sizes from 95 samples and 68 studies, in which healthy participants between 12 and 70 years repeatedly performed a working memory capacity test. Results yield a weighted average of g = 0.28 for retest effects from the first to the second test administration, and a significant increase in effect sizes was observed up to the fourth test administration. The length of the test-retest interval and publication year were found to moderate the size of retest effects. Retest effects differed between the paradigms of working memory capacity tests. These findings call for the development and use of appropriate experimental or statistical methods to address retest effects in working memory capacity tests.


Experimental study on nitrification in a submerged aerated biofilter.
The aim of the present work was to evaluate the performance of a semi-pilot scale BAF in order to obtain a highly polished effluent in terms of removal of organic matter, suspended solids and ammonia and to observe the influence of temperature, pH and nitrite accumulation on the nitrification process. The ammonia removal efficiency during summer and winter and the nitrite accumulation in presence of free ammonia were observed. The biomass density was measured at different filter bed heights and the sludge production from the effluent of the backwashing water was evaluated. The results obtained were used to calibrate a mathematical model for the prediction of the ammonia removal profile in the filter bed and of biomass thickness.


Engineering CRISPR/Cpf1 with tRNA promotes genome editing capability in mammalian systems.
CRISPR/Cpf1 features a number of properties that are distinct from CRISPR/Cas9 and provides an excellent alternative to Cas9 for genome editing. To date, genome engineering by CRISPR/Cpf1 has been reported only in human cells and mouse embryos of mammalian systems and its efficiency is ultimately lower than that of Cas9 proteins from Streptococcus pyogenes. The application of CRISPR/Cpf1 for targeted mutagenesis in other animal models has not been successfully verified. In this study, we designed and optimized a guide RNA (gRNA) transcription system by inserting a transfer RNA precursor (pre-tRNA) sequence downstream of the gRNA for Cpf1, protecting gRNA from immediate digestion by 3'-to-5' exonucleases. Using this new gRNAtRNA system, genome editing, including indels, large fragment deletion and precise point mutation, was induced in mammalian systems, showing significantly higher efficiency than the original Cpf1-gRNA system. With this system, gene-modified rabbits and pigs were generated by embryo injection or somatic cell nuclear transfer (SCNT) with an efficiency comparable to that of the Cas9 gRNA system. These results demonstrated that this refined gRNAtRNA system can boost the targeting capability of CRISPR/Cpf1 toolkits.


In vitro study of trileaflet polytetrafluoroethylene conduit and its valve-in-valve transformation.
Handmade trileaflet expanded polytetrafluoroethylene valved conduit developed using the flip-over method has been tailored for pulmonary valve reconstruction with satisfactory outcomes. We investigated the in vitro performance of the valve design in a mock circulatory system with various conduit sizes. In our study, the design was transformed into a transcatheter stent graft system which could fit in original valved conduits in a valve-in-valve fashion. Five different sizes of valved polytetrafluoroethylene vascular grafts (16, 18, 20, 22 and 24 mm) were mounted onto a mock circulatory system with a prism window for direct leaflets motion observation. Transvalvular pressure gradients were recorded using pressure transducers. Mean and instant flows were determined via a rotameter and a flowmeter. Similar flip-over trileaflet valve design was then carried out in 3 available stent graft sizes (23, 26 and 28.5 mm, Gore aortic extender), which were deployed inside the valved conduits. Peak pressure gradient across 5 different sized graft valves, in their appropriate flow setting (2.0, 2.5 and 5.0 l/min), ranged from 4.7 to 13.2 mmHg. No significant valve regurgitation was noted (regurgitant fraction: 1.6-4.9%) in all valve sizes and combinations. Three sizes of the trileaflet-valved stent grafts were implanted in the 4 sizes of valved conduits except for the 16-mm conduit. Peak pressure gradient increase after valved-stent graft-in-valved-conduit setting was <10 mmHg in all 4 conduits. The study showed excellent in vitro performance of trileaflet polytetrafluoroethylene valved conduits. Its valved stent graft transformation provided data which may serve as a reference for transcatheter valve-in-valve research in the future.


Expression of basement membrane type IV collagen and type IV collagenases (MMP-2 and MMP-9) in human fetal teeth.
Formation and degradation of dental basement membrane (BM) are important for tooth development. Data on the expression of genes for type IV collagen (the major structural component of the BM) and type IV collagenases [MMP-2 (72 kDa) and MMP-9 (92 kDa)], enzymes that degrade type IV collagen during human tooth development, are lacking. We studied expression of type IV collagen and the MMP-2 and MMP-9 in human fetal teeth (from the 13th to the 20th gestational weeks, covering cap stage through early hard tissue formation). During cap and bell stages, in situ hybridization located transcripts for alpha 1 type IV collagen chain in the fibroblasts surrounding the enamel organ. No alpha 1 type IV collagen chain mRNA was detected in tooth germ epithelium or dental papilla. However, type IV collagen immunoreactivity was observed in BM underlying the dental epithelium up to the appositional stage. Transcripts for MMP-2 were located mostly in the cells of the dental papilla and follicle. Transient expression of MMP-2 mRNA was observed in the inner enamel epithelium of late cap/early bell-stage teeth. During early apposition, a high level of MMP-2 was confined to secretory odontoblasts. Transcripts for MMP-9 were detected by the sensitive reverse-transcription polymerase chain reaction (RT-PCR) in developing teeth. Thus, in dental BM, alpha 1 type IV collagen chain may be of mesenchymal cell origin. Further, MMP-2 but not MMP-9 may participate in remodeling and degradation of BM during human tooth morphogenesis.


Rate of buthionine sulfoximine entry into brain and xenotransplanted human gliomas.
Buthionine sulfoximine (BSO) is an inhibitor of glutathione synthesis and can be used to potentiate the effects of chemotherapeutic alkylating agents and radiotherapy. We examined the rates of influx and efflux of [35S]BSO administered to athymic mice with and without xenografted D-54MG human gliomas. Three analytic approaches were applied to the experimental data to obtain values of the blood-to-tissue influx constant, K1, of BSO. Multiple time point experiments in tumor-bearing mice were analyzed with a two-compartment model and nonlinear fitting routines, and by graphical analysis which assumed no backflux of BSO from tissue to blood. A third approach used single time point data in nontumor-bearing mice and assumed no backflux. Calculated values of the K1 of BSO ranged from 0.23 to 1.35 microliters/g/min in tumor-free cortex, and from 5.3 to 6.3 microliters/g/min in the D-54MG gliomas. The tissue-to-blood efflux constant, k2, was zero in both cortex and tumor, suggesting that BSO entered cells and was trapped once it crossed the blood-brain barrier. Estimates of plasma vascular space (Vp) ranged from 2 to 20 microliters/g in cortex, and from 103 to 169 microliters/g in tumor. Another set of experiments, done in normal mice with different doses of BSO, suggested that BSO competes for neutral amino acid transport sites at the blood-brain barrier, but that the capacity of the carrier-mediated transport system is low and saturates at administered doses of about 0.5 mmol/kg (corresponding to plasma concentrations of about 12 mumol/ml). The rate of entry into brain was proportional to the octanol/water partition coefficient and molecular weight of BSO, which also supports passive diffusion as the means of entry. Consequently, although the rate of BSO entry into D-54MG gliomas was between 4 and 30 times higher than the rate of entry into tumor-free cortex, the results of these experiments suggest that most of the BSO that enters brain tumors in the doses commonly used in experimental situations will cross capillaries by passive diffusion.


Cholesterol Lowering and Antioxidative Effect of Pregerminated Brown Rice in Hypercholesterolemic Rats.
Pregerminated brown rice (GBR) is assumed to be more beneficial than polished white rice (WR), with regard to nutrition and cardiovascular health. To support this with scientific evidence, cholesterol-lowering and antioxidative effects of GBR were studied in the present investigation. The most popular rice variety in Bangladesh BIRI-29 was used to prepare GBR and WR. Initially, we analyzed the proximate composition, antioxidative phytochemicals, in vitro 2, 2-diphenyl-1-picrylhydrazyl (DPPH)-free radical scavenging ability and anti-hemolytic effects of GBR. To examine the dietary impact and possible benefits of the GBR, experimentally-induced hypercholesterolemic (HC, 1% cholesterol) rats were fed with GBR against WR for 12 wk. At the end, plasma total cholesterol (TC), low- and high-density lipoprotein-cholesterol (LDL-C and HDL-C), triglyceride (TG), fecal TC, and hepatic TC, lipid peroxide (LPO) and proinflammatory TNFα levels were determined. Relative to WR, GBR contained higher amounts of total polyphenols, total flavonoids, β-carotene and lycopene, and exhibited a stronger in vitro DPPH-free radical scavenging ability and antihemolytic potentials. Levels of plasma TC, LDL-C, TG, and hepatic TC and TG significantly decreased, while plasma HDL-C and fecal TC levels significantly increased in the GBR-fed HC-rats, indicating dietary GBR demonstrates a stronger antilipidemic effect than WR. The hepatic levels of LPO and TNFα also decreased (p<0.05) to a greater extent in GBR-fed HC-rats than those in the WR-fed rats. It is thus concluded that dietary GBR could be a natural treatment of hypercholesterolemia and related cardiovascular risk factors, and a source of antioxidants to reduce hemolysis and related anemia.


Estradiol modulates the expression pattern of myosin heavy chain subtypes via an ERα-mediated pathway in muscle-derived tissues and satellite cells.
Muscle-derived satellite cells (MDSCs) express MHC molecules intimately related to muscle function, which is supposed to be affected by local estrogen (E2) levels. However, cellular targets and molecular mechanisms involved are poorly understood. Genioglossus (GG) muscle tissues and MDSCs were derived from SHAM, ovariectomized or ovariectomized and 17 β-estradiol injected rats (n=10/group). ERα, ERβ, MHC expression and underlying regulatory mechanisms were investigated by RT-PCR, western blot and immunohistochemistry, inter alia upon selective antagonist exposure and Si-RNA transfection. MDSC viability and cell cycle were examined by MTT and flow cytometry. E2 upregulated MHC-I and downregulated MHC-IIb expression in MDSCs. E2 mediated effects on these molecules were inhibited by ERα-selective antagonist MPP and si-ERα, whereas they persisted upon exposure to ERβ-selective antagonist PHTPP. ERα was significantly higher expressed in muscle tissues compared to ERβ. ER positive stainings were fewer in the ovariectomized than in the SHAM group. Injection of E2 only increased the positive staining of ERα, but not of ERβ. Results suggest that E2 regulates MHC expression mainly through an ERα-mediated pathway with opposing effects on MHC-I and MHC-IIb. Thus, different hormonal processes that impact muscular pathophysiology presumably govern the functional properties of these molecules.


Computational Approaches for Decoding Select Odorant-Olfactory Receptor Interactions Using Mini-Virtual Screening.
Olfactory receptors (ORs) belong to the class A G-Protein Coupled Receptor superfamily of proteins. Unlike G-Protein Coupled Receptors, ORs exhibit a combinatorial response to odors/ligands. ORs display an affinity towards a range of odor molecules rather than binding to a specific set of ligands and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. The diversity in odor recognition is linked to the highly variable transmembrane domains of these receptors. The purpose of this study is to decode the odor-olfactory receptor interactions using in silico docking studies. In this study, a ligand (odor molecules) dataset of 125 molecules was used to carry out in silico docking using the GLIDE docking tool (SCHRODINGER Inc Pvt LTD). Previous studies, with smaller datasets of ligands, have shown that orthologous olfactory receptors respond to similarly-tuned ligands, but are dramatically different in their efficacy and potency. Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences. This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity. A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.


Metabolic and cardiovascular effects of chronic mild hyperuricemia in rodents.
Mildly elevated serum uric acid levels are common in people with metabolic syndrome and type 2 diabetes mellitus (T2DM), but whether elevated uric acid has a causal role in the pathogenesis of diabetes remains uncertain. We tested whether chronic mild hyperuricemia in rodents under controlled laboratory conditions can cause glucose intolerance in otherwise healthy animals, or whether it can worsen glucometabolic control in animals that are genetically predisposed to T2DM. We used an established model of experimental hyperuricemia in rodents with potassium oxonate dietary supplementation, which led to sustained, approximately two-fold elevation of uric acid compared with control animals. We also reversed the hyperuricemic effect of oxonate in some animals by treatment with a xanthine oxidase inhibitor. Manipulation of serum uric acid levels in Sprague-Dawley rats for up to 18 weeks did not affect fasting glucose and glucose tolerance. Blood pressure was also not affected by hyperuricemia in rats fed a Western-type diet. We next sought to determine whether uric acid may aggravate or accelerate the onset of glucometabolic abnormalities in rats already predisposed to T2DM. Chronic oxonate treatment in Zucker diabetic fatty (ZDF) and lean control rats for up to 6 weeks did not affect fasting glucose, insulin, and glucose tolerance in ZDF rats. Taken together, these findings indicate that elevated uric acid does not directly contribute to the pathogenesis of glucose intolerance and T2DM in rodents.


Apomorphine infusional therapy in Parkinson's disease: clinical utility and lack of tolerance.
We assessed the clinical utility of apomorphine infusional therapy in patients with parkinsonism and motor fluctuations and sought evidence for alterations in drug response resulting from chronic treatment. Six patients with Parkinson's disease were treated for 3 months with s.c. infusions of apomorphine administered during waking hours. At the beginning and the end of the study, test doses of apomorphine (12.5-100 micrograms/kg) were administered to establish a dose-response curve. Over the study, the patients reported a significant improvement in the number of "on" hours experienced per day and substantially reduced the dose and frequency of levodopa and other antiparkinsonian medications. No average change in apomorphine dose-response relationships or pharmacokinetics was observed during the study. However, two patients lowered the infusion rate during the 3-month observation and exhibited higher drug levels and longer responses following test doses of apomorphine given at the end of the study. Although pragmatic concerns with the use of infusion pumps solutions and adverse effects limited the overall benefit afforded by the treatment, this kind of drug treatment may be useful in selected patients with severe parkinsonism and fluctuations.


Prognostic importance of the cause of renal failure in patients with cirrhosis.
The prognostic value of the different causes of renal failure in cirrhosis is not well established. This study investigated the predictive value of the cause of renal failure in cirrhosis. Five hundred sixty-two consecutive patients with cirrhosis and renal failure (as defined by serum creatinine > 1.5 mg/dL on 2 successive determinations within 48 hours) hospitalized over a 6-year period in a single institution were included in a prospective study. The cause of renal failure was classified into 4 groups: renal failure associated with bacterial infections, renal failure associated with volume depletion, hepatorenal syndrome (HRS), and parenchymal nephropathy. The primary end point was survival at 3 months. Four hundred sixty-three patients (82.4%) had renal failure that could be classified in 1 of 4 groups. The most frequent was renal failure associated with infections (213 cases; 46%), followed by hypovolemia-associated renal failure (149; 32%), HRS (60; 13%), and parenchymal nephropathy (41; 9%). The remaining patients had a combination of causes or miscellaneous conditions. Prognosis was markedly different according to cause of renal failure, 3-month probability of survival being 73% for parenchymal nephropathy, 46% for hypovolemia-associated renal failure, 31% for renal failure associated with infections, and 15% for HRS (P < .0005). In a multivariate analysis adjusted for potentially confounding variables, cause of renal failure was independently associated with prognosis, together with MELD score, serum sodium, and hepatic encephalopathy at time of diagnosis of renal failure. A simple classification of patients with cirrhosis according to cause of renal failure is useful in assessment of prognosis and may help in decision making in liver transplantation.


Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxyethyl)adenine, a potent anti-human immunodeficiency virus compound.
9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of retrovirus (i.e., human immunodeficiency virus) replication in vitro and in vivo. Uptake of PMEA by human MT-4 cells and subsequent conversion to the mono- and diphosphorylated metabolites (PMEAp and PMEApp) are dose-dependent and occur proportionally with the initial extracellular PMEA concentrations. Adenylate kinase is unable to phosphorylate PMEA. However, 5-phosphoribosyl-1-pyrophosphate synthetase directly converts PMEA to PMEApp with a Km of 1.47 mM and a Vmax that is 150-fold lower than the Vmax for AMP. ATPase, 5'-phosphodiesterase, and nucleoside diphosphate kinase are able to dephosphorylate PMEApp to PMEAp, albeit to a much lower extent than the dephosphorylation of ATP. PMEApp has a relatively long intracellular half-life (16-18 hr) and has a much higher affinity for the human immunodeficiency virus-specified reverse transcriptase than for the cellular DNA polymerase alpha (Ki/Km: 0.01 and 0.60, respectively). PMEApp is at least as potent an inhibitor of human immunodeficiency virus reverse transcriptase as 2',3'-dideoxyadenosine 5'-triphosphate. Being an alternative substrate to dATP, PMEApp acts as a potent DNA chain terminator, and this may explain its anti-retrovirus activity.


An Asymptomatic Primary Renal Carcinoid Tumor: A Case Report.
Primary renal carcinoid tumors are exceedingly rare, with less than 100 total cases being documented in world literature. A 32-year old male was referred to our service for a slow-growing, renal mass, which was first diagnosed 9-years prior. The patient was successfully treated with radical nephrectomy. In this article, we present our case report on an asymptomatic primary renal carcinoid tumor.


Exploring the Catalytic Mechanism of Human Glutamine Synthetase by Computer Simulations.
Glutamine synthetase is an important enzyme that catalyzes the ATP-dependent formation of glutamine from glutamate and ammonia. In mammals, it plays a key role in preventing excitotoxicity in the brain and detoxifying ammonia in the liver. In plants and bacteria, it is fundamental for nitrogen metabolism, being critical for the survival of the organism. In this work, we show how the use of classical molecular dynamics simulations and multiscale quantum mechanics/molecular mechanics simulations allowed us to examine the structural properties and dynamics of human glutamine synthetase (HsGS), as well as the reaction mechanisms involved in the catalytic process with atomic level detail. Our results suggest that glutamine formation proceeds through a two-step mechanism that includes a first step in which the γ-glutamyl phosphate intermediate forms, with a 5 kcal/mol free energy barrier and a -8 kcal/mol reaction free energy, and then a second rate-limiting step involving the ammonia nucleophilic attack, with a free energy barrier of 19 kcal/mol and a reaction free energy of almost zero. A detailed analysis of structural features within each step exposed the relevance of the acid-base equilibrium related to protein residues and substrates in the thermodynamics and kinetics of the reactions. These results provide a comprehensive study of HsGS dynamics and establish the groundwork for further analysis regarding changes in HsGS activity, as occur in natural variants and post-translational modifications.


Design study for transmission improvement of resonant surface plasmons using dielectric diffraction gratings.
A transmission-type surface plasmon resonance configuration with dielectric gratings regularly patterned on a silver film was investigated with the aim of enhancing the diffraction efficiency of radiative surface plasmons. The theoretical work was conducted using rigorous coupled-wave analysis in terms of first order diffraction efficiency and conversion efficiency (CE). The results show that pyramid gratings can produce a higher transmittance compared with other grating profiles. Design optimization of the pyramid grating at a wide range of grating thicknesses and periods resulted in a maximum transmittance that was larger than 77% and a peak CE of about 85%. This study demonstrates the potential of using transmitted surface plasmon waves in various optical devices, such as optical biosensors, optical imaging systems, and polarization filters.


Systems performance comparison of three all-optical generation schemes for quasi-Nyquist WDM.
Orthogonal time division multiplexing (OrthTDM) interleaves sinc-shaped pulses to form a high baud-rate signal, with a rectangular spectrum suitable for multiplexing into a Nyquist WDM (N-WDM)-like signal. The problem with generating sinc-shaped pulses is that they theoretically have infinite durations, and even if time bounded for practical implementation, they still require a filter with a long impulse response, hence a large physical size. Previously a method of creating chirped-orthogonal frequency division multiplexing (OFDM) pulses with a chirped arrayed waveguide (AWG) filter, then converting them into interleaved quasi-sinc pulses using dispersive fiber (DF), has been proposed. This produces a signal with a wider spectrum than the equivalent N-WDM signal. We show that a modification to the scheme enables the spectral extent to be reduced for the same data rate. We then analyse the key factors in designing an OrthTDM transmitter, and relate these to the performance of a N-WDM system. We show that the modified transmitter reduces the required guard band between the N-WDM channels. We also simulate a simpler scheme using an unchirped finite-impulse response filter of similar size, which directly creates truncated-sinc pulses without needing a DF. This gives better system performance than either chirped scheme.


Influence of Bcl-2 overexpression on Na+/K(+)-ATPase pump activity: correlation with radiation-induced programmed cell death.
Bcl-2 overexpression in transfected PW cells is associated with inhibition of radiation-induced programmed cell death (PCD). We have previously reported that there is a relationship between inhibition of radiation-induced PCD and membrane hyperpolarization in these cells. In this article, we report that Na+/ K(+)-ATPase pump activity, as measured by the uptake of Rubidium-86 (86Rb+), is significantly higher in Bcl-2 overexpressing PW cells than in control PW cells, and that pump activity following irradiation with doses > or = 500 cGy was reduced to a lesser extent in the Bcl-2 transfectants than in the control cells. When PW-Bcl-2 cells were incubated with a dose of ouabain (1 microM) that decreased pump activity significantly, but did not induce PCD, the previously reported protection from radiation-induced PCD associated with overexpression of Bcl-2 no longer existed. In order to demonstrate that reactive oxygen species (ROS) affected Na+/ K(+)-ATPase pump activity, cells were incubated with N-acetyl cysteine (NAC) prior to irradiation, or treated with the ROS generating drug buthionine sulphoxamine (BSO). 86Rb+ uptake was significantly higher in irradiated cells incubated with NAC compared to cells irradiated in the absence of NAC, while BSO resulted in lower levels of 86Rb+ uptake, suggesting that the effects of radiation on the Na+/K(+)-ATPase pump were due to ROS. Furthermore, the resting cell membrane potential of cells exposed to NAC were slightly hyperpolarized compared to control PW cells, whereas cells exposed to BSO were depolarized in comparison to control PW cells. In summary, this data suggests that Bcl-2 affects Na+/K(+)-ATPase pump activity, which is associated with the resting membrane potential and the level of susceptibility to radiation-induced PCD.


Mitochondrial complex I as a novel target for intraneuronal DA: modulation of respiration in intact cells.
Accumulating evidence suggests a role for mitochondria in synaptic potentiation and neurotransmission as well as in morphogenesis and plasticity of spines and synapses. However, studies investigating the ability of neurotransmitters to reciprocally affect mitochondrial function are sparse. In the present study we investigated whether dopamine can affect mitochondrial function in intact neuronal cells. We have shown that short- or long-term exposure of human neuroblastoma SH-SY5Y cells to dopamine (DA) inhibited mitochondrial respiration. This inhibition was associated with an increase in DA intracellular levels, and was prevented by the DA membrane transporter inhibitors, cocaine and GBR-12909. DA inhibited respiration driven through complex I but not through complexes II or III, in line with DA ability to specifically inhibit complex I activity in mitochondrial preparations. The effect of DA on complex I was not associated with altered expression of three subunits of complex I, which were formerly reported abnormal in DA-related pathologies. DA effects on respiration were not due to its ability to form reactive oxygen species. Antipsychotic drugs, which compete with DA on its receptors and inhibit complex I activity, also decreased complex I driven mitochondrial respiration. These findings may suggest that DA, which is taken up by neurons, can affect mitochondria and thereby neurotransmission and synaptic plasticity. Such a mechanism may be of relevance to DA-related non-degenerative pathologies such as schizophrenia.


Chemoselective reduction of quinols as an alternative to Sonogashira coupling: synthesis of polysubstituted benzofurans.
An efficient synthetic approach to polysubstituted benzofurans is described, using 2-methoxyquinone as a benzofuran backbone. Nucleophilic addition of terminal alkynes to 2-methoxy-1,4-benzoquinone afforded the corresponding quinols containing an alkyne unit, which were converted to phenols via mild Zn-mediated reduction. After proper protection of the free phenolic OH, 5-endo-dig iodocyclization allowed facile access to a number of 3-iodobenzofurans. In addition, it was demonstrated for the first time that o-methoxyarylalkynes underwent intramolecular hydroalkoxylation under the influence of AgOTf furnishing the corresponding benzofurans.


High-affinity inhibitors of human NAD-dependent 15-hydroxyprostaglandin dehydrogenase: mechanisms of inhibition and structure-activity relationships.
15-Hydroxyprostaglandin dehydrogenase (15-PGDH, EC 18.104.22.168) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies. To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing >160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with their mechanism of action. We solved the structure of human 15-PGDH and explored the binding modes of the inhibitors to the enzyme in silico. We found binding modes that are consistent with the observed mechanisms of action. Low cross-reactivity in screens of over 320 targets, including three other human dehydrogenases/reductases, suggest selectivity of the present inhibitors for 15-PGDH. The high potencies and different mechanisms of action of these chemotypes make them a useful set of complementary chemical probes for functional studies of prostaglandin-signaling pathways. This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S2.


T cell receptor gamma/delta chain diversity.
The TCR-gamma and -delta chains of six murine hybridomas were compared by one-dimensional SDS-PAGE and two-dimensional NEPHGE/SDS-PAGE analysis. This allowed the identification of three distinct gamma chains (gamma a, gamma b, and gamma c) and three distinct delta chains (delta a, delta b, and delta c). Four gamma/delta chain combinations (gamma a delta a, gamma b delta b, gamma b delta c, and gamma c delta a) were observed. These results indicate that multiple forms of the delta chain are expressed and suggest that the delta chains are encoded for by an Ig-like rearranging gene. This delta chain polymorphism significantly enhances the potential diversity of TCR-gamma/delta, which may be of importance for a better understanding of the putative ligand(s) recognized by this receptor.


Spatial Optimization of Future Urban Development with Regards to Climate Risk and Sustainability Objectives.
Future development in cities needs to manage increasing populations, climate-related risks, and sustainable development objectives such as reducing greenhouse gas emissions. Planners therefore face a challenge of multidimensional, spatial optimization in order to balance potential tradeoffs and maximize synergies between risks and other objectives. To address this, a spatial optimization framework has been developed. This uses a spatially implemented genetic algorithm to generate a set of Pareto-optimal results that provide planners with the best set of trade-off spatial plans for six risk and sustainability objectives: (i) minimize heat risks, (ii) minimize flooding risks, (iii) minimize transport travel costs to minimize associated emissions, (iv) maximize brownfield development, (v) minimize urban sprawl, and (vi) prevent development of greenspace. The framework is applied to Greater London (U.K.) and shown to generate spatial development strategies that are optimal for specific objectives and differ significantly from the existing development strategies. In addition, the analysis reveals tradeoffs between different risks as well as between risk and sustainability objectives. While increases in heat or flood risk can be avoided, there are no strategies that do not increase at least one of these. Tradeoffs between risk and other sustainability objectives can be more severe, for example, minimizing heat risk is only possible if future development is allowed to sprawl significantly. The results highlight the importance of spatial structure in modulating risks and other sustainability objectives. However, not all planning objectives are suited to quantified optimization and so the results should form part of an evidence base to improve the delivery of risk and sustainability management in future urban development.


User-interfaces layout optimization using eye-tracking, mouse movements and genetic algorithms.
Establishing the best layout configuration for software-generated interfaces and control panels is a complex problem when they include many controls and indicators. Several methods have been developed for arranging the interface elements; however, the results are usually conceptual designs that must be manually adjusted to obtain layouts valid for real situations. Based on these considerations, in this work we propose a new automatized procedure to obtain optimal layouts for software-based interfaces. Eye-tracking and mouse-tracking data collected during the use of the interface is used to obtain the best configuration for its elements. The solutions are generated using a slicing-trees based genetic algorithm. This algorithm is able to obtain really applicable configurations that respect the geometrical restrictions of elements in the interface. Results show that this procedure increases effectiveness, efficiency and satisfaction of the users when they interact with the obtained interfaces.


Historical photogrammetry: Bird's Paluxy River dinosaur chase sequence digitally reconstructed as it was prior to excavation 70 years ago.
It is inevitable that some important specimens will become lost or damaged over time, conservation is therefore of vital importance. The Paluxy River dinosaur tracksite is among the most famous in the world. In 1940, Roland T. Bird described and excavated a portion of the site containing associated theropod and sauropod trackways. This excavated trackway was split up and housed in different institutions, and during the process a portion was lost or destroyed. We applied photogrammetric techniques to photographs taken by Bird over 70 years ago, before the trackway was removed, to digitally reconstruct the site as it was prior to excavation. The 3D digital model offers the opportunity to corroborate maps drawn by R.T. Bird when the tracksite was first described. More broadly, this work demonstrates the exciting potential for digitally recreating palaeontological, geological, or archaeological specimens that have been lost to science, but for which photographic documentation exists.


Feasibility study of a single-blind randomised controlled trial of an occupational therapy intervention.
Several factors facilitate or hinder efficacy research in occupational therapy. Strategies are needed, therefore, to support the successful implementation of trials. To assess the feasibility of conducting a randomised controlled trial (RCT). The main feasibility objectives of this study were to assess the process, resources, management, and scientific basis of a trial RCT. A total of 10 occupational therapists, between the ages of 30 and 55 (M 43.4; SD 8.3) with seven to 26 years' (M 14.3; SD 6.1) experience, participated in this study. Qualitative data collected included minutes of meetings, reports, and field notes. The data were analysed based on the principles of content analysis, using feasibility objectives as the main categories. Data analysis revealed strengths in relation to retention and inclusion criteria of participants, the study protocol, study organisation, and the competence of researchers. Weaknesses were found related to recruitment, randomisation, data collection, time for training and communication, commitment, and design. The findings indicated that there are several factors which had a considerable impact on the implementation of an RCT in practice. However, it was useful to assess methods and procedures of the trial RCT as a basis to refine research plans.


Minimal Clinically Important Difference of the Loewenstein Occupational Therapy Cognitive Assessment-Geriatric (LOTCA-G) in People With Dementia.
The Loewenstein Occupational Therapy Cognitive Assessment-Geriatric (LOTCA-G) can provide multifaceted and comprehensive measures of cognitive function with reduced literacy demands; however, its minimal clinically important difference (MCID) has not been determined for interpreting the change scores. To establish the LOTCA-G MCID for people with dementia. Psychometric field study. Data were collected in communities. Forty-nine participants with mild to moderate dementia who were enrolled in previous research investigating the effects of cognitive stimulation-related interventions with equivalent training hours. The Mini-Mental State Examination and LOTCA-G were used to assess cognitive function before and after the interventions. The anchor-based and distribution-based approaches were used to estimate the LOTCA-G MCID. Using the anchor-based method, we defined 16 participants as the improvement group, with a mean change score of 5.75 points (the first MCID estimate). The second MCID estimate was 6.23 points, which we calculated from the 49 participants by using the distribution-based method with the medium effect size. Current results suggest that a LOTCA-G change score greater than 5.75 points should be considered as meaningful change for people with dementia. It is important to consider the LOTCA-G MCID as one of the indexes for determining the success of interventions in people with dementia. This study is the first to report the LOTCA-G MCID for dementia. Establishing an MCID for standardized cognitive assessment tools for the aging population can be used to support evidence-based practice in rehabilitation clinics.


Effect of ionic liquids on enzymatic synthesis of caffeic acid phenethyl ester.
Although caffeic acid phenethyl ester (CAPE), an active flavonoid, plays an important role in the antioxidant activity of honeybee propolis, the isolation of CAPE from honeybee propolis is time-consuming due to wide variety of impurities present. Therefore, biochemical method to synthesize CAPE was investigated in this study. Since ionic liquids (ILs) possess some unique characteristics as appreciated alternatives to conventional solvents for certain biotransformation, the effect of ILs as reaction media for enzymatic synthesis of CAPE was assessed. Several factors including substrate molar ratio, and reaction temperature affecting the conversion yield of lipase-catalyzed CAPE synthesis were also investigated. Reaction yields were significantly higher in hydrophobic ILs than in hydrophilic ILs (almost zero). Among nine hydrophobic ILs tested, the highest conversion of synthetic reaction was obtained in 1-ethyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([Emim][Tf(2)N]). A reaction temperature of 70 °C was found to give high conversion. In addition, optimal substrate molar ratio between phenethyl alcohol and caffeic acid (CA) was decreased significantly from 92:1 to 30:1 when ILs were used instead of isooctane.


Downregulation of nicotinamide N-methyltransferase inhibits migration and epithelial-mesenchymal transition of esophageal squamous cell carcinoma via Wnt/β-catenin pathway.
Nicotinamide N-methyltransferase (NNMT) is an important methyltransferase involved in the biotransformation of many drugs and exogenous compounds. Abnormal expression of NNMT protein is closely associated with the onset and progression of many malignancies, but little is known about its role in esophageal squamous cell carcinoma (ESCC). Therefore, we aimed to explore whether NNMT plays any roles in carcinogenesis and metastasis in ESCC. NNMT expression was determined by immunohistochemistry in ESCC and corresponding adjacent normal tissues. Functional experiments were performed to elucidate the effects of NNMT knockdown on the proliferation, apoptosis, cell cycle, migration, and epithelial-mesenchymal transition (EMT) in EC9706 and TE1 cells. NNMT expression was significantly elevated in ESCC tissues compared with corresponding adjacent normal tissues. Moreover, a significant association emerged between NNMT expression and lymph node metastasis. SiRNA-mediated knockdown of NNMT in ESCC cells can significantly suppress cell viability and migration, induce cell cycle arrest, and promote cell apoptosis. In addition, NNMT downregulation led to the reversal of EMT, as reflected by upregulation of the intercellular adhesion molecule E-cadherin and downregulation of the mesenchymal markers N-cadherin and Vimentin. Further study found that NNMT knockdown suppressed the Wnt/β-catenin signaling pathway. Taken together, these findings indicate that NNMT is a critical regulator of EMT in ESCC and may be a potential therapeutic target for ESCC metastasis.


Modelling as a tool for analysing the temperature-dependent future of the Colorado potato beetle in Europe.
A warmer climate may increase the risk of attacks by insect pests on agricultural crops, and questions on how to adapt management practice have created a need for impact models. Phenological models driven by climate data can be used for assessing the potential distribution and voltinism of different insect species, but the quality of the simulations is influenced by a range of uncertainties. In this study, we model the temperature-dependent activity and development of the Colorado potato beetle, and analyse the influence of uncertainty associated with parameterization of temperature and day length response. We found that the developmental threshold has a major impact on the simulated number of generations per year. Little is known about local adaptations and individual variations, but the use of an upper and a lower developmental threshold gave an indication on the potential variation. The day length conditions triggering diapause are known only for a few populations. We used gridded observed temperature data to estimate local adaptations, hypothesizing that cold autumns can leave a footprint in the population genetics by low survival of individuals not reaching the adult stage before winter. Our study indicated that the potential selection pressure caused by climate conditions varies between European regions. Provided that there is enough genetic variation, a local adaption at the northern distribution limit would reduce the number of unsuccessful initiations and thereby increase the potential for spreading to areas currently not infested. The simulations of the impact model were highly sensitive to biases in climate model data, i.e. systematic deviations in comparison with observed weather, highlightening the need of improved performance of regional climate models. Even a moderate temperature increase could change the voltinism of Leptinotarsa decemlineata in Europe, but knowledge on agricultural practice and strategies for countermeasures is needed to evaluate changes in risk of attacks.


The quest for identity in adolescence: Heterogeneity in daily identity formation and psychosocial adjustment across 5 years.
Identity formation is one of the key developmental tasks in adolescence. According to Erikson (1968) experiencing identity uncertainty is normative in adolescence. However, empirical studies investigating identity uncertainty on a daily basis are lacking. Hence, studying individual differences in daily certainty (i.e., identity commitment levels) and uncertainty (i.e., identity commitment fluctuations and identity reconsideration) in the identity formation process may advance our knowledge about the extent to which adolescents' identity uncertainty is part of normative identity development. Therefore, this longitudinal study examined heterogeneity in certainty and uncertainty dynamics of adolescents' daily identity formation using a longitudinal microlevel approach. Dutch adolescents (N = 494; Mage = 13.03 years at T1; 56.7% boys) reported on 2 key dimensions of identity formation (i.e., commitment and reconsideration) in both the educational and interpersonal domain on a daily basis for 3 weeks within 1 year, across 5 successive years. Multivariate latent class growth analyses suggested both in the educational and interpersonal identity domain a class of adolescents displaying a "crisis-like" identity formation process, and an "identity synthesis" class. Classes revealed differential development of (global and school) anxiety, aggression, and best friend support. Taken together, the present study confirmed Erikson's notion that experiencing daily identity uncertainty is common during adolescence. However, a substantial amount of adolescents also showed a process toward identity maturation already during adolescence. (PsycINFO Database Record


Fully automated structural MRI of the brain in clinical dementia workup.
Background The dementia syndrome has been regarded a clinical diagnosis but the focus on supplemental biomarkers is increasing. An automatic magnetic resonance imaging (MRI) volumetry method, NeuroQuant® (NQ), has been developed for use in clinical settings. Purpose To evaluate the clinical usefulness of NQ in distinguishing Alzheimer's disease dementia (AD) from non-dementia and non-AD dementia. Material and Methods NQ was performed in 275 patients diagnosed according to the criteria of ICD-10 for AD, vascular dementia and Parkinson's disease dementia (PDD); the Winblad criteria for mild cognitive impairment; the Lund-Manchester criteria for frontotemporal dementia; and the revised consensus criteria for Lewy body dementia (LBD). Receiver operating curve (ROC) analyses with calculation of area under the curve (AUC) and regression analyses were carried out. Results Forebrain parenchyma (AUC 0.82), hippocampus (AUC 0.80), and inferior lateral ventricles (AUC 0.78) yielded the highest AUCs for AD/non-dementia discrimination. Only hippocampus (AUC 0.62) and cerebellum (AUC 0.67) separated AD from non-AD dementia. Cerebellum separated AD from PDD-LBD (AUC 0.83). Separate multiple regression analyses adjusted for age and gender, showed that memory (CERAD 10-word delayed recall) (beta 0.502, P < 0.001) was more strongly associated to the hippocampus volume than the diagnostic distinction of AD versus non-dementia (beta -0.392, P < 0.001). Conclusion NQ measures could separate AD from non-dementia fairly well but generally poorer from non-AD dementia. Degree of memory impairment, age, and gender, but not diagnostic distinction, were associated to the hippocampus volume in adjusted analyses. Surprisingly, cerebellum was found relevant in separating AD from PDD-LBD.


Amiodarone-induced pulmonary toxicity. Immunoallergologic tests and bronchoalveolar lavage phospholipid content.
Amiodarone (A) is a widely-used antiarrhythmic drug. Pulmonary toxicity is the most serious adverse effect with an estimated mortality of 1 to 33 percent. In order to determine an element helpful for diagnosis, we examined four patients with amiodarone-induced pulmonary toxicity, three patients treated with A, without evidence of pulmonary toxicity but with a main underlying pulmonary disease, and four healthy volunteers. Daily and cumulative doses or duration of treatment were similar in the first two groups. Pulmonary function tests (spirometry, CO-diffusing capacity, arterial blood gases), roentgenographic examinations, pulmonary biopsies or immunoallergologic tests (skin reaction, lymphoblastic transformation test and human basophile degranulation test) did not provide any discriminatory element. In APT+, we observed an increased cellularity of the bronchoalveolar lavage. Neither the differential cell count nor the presence of foamy macrophages were distinguishable between APT+ and APT-. The phospholipid composition of BAL fluid showed a decreased total phospholipid and phospholipid/protein ratio in all patients compared to normal subjects. These changes reflect more the severity of pulmonary disease than the specificity of the causative agent. However, we observed that the unique PL which decreases in APT- and remains normal in APT+ is phosphatidyl-serine + phosphatidylinositol (PS + PI). This has to be confirmed and should be evaluated at different stages of the disease to determine an eventual specific element. We conclude that there are no data currently available to establish the diagnosis of APT except perhaps for the analysis of BAL PL content.


Increased severity of lower urinary tract symptoms and daytime somnolence in primary Sjögren's syndrome.
Functional antimuscarinic receptor autoantibodies have recently been described in both primary and secondary Sjögren's syndrome (SS) in a mouse bladder contraction assay. Most patients with these antibodies complained of severe lower urinary tract disturbances, which are not a recognized feature of SS. We compared the severity of self-reported urological symptoms, daytime somnolence, and fatigue between a cohort of patients with primary SS and controls with osteoarthritis (OA). Female patients were recruited from rheumatology outpatient clinics at 2 hospitals. The American Urological Symptom Index (AUA-7), Epworth Sleepiness Scale, and FACIT-F fatigue self-administered instruments were employed. Results were obtained for 76 patients with primary SS and 43 controls (response rates 85% and 67%, respectively). The patient groups were matched for parity, hormone replacement and diuretic therapy, and number of bladder operations and urinary tract infections, although OA patients were slightly older. AUA-7 urological symptoms were more severe in patients with primary SS compared to OA controls (p = 0.039). Severe urological symptoms were reported by 61% of primary SS patients compared with 40% of OA controls. This difference was predominantly attributable to bladder irritability associated with urgency (p = 0.015) and not nocturia (p = 0.85). Epworth Sleepiness Scale scores were also more severe in primary SS patients compared to OA controls (p = 0.02), independent of nocturia. The FACIT-F fatigue severity scores were not significantly different between patient groups (p = 0.14). Urological symptoms and daytime somnolence may be previously unrecognized symptoms of primary SS. These symptoms are consistent with functional disturbances of muscarinic receptors, possibly mediated by muscarinic receptor autoantibodies.


Assessment of automatic associations with bodily sensations and agoraphobic situations in panic disorder.
One of the central assumptions of cognitive models of Panic Disorder (PD) is that automatic panic-related associations are a core feature of PD. However, empirical findings are mixed and inconsistent, rendering it difficult to evaluate the role of panic-related associations adequately, particularly in relation to the relevant theories. The present study aimed to further advance our understanding of automatic associations in PD, and therefore applied a paradigm novel in this context, namely an Extrinsic Affective Simon Task (EAST). Participants involved treatment seeking, unmedicated panic patients (n = 45) and healthy controls (n = 38). The EAST was applied prior to treatment. It included the following stimuli as targets: panic-related bodily sensations and agoraphobia-related situations, and as attributes: pleasant versus unpleasant, fear-related words. Contrary to our expectations, panic patients did not show stronger negative than positive automatic associations for either panic-related symptoms or agoraphobia-related situations, compared to healthy controls. Moreover, EAST effects did not correlate with panic-related self-report measures. Although the present study involved patients who were actively seeking treatment, panic-related associations might not have been activated sufficiently. Hence, a brief activation procedure (e.g., hyperventilation) might have been needed to optimize the assessment condition. The present findings do not support contemporary theories of panic-related associations. Therefore, follow-up work is needed to disentangle their functional and operational properties more thoroughly.


Mechanical non-surgical treatment of peri-implantitis: a single-blinded randomized longitudinal clinical study. II. Microbiological results.
Peri-implantitis is common in patients with dental implants. We performed a single-blinded longitudinal randomized study to assess the effects of mechanical debridement on the peri-implant microbiota in peri-implantitis lesions. An expanded checkerboard DNA-DNA hybridization assay encompassing 79 different microorganisms was used to study bacterial counts before and during 6 months following mechanical treatment of peri-implantitis in 17 cases treated with curettes and 14 cases treated with an ultrasonic device. Statistics included non-parametric tests and GLM multivariate analysis with p<0001 indicating significance and 80% power. At selected implant test sites, the most prevalent bacteria were: Fusobacterium nucleatum sp., Staphylococci sp., Aggregatibacter actinomycetemcomitans, Helicobacter pylori, and Tannerella forsythia. 30 min. after treatment with curettes, A. actinomycetemcomitans (serotype a), Lactobacillus acidophilus, Streptococcus anginosus, and Veillonella parvula were found at lower counts (p<0.001). No such differences were found for implants treated with the ultrasonic device. Inconsistent changes occurred following the first week. No microbiological differences between baseline and 6-month samples were found for any species or between treatment study methods in peri-implantitis. Both methods failed to eliminate or reduce bacterial counts in peri-implantitis. No group differences were found in the ability to reduce the microbiota in peri-implantitis.


The endoplasmic reticulum cation P-type ATPase Cta4p is required for control of cell shape and microtubule dynamics.
Here we describe the phenotypic characterization of the cta4+ gene, encoding a novel member of the P4 family of P-type ATPases of fission yeast. The cta4Delta mutant is temperature sensitive and cold sensitive lethal and displays several morphological defects in cell polarity and cytokinesis. Microtubules are generally destabilized in cells lacking Cta4p. The microtubule length is decreased, and the number of microtubules per cell is increased. This is concomitant with an increase in the number of microtubule catastrophe events in the midzone of the cell. These defects are likely due to a general imbalance in cation homeostasis. Immunofluorescence microscopy and membrane fractionation experiments revealed that green fluorescent protein-tagged Cta4 localizes to the ER. Fluorescence resonance energy transfer experiments in living cells using the yellow cameleon indicator for Ca2+ indicated that Cta4p regulates the cellular Ca2+ concentration. Thus, our results reveal a link between cation homeostasis and the control of cell shape, microtubule dynamics, and cytokinesis, and appoint Ca2+ as a key ion in controlling these processes.


Presence and physiologic function of the renin-angiotensin system in mouse lacrimal gland.
To investigate the expression, localization, and physiologic function of renin-angiotensin system (RAS) components in the mouse lacrimal gland. Lacrimal glands and cultured lacrimal gland fibroblasts from wild-type (WT) BALB/c (H-2(d)) mice were used. Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to determine the expression and localization of the RAS components, prorenin/renin, angiotensin-converting enzyme (ACE), angiotensin II, angiotensin II type 1 receptor (AT1R), and angiotensin II type 2 receptor (AT2R) in the normal mouse lacrimal gland. To examine the change in tear secretion, mice received ARB (AT1R blocker) or AT2R antagonist. Tear secretion was assessed by cotton thread test before and after drug administration. The mRNAs coding for angiotensinogen, prorenin, ACE, and both AT1R and AT2R were found in normal lacrimal gland tissue and cultured lacrimal gland fibroblasts. Prorenin/renin and ACE were identified in myoepithelial cells around ducts and acini and in blood vessels. Angiotensin II, AT1R, and AT2R were observed in the ducts and interstitial fibroblasts. AT1R and AT2R were also localized in blood vessels. All the cultured lacrimal gland fibroblasts expressed angiotensin II, AT1R, and AT2R. Tear secretion increased in mice that received ARB. The results are consistent with the hypothesis that a tissue-specific RAS is present in the lacrimal gland, and suggest that fibroblasts are one of the cell types playing a role in the tissue RAS. Tissue RAS might be involved in tissue function of regulating tear secretion in the lacrimal gland.


Efficacy of XP-endo finisher and TRUShape 3D conforming file compared to conventional and ultrasonic irrigation in removing calcium hydroxide.
The aim of this study was to compare the efficacy of the XP-endo Finisher and TRUShape 3D Conforming File to conventional and ultrasonic irrigation techniques for removing calcium hydroxide from artificially created grooves on root canals. The study used 32 human mandibular premolar teeth, which were decoronated and instrumented up to ProTaper Universal F5 (Dentsply Maillefer; Ballagiues, Switzerland). The teeth were split longitudinally, two standardised grooves were prepared in the apical and coronal portions and filled with calcium hydroxide. Each tooth was reassembled with wax. The samples were stored at 100% humidity at 37°C for 1 week, after which the specimens were grouped and irrigated using needle irrigation, ultrasonic irrigation, XP-endo Finisher via continuous irrigation or TRUShape 3D Conforming File via continuous irrigation. Two calibrated observers scored the amount of calcium hydroxide remaining, and the data were statistically analysed using the Kruskal-Wallis and Mann-Whitney U-tests, (P < 0.05). Needle irrigation had the poorest scores (P < .001), while the XP-endo Finisher, TRUShape 3D Conforming File via continuous irrigation and ultrasonic irrigation groups had similar results in removing calcium hydroxide.


Automatic Outcome in Manual Dexterity Assessment Using Colour Segmentation and Nearest Neighbour Classifier.
Objective assessment of motor function is an important component to evaluating the effectiveness of a rehabilitation process. Such assessments are carried out by clinicians using traditional tests and scales. The Box and Blocks Test (BBT) is one such scale, focusing on manual dexterity evaluation. The score is the maximum number of cubes that a person is able to displace during a time window. In a previous paper, an automated version of the Box and Blocks Test using a Microsoft Kinect sensor was presented, and referred to as the Automated Box and Blocks Test (ABBT). In this paper, the feasibility of ABBT as an automated tool for manual dexterity assessment is discussed. An algorithm, based on image segmentation in CIELab colour space and the Nearest Neighbour (NN) rule, was developed to improve the reliability of automatic cube counting. A pilot study was conducted to assess the hand motor function in people with Parkinson's disease (PD). Three functional assessments were carried out. The success rate in automatic cube counting was studied by comparing the manual (BBT) and the automatic (ABBT) methods. The additional information provided by the ABBT was analysed to discuss its clinical significance. The results show a high correlation between manual (BBT) and automatic (ABBT) scoring. The lowest average success rate in cube counting for ABBT was 92%. Additionally, the ABBT acquires extra information from the cubes' displacement, such as the average velocity and the time instants in which the cube was detected. The analysis of this information can be related to indicators of health status (coordination and dexterity). The results showed that the ABBT is a useful tool for automating the assessment of unilateral gross manual dexterity, and provides additional information about the user's performance.


Vaginal and (uncommon) cervical cancers in the Netherlands, 1989-2003.
The clinical and prognostic evaluation of cervical and vaginal tumors other than squamous cell and adenocarcinomas is hampered by the low incidence, and clinical and epidemiological studies on these uncommon tumors are scarce. Having close affinity with the pathology laboratories, the Netherlands Cancer Registry offers a great opportunity to study frequency, stage, treatment, and survival of uncommon tumors in the cervix and vagina and separately, the clear cell adenocarcinoma of the vagina and cervix. All invasive cervical tumors (n = 10,570) and all in situ and invasive vaginal tumors (n = 778) diagnosed in the Netherlands during 1989-2003 were selected from the Netherlands Cancer Registry. Age, stage at diagnosis, and treatment were described for each histological subgroup to find differences between common and uncommon tumors, including 5-year relative survival rates. Twenty-five patients (3%) with cervical cancer subsequently developed a vaginal tumor (during 1989-2003), and 19 of these patients underwent hysterectomy for their cervical cancer. A significantly worse prognosis was found for patients with small cell neuroendocrine cervical tumors and for patients with vaginal melanomas. Patients with clear cell adenocarcinoma of the vagina and cervix were found across all age categories. The less common histological types of cervical and vaginal cancers were clearly different from squamous cell carcinomas, especially with respect to age at diagnosis and survival rates. Spreading population-based knowledge of effects of treatment of these uncommon tumors should help clinical decision making and therefore improve prognosis.


Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer.
Chronic inflammation represents a major risk factor for tumor formation, but the underlying mechanisms have remained largely unknown. Epigenetic mechanisms can record the effects of environmental challenges on the genome level and could therefore play an important role in the pathogenesis of inflammation-associated tumors. Using single-base methylation maps and transcriptome analyses of a colitis-induced mouse colon cancer model, we identified a novel epigenetic program that is characterized by hypermethylation of DNA methylation valleys that are characterized by low CpG density and active chromatin marks. This program is conserved and functional in mouse intestinal adenomas and results in silencing of active intestinal genes that are involved in gastrointestinal homeostasis and injury response. Further analyses reveal that the program represents a prominent feature of human colorectal cancer and can be used to correctly classify colorectal cancer samples with high accuracy. Together, our results show that inflammatory signals establish a novel epigenetic program that silences a specific set of genes that contribute to inflammation-induced cellular transformation.


Measuring public health practice and outcomes in chronic disease: a call for coordination.
A strategic opportunity exists to coordinate public health systems and services researchers' efforts to develop local health department service delivery measures and the efforts of divisions within the Centers for Disease Control and Prevention's National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP) to establish outcome indicators for public health practice in chronic disease. Several sets of outcome indicators developed by divisions within NCCDPHP and intended for use by state programs can be tailored to assess outcomes of interventions within smaller geographic areas or intervention settings. Coordination of measurement efforts could potentially allow information to flow from the local to the state to the federal level, enhancing program planning, accountability, and even subsequent funding for public health practice.


Multitasking: multiple, domain-specific cognitive functions in a virtual environment.
Multitasking among three or more different tasks is a ubiquitous requirement of everyday cognition, yet rarely is it addressed in research on healthy adults who have had no specific training in multitasking skills. Participants completed a set of diverse subtasks within a simulated shopping mall and office environment, the Edinburgh Virtual Errands Test (EVET). The aim was to investigate how different cognitive functions, such as planning, retrospective and prospective memory, and visuospatial and verbal working memory, contribute to everyday multitasking. Subtasks were chosen to be diverse, and predictions were derived from a statistical model of everyday multitasking impairments associated with frontal-lobe lesions (Burgess, Veitch, de Lacy Costello, & Shallice, 2000b). Multiple regression indicated significant independent contributions from measures of retrospective memory, visuospatial working memory, and online planning, but not from independent measures of prospective memory or verbal working memory. Structural equation modelling showed that the best fit to the data arose from three underlying constructs, with Memory and Planning having a weak link, but with both having a strong directional pathway to an Intent construct that reflected implementation of intentions. Participants who followed their preprepared plan achieved higher scores than those who altered their plan during multitask performance. This was true regardless of whether the plan was efficient or poor. These results substantially develop and extend the Burgess et al. (2000b) model to healthy adults and yield new insight into the poorly understood area of everyday multitasking. The findings also point to the utility of using virtual environments for investigating this form of complex human cognition.


Airway and serum adipokines after allergen and diesel exposure in a controlled human crossover study of atopic adults.
Adipokines are mediators released from adipose tissue. These proteins are regarded as active elements of systemic and pulmonary inflammation, whose dysregulation can alter an individual's risk of developing allergic lung diseases. Despite this knowledge, adipokine responses to inhaled stimuli are poorly understood. We sought to measure serum and lung adiponectin, leptin, and resistin in an atopic adult study population following exposure to allergen and diesel exhaust (DE). Two types of lung samples including bronchoalveolar lavage (BAL) and bronchial wash (BW), and a time course of serum samples, were collected from the 18 subjects who participated in the randomized, double-blinded controlled human study. The two crossover exposure triads in this study were inhaled DE and filtered air each followed by instilled allergen or saline. Serum and lung adipokine responses to these exposures were quantified using enzyme-linked immunosorbent assay. Allergen significantly increased adiponectin and leptin in BAL, and adiponectin in the BW 48 hours after exposure. Serum leptin and resistin responses were not differentially affected by exposure, but varied over time. Coexposure with DE and allergen revealed significant correlations between the adiponectin/leptin ratio and FEV1 changes and airway responsiveness measures. Changes in lung and serum adipokines in response to allergen exposure were identified in the context of a controlled exposure study. Coexposure identified a potentially protective role of adiponectin in the lung. This response was not observed in those with baseline airway hyper-responsiveness, or after allergen exposure alone. The clinical relevance of this potentially adaptive adipokine pattern warrants further study.


Asymmetric Redundancy of ZERZAUST and ZERZAUST HOMOLOG in Different Accessions of Arabidopsis thaliana.
Divergence among duplicate genes is one of the important sources of evolutionary innovation. But, the contribution of duplicate divergence to variation in Arabidopsis accessions is sparsely known. Recently, we studied the role of a cell wall localized protein, ZERZAUST (ZET), in Landsberg erecta (Ler) accession, lack of which results in aberrant plant morphology. Here, we present the study of ZET in Columbia (Col) accession, which not only showed differential expression patterns in comparison to Ler, but also revealed its close homolog, ZERZAUST HOMOLOG (ZETH) Although, genetic analysis implied redundancy, expression analysis revealed divergence, with ZETH showing minimal expression in both Col and Ler In addition, ZETH shows relatively higher expression levels in Col compared to Ler Our data also reveal compensatory up-regulation of ZETH in Col, but not in Ler, implying it is perhaps dispensable in Ler However, a novel CRISPR/Cas9-induced zeth allele confirmed that ZETH has residual activity in Ler Finally, the synergistic interaction of the receptor-like kinase gene, ERECTA with ZET in ameliorating morphological defects suggests crucial role of modifiers on plant phenotype. The results provide genetic evidence for accession-specific differences in compensation mechanism and asymmetric gene contribution. Thus, our work reveals a novel example for how weakly expressed homologs contribute to diversity among accessions.


Response of olive fruit fly (Diptera: Tephritidae) to an attract-and-kill trap in greenhouse cage tests.
A novel attract-and-kill trap for olive fruit fly, Bactrocera oleae (Rossi) (Diptera: Tephritidae), was constructed with yellow corrugated plastic in an inverted cylindrical pan shape formed from a disk and collar. The trap components were tested under three greenhouse temperatures and humidities of warm, hot, and very hot for attractiveness to caged young or older adults. A greater proportion of adults regardless of age were found underneath the devices including disks, cylindrical pans, and pans with pheromone lures and test units of cylindrical pans sprayed with water, insecticidal bait spray, and with lures. The effect was related to lower temperatures on the underside compared with the top and the intolerance of the pest to heat. A circular collar added to the perimeter of the disk that formed the top of the inverted cylinder made the attract-and-kill trap more attractive to adults than the disk alone. Pheromone lures or bait sprays did not increase adult attraction, so were not needed for efficacy. The cylindrical pan was especially attractive to adults when temperatures were high by providing shelter from the heat. At very high temperatures, the pan became unattractive, possibly due to heating of the construction materials. Cylindrical pans sprayed with water on the underside attracted the highest number of adults especially at high temperatures. Greenhouse tests showed that the inverted cylindrical pan design has potential as an attract-and-kill device for olive fruit fly control.


The nano-scale mechanical properties of the extracellular matrix regulate dermal fibroblast function.
Changes in the mechanical properties of dermis occur during skin aging or tissue remodeling and affect the activity of resident fibroblasts. With the aim to establish elastic culture substrates that reproduce the variable softness of dermis, we determined Young's elastic modulus E of human dermis at the cell perception level using atomic force microscopy. The E of dermis ranged from 0.1 to 10 kPa, varied depending on body area and dermal layer, and tended to increase with age in 26-55-year-old donors. The activation state of human dermal fibroblasts cultured on "skin-soft" E (5 kPa) silicone culture substrates was compared with stiff plastic culture (GPa), collagen gel cultures (0.1-9 kPa), and fresh human dermal tissue. Fibroblasts cultured on skin-soft silicones displayed low mRNA levels of fibrosis-associated genes and increased expression of the matrix metalloproteinases (MMPs) MMP-1 and MMP-3 as compared with collagen gel and plastic cultures. The activation profile exhibited by fibroblasts on "skin-soft" silicone culture substrates was most comparable with that of human dermis than any other tested culture condition. Hence, providing biomimetic mechanical conditions generates fibroblasts that are more suitable to investigate physiologically relevant cell processes than fibroblasts spontaneously activated by stiff conventional culture surfaces.