Variation in Occurrence and Aflatoxigenicity of Aspergillus flavus from Two Climatically Varied Regions in Kenya.
Aflatoxins are carcinogenic chemical metabolites produced by Aspergillus spp. of the section Flavi. In Kenya, Aspergillus flavus is the most prevalent and has been associated with several acute and chronic aflatoxin outbreaks in the past. In this study, we evaluated the occurrence of A. flavus in soils from two agro-ecological regions with contrasting climatic conditions, aflatoxin contamination histories and cropping systems. Aspergillus spp. were first isolated from soils before the identification and determination of their aflatoxigenicity. Further, we determined the occurrence of Pseudomonas and Bacillus spp. in soils from the two regions. These bacterial species have long been associated with biological control of several plant pathogens including Aspergillus spp. Our results show that A. flavus occurred widely and produced comparatively higher total aflatoxin levels in all (100%) study sites from the eastern to the western regions of Kenya. For the western region, A. flavus was detected in 4 locations (66.7%) that were previously under maize cultivation with the isolates showing low aflatoxigenicity. A. flavus was not isolated from soils under sugarcane cultivation. Distribution of the two bacterial species varied across the regions but we detected a weak relationship between occurrence of bacterial species and A. flavus. We discuss these findings in the context of the influence of climate, microbial profiles, cropping systems and applicability in the deployment of biological control remedies against aflatoxin contamination.


Time dependent measurements of nitrous oxide and carbon dioxide collisional relaxation processes by a frequency down-chirped quantum cascade laser: rapid passage signals and the time dependence of collisional processes.
Intrapulse quantum cascade laser spectrometers are able to produce both saturation and molecular alignment of the gas sample. This is due to the rapid sweep of the radiation through the absorption features. The intrapulse time domain spectra closely resemble those recorded in coherent optical nutation experiments. In the present paper, the frequency down-chirped technique is employed to investigate the nitrous oxide-foreign gas collisions. We have demonstrated that the measurements may be characterized by the induced polarization dominated and collision dominated measurement limits. The first of these is directly related to the time dependence of the long range collision cross sections. Among the collisional partners considered, carbon dioxide shows a very unusual behavior of rapid polarization damping, resulting in the production of symmetrical line shapes at very low gas buffer pressures. In the collision dominated regime, the pressure broadening parameters, which we have derived, are comparable at slow chirp rates, with those derived from other experimental methods. By comparing the pressure broadening coefficients of Ar, N(2), and CO(2) with those of He, making use of the chirp rate independence of the pressure broadening by helium, we have shown that at higher chirp rates there is clear evidence of the chirp-rate dependence of the pressure broadening parameters of N(2) and CO(2).


Risk stratification in cervical cancer screening by complete screening history: Applying bioinformatics to a general screening population.
Women screened for cervical cancer in Sweden are currently treated under a one-size-fits-all programme, which has been successful in reducing the incidence of cervical cancer but does not use all of the participants' available medical information. This study aimed to use women's complete cervical screening histories to identify diagnostic patterns that may indicate an increased risk of developing cervical cancer. A nationwide case-control study was performed where cervical cancer screening data from 125,476 women with a maximum follow-up of 10 years were evaluated for patterns of SNOMED diagnoses. The cancer development risk was estimated for a number of different screening history patterns and expressed as Odds Ratios (OR), with a history of 4 benign cervical tests as reference, using logistic regression. The overall performance of the model was moderate (64% accuracy, 71% area under curve) with 61-62% of the study population showing no specific patterns associated with risk. However, predictions for high-risk groups as defined by screening history patterns were highly discriminatory with ORs ranging from 8 to 36. The model for computing risk performed consistently across different screening history lengths, and several patterns predicted cancer outcomes. The results show the presence of risk-increasing and risk-decreasing factors in the screening history. Thus it is feasible to identify subgroups based on their complete screening histories. Several high-risk subgroups identified might benefit from an increased screening density. Some low-risk subgroups identified could likely have a moderately reduced screening density without additional risk.


Statin-Associated Underactive Bladder.
Statins are widely used to treat hypercholesterolemia but can lead to side-effects. We present a case of statin-associated permanent urinary retention in a 69-year-old woman. Oral Cerivastatin was prescribed 2 months prior to the onset of retention. With the discontinuation of Cerivastatin, the patient reported modest improvement in symptoms. The findings of this case support the potential risk of permanent bladder smooth muscle damage due to statin that may lead to underactive bladder and urinary retention.


Indications, methods, and outcomes of percutaneous liver biopsy in England and Wales: an audit by the British Society of Gastroenterology and the Royal College of Physicians of London.
The liver section of the British Society of Gastroenterology and the research unit of the Royal College of Physicians collaborated to set up a nationwide audit to investigate the practice of percutaneous liver biopsy in England and Wales. Each of 189 health districts in England and Wales was approached to provide a list of 10 consecutive percutaneous biopsies performed during 1991, and details of demographic data, indications, suspected diagnosis, investigations, biopsy technique, outcome, and influence on patient management were collected. Data were retrieved on 1500 (79%). The age distribution showed 6% of biopsies were done in those over 80 years of age and as many over 90 as under 10 years of age. Suspected malignancy and chronic liver disease each contributed one third of the indications. In 34% the procedure was carried out by radiologists under ultrasound image control. The remainder were done by general physicians and gastroenterologists, with the operator in the second group being more senior and experienced. The Trucut biopsy needle accounted for two thirds of biopsies, the remainder being the Menghini type. For both needles the samples were recorded as excellent or satisfactory in 83% and inadequate in only 5%. Bleeding complicated 26 procedures (1.7%), requiring transfusion in 11, and was commoner when clotting was impaired or serum bilirubin raised. There were two definite and three possible procedure related, given an overall mortality of 0.13-0.33%. The diagnosis made before biopsy was confirmed in 63% of patients, and the clinician found the biopsy helpful in treatment in 75%. Day case biopsy and techniques to reduce the risk of bleeding were surprisingly rare in this series, which has given a unique opportunity to examine everyday practice across a wide range of hospitals.


Evolutionary conservation of the human nucleolar protein fibrillarin and its functional expression in yeast.
NOP1 is an essential nucleolar protein in yeast that is associated with small nucleolar RNA and required for ribosome biogenesis. We have cloned the human nucleolar protein, fibrillarin, from a HeLa cDNA library. Human fibrillarin is 70% identical to yeast NOP1 and is also the functional homologue since either human or Xenopus fibrillarin can complement a yeast nop1- mutant. Human fibrillarin is localized in the yeast nucleolus and associates with yeast small nucleolar RNAs. This shows that the signals within eucaryotic fibrillarin required for nucleolar association and nucleolar function are conserved from yeast to man. However, human fibrillarin only partially complements in yeast resulting in a temperature-sensitive growth, concomitantly altered rRNA processing and aberrant nuclear morphology. A suppressor of the human fibrillarin ts-mutant was isolated and found to map intragenically at a single amino acid position of the human nucleolar protein. The growth rate of yeast nop1- strains expressing Xenopus or human fibrillarin or the human fibrillarin suppressor correlates closely with their ability to efficiently and correctly process pre-rRNA. These findings demonstrate for the first time that vertebrate fibrillarin functions in ribosomal RNA processing in vivo.


New nonlocal forward model for diffuse optical tomography.
The forward model in diffuse optical tomography (DOT) describes how light propagates through a turbid medium. It is often approximated by a diffusion equation (DE) that is numerically discretized by the classical finite element method (FEM). We propose a nonlocal diffusion equation (NDE) as a new forward model for DOT, the discretization of which is carried out with an efficient graph-based numerical method (GNM). To quantitatively evaluate the new forward model, we first conduct experiments on a homogeneous slab, where the numerical accuracy of both NDE and DE is compared against the existing analytical solution. We further evaluate NDE by comparing its image reconstruction performance (inverse problem) to that of DE. Our experiments show that NDE is quantitatively comparable to DE and is up to 64% faster due to the efficient graph-based representation that can be implemented identically for geometries in different dimensions. The proposed discretization method can be easily applied to other imaging techniques like diffuse correlation spectroscopy which are normally modeled by the diffusion equation.


[Treatment of patients with hypertonic disease with plasmapheresis].
The paper presents a discussion on therapeutic results obtained with plasmapheresis treatment in 16 patients with stage II essential hypertension. Thirty-three comparable patients entered a control group of conventional treatment. The test and control patients with stage II hypertension were examined for time-course changes in T- and B-lymphocytes counts, the activity of the energetic enzymes (alpha-glycerophosphate dehydrogenase, succinic dehydrogenase, lactate dehydrogenase), serum immunoglobulins and circulating immune complex levels. It was established that the standard antihypertensive treatment failed to restore normal parameters of immunity and to favor positive alterations in the activity of the enzymes in the blood lymphocytes, whereas therapeutic plasmapheresis was found to stimulate immunity, especially cellular one. This occurred in line with a rise in the levels of lymphocytic dehydrogenases.


DNA-mediated self-assembly of taste cells and neurons for taste signal transmission.
Cells can communicate with one another through physical connections and chemical signaling, activating various signaling pathways that can affect cellular functions and behaviors. In taste buds, taste cells transmit taste information to neurons via paracrine signaling. However, no previous studies have reported the in vitro co-culture of taste and neuronal cells, which allows us to monitor intercellular communications and better understand the mechanism of taste perception. Here, we introduce the first investigation on the proximate assembly and co-culture of taste cells and neurons to monitor the intercellular transmission of taste signals. Taste cells and neurons are placed closely using a pair of single-stranded oligonucleotides conjugated with polyethylene glycol and a phospholipid. Complementary oligonucleotide conjugates are anchored into the cellular membrane of neonatal taste cells and embryonic hippocampal neuronal cells, respectively, and then the cells are self-assembled into a functional multicellular unit for taste perception. Treatment of the assembled cells with a bitter tastant generates the sequential influx of calcium ions into the cytoplasm in taste cells and then in neuronal cells. Our work demonstrates that the cellular self-assembly is critical for efficient taste signal transduction, which can be used as a promising platform to construct cell-based biosensors for taste sensing.


Climate change in the oceans: evolutionary versus phenotypically plastic responses of marine animals and plants.
I summarize marine studies on plastic versus adaptive responses to global change. Due to the lack of time series, this review focuses largely on the potential for adaptive evolution in marine animals and plants. The approaches were mainly synchronic comparisons of phenotypically divergent populations, substituting spatial contrasts in temperature or CO2 environments for temporal changes, or in assessments of adaptive genetic diversity within populations for traits important under global change. The available literature is biased towards gastropods, crustaceans, cnidarians and macroalgae. Focal traits were mostly environmental tolerances, which correspond to phenotypic buffering, a plasticity type that maintains a functional phenotype despite external disturbance. Almost all studies address coastal species that are already today exposed to fluctuations in temperature, pH and oxygen levels. Recommendations for future research include (i) initiation and analyses of observational and experimental temporal studies encompassing diverse phenotypic traits (including diapausing cues, dispersal traits, reproductive timing, morphology) (ii) quantification of nongenetic trans-generational effects along with components of additive genetic variance (iii) adaptive changes in microbe-host associations under the holobiont model in response to global change (iv) evolution of plasticity patterns under increasingly fluctuating environments and extreme conditions and (v) joint consideration of demography and evolutionary adaptation in evolutionary rescue approaches.


Stimuli-sensitive hydrogels: an excellent carrier for drug and cell delivery.
The stimuli-sensitive hydrogel is an injectable formulation that is used to deliver drugs, cells, and genes into the body. Hydrogels are available in various physical forms such as solid molded, pressed powder matrix, microparticle, coating, or membrane forms. The network structure of hydrogels can be macroporous, microporous, or nonporous. Different categories of biomaterials, such as natural, synthetic, and combinations (e.g., semisynthetic such as natural-natural, natural-synthetic, and synthetic-synthetic polymers), are commonly used in hydrogel preparation. Classification of hydrogels mainly depends upon physical stimuli (temperature, electric fields, solvent composition, light, pressure, sound, and magnetic fields) and chemical or biochemical stimuli (pH, ions, and specific molecular recognition events). Several approaches for the synthesis of hydrogels have been reported, including emulsification, micromolding, photolithography, isostatic ultra high pressure, and microfluidic techniques. Hydrogels provide structural integrity and cellular organization, serve as tissue barriers, act as bioadhesive and drug depots, deliver bioactive agents and cells, and possess unique swelling properties and structures. This review provides a detailed account of the need for development of hydrogels, along with the materials used and techniques adopted to manufacture scaffolds for tissue engineering and for prolonged drug, cell, and gene delivery.


Cloning and characterization of DNA damage-inducible promoter regions from Bacillus subtilis.
DNA damage-inducible (din) genes in Bacillus subtilis are coordinately regulated and together compose a global regulatory network that has been termed the SOS-like or SOB regulon. To elucidate the mechanisms of SOB regulation, operator/promoter regions from three din loci (dinA, dinB, and dinC) of B. subtilis were cloned. Operon fusions constructed with these cloned din promoter regions rendered reporter genes damage inducible in B. subtilis. Induction of all three din promoters was dependent upon a functional RecA protein. Analysis of these fusions has localized sequences required for damage-inducible expression of the dinA, dinB, and dinC promoters to within 120-, 462-, and 139-bp regions, respectively. Comparison of the nucleotide sequences of these three din promoters with the recA promoter, as well as with the promoters of other loci associated with DNA repair in B. subtilis, has identified the consensus sequence GAAC-N4-GTTC as a putative SOB operator site.


Water growth on metals and oxides: binding, dissociation and role of hydroxyl groups.
We discuss the role of the presence of dangling H-bonds from water or from surface hydroxyl species on the wetting behavior of surfaces. Using scanning tunneling and atomic force microscopies and photoelectron spectroscopy, we have examined a variety of surfaces, including mica, oxides and pure metals. We find that in all cases, the availability of free, dangling H-bonds at the surface is crucial for the subsequent growth of wetting water films. In the case of mica, electrostatic forces and H-bonding to surface O atoms determine the water orientation in the first layer and also in subsequent layers with a strong influence in its wetting characteristics. In the case of oxides like TiO2, Cu2O, SiO2 and Al2O3, surface hydroxyls form readily on defects upon exposure to water vapor and help nucleate the subsequent growth of molecular water films. On pure metals, such as Pt, Pd and Ru, the structure of the first water layer and whether or not it exhibits dangling H-bonds is again crucial. Dangling H-bonds are provided by molecules with their plane oriented vertically, or by OH groups formed by the partial dissociation of water. By tying the two H atoms of the water molecules into strong H-bonds with pre-adsorbed O on Ru can also quench the wettability of the surface.


Comparative Evaluation of Physicochemical Properties and Apical Sealing Ability of a Resin Sealer Modified with Pachymic Acid.
The addition of pachymic acid (PA) to AH Plus (an epoxy resin sealer) offsets the cytotoxicity of the latter. Prior to the clinical implementation of this formulation, a thorough knowledge of its physicochemical properties and sealing ability becomes mandatory. Hence, this in vitro study aimed to characterize and evaluate the physicochemical properties and apical sealing ability of AH Plus (AHP) with and without the addition of PA. Flow, setting time, film thickness, solubility and radiopacity of AHP (group 1) and AHP modified with PA (AHP/PA, group 2) were evaluated in accordance with the guidelines put forth by ISO 6876:2012. The percentage was determined under each parameter. Apical sealing ability was assessed using fluid filtration device. An independent samples t-test was used for inter- and intra-group comparisons of mean fluid flow (MFF). Incorporating PA to AHP decreased its flow, setting time and film thickness by 24.34%, 2.14% and 31.71% respectively. The solubility of group 2 increased on day 1 by 85.71% and decreased on days 3, 7 and 14 by 46.67%, 34.79% and 13.8% respectively. The radiopacity of AHP was not altered by the addition of PA. MFF rates of group 2 was significantly higher than group 1 on day 1, but not significantly different on day 7. AHP/PA exhibited physicochemical properties that were within the requirements of ISO and with time, and showed fluid flow similar to AHP.


Strain mediated enzymatic degradation of arterial tissue: Insights into the role of the non-collagenous tissue matrix and collagen crimp.
Collagen fibre remodelling is a strain dependent process which is stimulated by the degradation of existing collagen. To date, literature has focussed on strain dependent degradation of pure collagen or structurally simple collagenous tissues, often overlooking degradation within more complex, heterogenous soft tissues. The aim of this study is to identify, for the first time, the strain dependent degradation behaviour and mechanical factors influencing collagen degradation in arterial tissue using a combined experimental and numerical approach. To achieve this, structural analysis was carried out using small angle light scattering to determine the fibre level response due to strain induced degradation. Next, strain dependent degradation rates were determined from stress relaxation experiments in the presence of crude and purified collagenase to determine the tissue level degradation response. Finally, a 1D theoretical model was developed, incorporating matrix stiffness and a gradient of collagen fibre crimp to decouple the mechanism behind strain dependent arterial degradation. SALS structural analysis identified a strain mediated degradation response in arterial tissue at the fibre level not dissimilar to that found in literature for pure collagen. Interestingly, two distinctly different strain mediated degradation responses were identified experimentally at the tissue level, not seen in other collagenous tissues. Our model was able to accurately predict these experimental findings, but only once the load bearing matrix, its degradation response and the gradient of collagen fibre crimp across the arterial wall were incorporated. These findings highlight the critical role that the various tissue constituents play in the degradation response of arterial tissue. Collagen fibre architecture is the dominant load bearing component of arterial tissue. Remodelling of this architecture is a strain dependent process stimulated by the degradation of existing collagen. Despite this, degradation of arterial tissue and in particular, arterial collagen, is not fully understood or studied. In the current study, we identified for the first time, the strain dependent degradation response of arterial tissue, which has not been observed in other collagenous tissues in literature. We hypothesised that this unique degradation response was due to the complex structure observed in arterial tissue. Based on this hypothesis, we developed a novel numerical model capable of explaining this unique degradation response which may provide critical insights into disease development and aid in the design of interventional medical devices.


The lens after renal transplantation.
A single masked observer examined 55 non-diabetic patients chosen randomly from a population of patients who had undergone renal transplant. The mean age was 41 years and mean time from transplant was 4.4 years (1-10 years). Fourteen patients were found to have a posterior subcapsular cataract (PSC). The axial thickness of the right lens of the renal transplant population, even in the presence of a PSC, was significantly larger than in a control population of 99 patients with clear lenses. The PSC of renal transplantation is readily distinguished from age related PSC because the opacity lies in the superficial cortex at a depth proportional to time from transplant and the lens maintains a normal anterior clear zone. It is proposed that this type of cataract be called 'recovering' PSC. It is concluded that the cataractogenic insult occurs mainly during the peritransplant period. Maintenance doses of immunosuppressives or steroids are therefore probably not cataractogenic.


Label noise in subtype discrimination of class C G protein-coupled receptors: A systematic approach to the analysis of classification errors.
The characterization of proteins in families and subfamilies, at different levels, entails the definition and use of class labels. When the adscription of a protein to a family is uncertain, or even wrong, this becomes an instance of what has come to be known as a label noise problem. Label noise has a potentially negative effect on any quantitative analysis of proteins that depends on label information. This study investigates class C of G protein-coupled receptors, which are cell membrane proteins of relevance both to biology in general and pharmacology in particular. Their supervised classification into different known subtypes, based on primary sequence data, is hampered by label noise. The latter may stem from a combination of expert knowledge limitations and the lack of a clear correspondence between labels that mostly reflect GPCR functionality and the different representations of the protein primary sequences. In this study, we describe a systematic approach, using Support Vector Machine classifiers, to the analysis of G protein-coupled receptor misclassifications. As a proof of concept, this approach is used to assist the discovery of labeling quality problems in a curated, publicly accessible database of this type of proteins. We also investigate the extent to which physico-chemical transformations of the protein sequences reflect G protein-coupled receptor subtype labeling. The candidate mislabeled cases detected with this approach are externally validated with phylogenetic trees and against further trusted sources such as the National Center for Biotechnology Information, Universal Protein Resource, European Bioinformatics Institute and Ensembl Genome Browser information repositories. In quantitative classification problems, class labels are often by default assumed to be correct. Label noise, though, is bound to be a pervasive problem in bioinformatics, where labels may be obtained indirectly through complex, many-step similarity modelling processes. In the case of G protein-coupled receptors, methods capable of singling out and characterizing those sequences with consistent misclassification behaviour are required to minimize this problem. A systematic, Support Vector Machine-based method has been proposed in this study for such purpose. The proposed method enables a filtering approach to the label noise problem and might become a support tool for database curators in proteomics.


Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): a comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine.
Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET. Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]-doxepin, a potent H1-receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions. Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1-receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)-chlorpheniramine (2 mg). H1-receptor occupancies in cortex were approximately 10% by ebastine and > or = 50% by either dose of (+)-chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. Ebastine (10 mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.


Large extents of intensive land use limit community reorganization during climate warming.
Climate change is increasingly altering the composition of ecological communities, in combination with other environmental pressures such as high-intensity land use. Pressures are expected to interact in their effects, but the extent to which intensive human land use constrains community responses to climate change is currently unclear. A generic indicator of climate change impact, the community temperature index (CTI), has previously been used to suggest that both bird and butterflies are successfully 'tracking' climate change. Here, we assessed community changes at over 600 English bird or butterfly monitoring sites over three decades and tested how the surrounding land has influenced these changes. We partitioned community changes into warm- and cold-associated assemblages and found that English bird communities have not reorganized successfully in response to climate change. CTI increases for birds are primarily attributable to the loss of cold-associated species, whilst for butterflies, warm-associated species have tended to increase. Importantly, the area of intensively managed land use around monitoring sites appears to influence these community changes, with large extents of intensively managed land limiting 'adaptive' community reorganization in response to climate change. Specifically, high-intensity land use appears to exacerbate declines in cold-adapted bird and butterfly species, and prevent increases in warm-associated birds. This has broad implications for managing landscapes to promote climate change adaptation.


New synthesis of phenyl-isothiocyanate C-functionalised cyclams. Bioconjugation and (64)Cu phenotypic PET imaging studies of multiple myeloma with the te2a derivative.
Azamacrocyclic bifunctional chelating agents (BCAs) are essential for the development of radiopharmaceuticals in nuclear medicine and we wish to prove that their bioconjugation by a function present on a carbon atom of the macrocyclic skeleton is a solution of choice to maintain their in vivo inertness. Based on our very recent methodology using a bisaminal template and selective N-alkylation approach, a new synthesis of conjugable C-functionalised teta, te2a and cb-te2a has been developed. These chelators have indeed a growing interest in nuclear medicine for positron emission tomography (PET) and radioimmunotherapy (RIT) where they show in several cases better complexation properties than dota or dota-like macrocycles, especially with (64)Cu or (67)Cu radioisotopes. Chelators are bearing an isothiocyanate grafting function introduced by C-alkylation to avoid as much as possible a critical decrease of their chelating properties. The synthesis is very efficient and yields the targeted ligands, teta-Ph-NCS, te2a-Ph-NCS and cb-te2a-Ph-NCS without fastidious work-up and could be easily extended to other cyclam based-BCAs. The newly synthetised te2a-Ph-NCS has been conjugated to an anti mCD138 monoclonal antibody (mAb) to evaluate its in vivo behavior and potentiality as BCA and to explore a first attempt of PET-phenotypic imaging in multiple myeloma (MM). Mass spectrometry analysis of the immunoconjugate showed that up to 4 chelates were conjugated per 9E7.4 mAb. The radiolabeling yield and specific activity post-purification of the bioconjugate 9E7.4-CSN-Ph-te2a were 95 ± 2.8% and 188 ± 27 MBq mg(-1) respectively and the immunoreactivity of (64)Cu-9E7.4-CSN-Ph-te2a was 81 ± 7%. Animal experiments were carried out on 5T33-Luc(+) tumor bearing mice, either in subcutaneous or orthotopic. To achieve PET imaging, mice were injected with (64)Cu-9E7.4-CNS-Ph-te2a and acquisitions were conducted 2 and 20 h post-injection (PI). A millimetric bone uptake was localised in a sacroiliac of a MM orthotopic tumor. Nonspecific uptakes were observed at 2 h PI but, unlike for the tumor, a significant decrease was observed at 20 h PI which improves the contrast of the images.


Lipid-lowering treatment patterns in patients with new cardiovascular events - estimates from population-based register data in Sweden.
The aim of this study was to assess treatment patterns of lipid-lowering therapy (LLT) in patients with hyperlipidaemia or prior cardiovascular (CV) events who experience new CV events. A retrospective population-based cohort study was conducted using Swedish medical records and registers. Patients were included in the study based on a prescription of LLT or CV event history and followed up for up to 7 years for identification of new CV events and assessment of LLT treatment patterns. Patients were stratified into three cohorts based on CV risk level. All outcomes were assessed during the year following index (the date of first new CV event). Adherence was defined as medication possession ratio (MPR) > 0.80. Persistence was defined as no gaps > 60 days in supply of drug used at index. Of patients with major cardiovascular disease (CVD) history (n = 6881), 49% were not on LLT at index. Corresponding data for CV risk equivalent and low/unknown CV risk patients were 37% (n = 3226) and 38% (n = 2497) respectively. MPR for patients on LLT at index was similar across cohorts (0.74-0.75). The proportions of adherent (60-63%) and persistent patients (56-57%) were also similar across cohorts. Dose escalation from dose at index was seen within all cohorts and 2-3% of patients switched to a different LLT after index while 5-6% of patients augmented treatment by adding another LLT. Almost 50% of patients with major CVD history were not on any LLT, indicating a potential therapeutic gap. Medication adherence and persistence among patients on LLT were suboptimal.


High-efficient and precise base editing of C•G to T•A in the allotetraploid cotton (Gossypium hirsutum) genome using a modified CRISPR/Cas9 system.
The base-editing technique using CRISPR/nCas9 (Cas9 nickase) or dCas9 (deactivated Cas9) fused with cytidine deaminase is a powerful tool to create point mutations. In this study, a novel G. hirsutum-Base Editor 3 (GhBE3) base-editing system has been developed to create single-base mutations in the allotetraploid genome of cotton (Gossypium hirsutum). A cytidine deaminase sequence (APOBEC) fused with nCas9 and uracil glycosylase inhibitor (UGI) was inserted into our CRISPR/Cas9 plasmid (pRGEB32-GhU6.7). Three target sites were chosen for two target genes, GhCLA and GhPEBP, to test the efficiency and accuracy of GhBE3. The editing efficiency ranged from 26.67 to 57.78% at the three target sites. Targeted deep sequencing revealed that the C→T substitution efficiency within an 'editing window', approximately six-nucleotide windows of -17 to -12 bp from the PAM sequence, was up to 18.63% of the total sequences. The 27 most likely off-target sites predicted by CRISPR-P and Cas-OFFinder tools were analysed by targeted deep sequencing, and it was found that rare C→T substitutions (average < 0.1%) were detected in the editing windows of these sites. Furthermore, whole-genome sequencing analyses on two GhCLA-edited and one wild-type plants with about 100× depth showed that no bona fide off-target mutations were detectable from 1500 predicted potential off-target sites across the genome. In addition, the edited bases were inherited to T1 progeny. These results demonstrate that GhBE3 has high specificity and accuracy for the generation of targeted point mutations in allotetraploid cotton.


The simplest formal argument for fitness optimization.
The Formal Darwinism Project aims to provide a formal argument linking population genetics to fitness optimization, which of necessity includes defining fitness. This bridges the gulf between those biologists who assume that natural selection leads to something close to fitness optimization and those biologists who believe on theoretical grounds that there is no sense of fitness that can usefully be said to be optimized. The current paper's main objective is to provide a careful mathematical introduction to the project, and it also reflects on the project's scope and limitations. The central argument is the proof of close ties between the mathematics of motion, as embodied in the Price equation, and the mathematics of optimization, as represented by optimization programmes. To make these links, a general and abstract model linking genotype, phenotype and number of successful gametes is assumed. The project has begun with simple dynamic models and simple linking models, and its progress will involve more realistic versions of them. The versions given here are fully mathematically rigorous, but elementary enough to serve as an introduction.


Structural antioxidant defense mechanisms in the mammalian and nonmammalian kidney: different solutions to the same problem?
Tissue oxygen levels are tightly regulated in all organs. This poses a challenge for the kidney, as its function requires blood flow, and thus, oxygen delivery to greatly exceed its metabolic requirements. Because superoxide production in the kidney is dependent on oxygen availability, tissue hyperoxia could drive oxidative stress. In the mammalian renal cortex, this problem may have been solved, in part, through a structural antioxidant defense mechanism. That is, arteries and veins are closely associated in a countercurrent arrangement, facilitating diffusional arterial-to-venous (AV) oxygen shunting. Because of this mechanism, a proportion of the oxygen delivered in the renal artery never reaches kidney tissue but instead diffuses to the closely associated renal veins, thus limiting oxygen transport to tissue. In the nonmammalian kidney, arteries and veins are not arranged in an intimate countercurrent fashion as in mammals; thus AV oxygen shunting is likely less important in regulation of kidney oxygenation in these species. Instead, the kidney's blood supply is predominately of venous origin. This likely has a similar impact on tissue oxygenation as AV oxygen shunting, of limiting delivery of oxygen to renal tissue. Thus, we hypothesize the evolution of structural antioxidant mechanisms that are anatomically divergent but functionally homologous in the mammalian and nonmammalian kidney.


SarA and not sigmaB is essential for biofilm development by Staphylococcus aureus.
Staphylococcus aureus biofilm formation is associated with the production of the polysaccharide intercellular adhesin (PIA/PNAG), the product of the ica operon. The staphylococcal accessory regulator, SarA, is a central regulatory element that controls the production of S. aureus virulence factors. By screening a library of Tn917 insertions in a clinical S. aureus strain, we identified SarA as being essential for biofilm development. Non-polar mutations of sarA in four genetically unrelated S. aureus strains decreased PIA/PNAG production and completely impaired biofilm development, both in steady state and flow conditions via an agr-independent mechanism. Accordingly, real-time PCR showed that the mutation in the sarA gene resulted in downregulation of the ica operon transcription. We also demonstrated that complete deletion of sigmaB did not affect PIA/PNAG production and biofilm formation, although it slightly decreased ica operon transcription. Furthermore, the sarA-sigmaB double mutant showed a significant decrease of ica expression but an increase of PIA/PNAG production and biofilm formation compared to the sarA single mutant. We propose that SarA activates S. aureus development of biofilm by both enhancing the ica operon transcription and suppressing the transcription of either a protein involved in the turnover of PIA/PNAG or a repressor of its synthesis, whose expression would be sigmaB-dependent.


Characterization of the nasopharyngeal microbiota in health and during rhinovirus challenge.
The bacterial communities of the nasopharynx play an important role in upper respiratory tract infections (URTIs). Our study represents the first survey of the nasopharynx during a known, controlled viral challenge. We aimed to gain a better understanding of the composition and dynamics of the nasopharyngeal microbiome during viral infection. Rhinovirus illnesses were induced by self-inoculation using the finger to nose or eye natural transmission route in ten otherwise healthy young adults. Nasal lavage fluid samples (NLF) samples were collected at specific time points before, during, and following experimental rhinovirus inoculation. Bacterial DNA from each sample (N = 97 from 10 subjects) was subjected to 16S rRNA sequencing by amplifying the V1-V2 hypervariable region followed by sequencing using the 454-FLX platform. This survey of the nasopharyngeal microbiota revealed a highly complex microbial ecosystem. Taxonomic composition varied widely between subjects and between time points of the same subject. We also observed significantly higher diversity in not infected individuals compared to infected individuals. Two genera - Neisseria and Propionibacterium - differed significantly between infected and not infected individuals. Certain phyla, including Firmicutes, Actinobacteria, and Proteobacteria, were detected in all samples. Our results reveal the complex and diverse nature of the nasopharyngeal microbiota in both healthy and viral-challenged adults. Although some phyla were common to all samples, differences in levels of diversity and selected phyla were detected between infected and uninfected participants. Deeper, species-level metagenomic sequencing in a larger sample is warranted.


Measuring gender-based violence risk mitigation in humanitarian settings: results from a comprehensive desk review and systematic mapping.
To systematically document measurement approaches used in the monitoring and evaluation of gender-based violence (GBV) risk mitigation activities, categorise the types of available literature produced by sector, identify existing tools and measures and identify knowledge gaps within the humanitarian sector. Systematic mapping and in-depth review. Pubmed, Global Health, PsychInfo, ReliefWeb, OpenGrey (grey literature), Google Scholar, Web of Science (Social Science Index)Eligibility criteria: a structured search strategy was systematically applied to 17 databases as well as registers, websites and other resources to identify materials published between 1 January 2005 and 15 May 2019. Those resources that met the inclusion criteria underwent a comprehensive full-text review. A detailed matrix was developed and key data from each resource were extracted to allow for the assessment of patterns in thematic areas. A total of 2108 documents were screened. Overall, 145 documents and 112 tools were reviewed, representing 10 different humanitarian sectors. While numerous resources exist, many lack sufficient information on how to monitor outputs or outcomes of GBV risk mitigation activities. There is also limited guidance on how to integrate the measurement of GBV risk mitigation into existing monitoring and evaluation frameworks. Those reports that aimed to measure GBV risk mitigation activities mostly employed qualitative methods and few measured the impact of a GBV risk mitigation with robust research designs. Recent efforts to adapt humanitarian response to COVID-19 have highlighted new and existing challenges for GBV risk mitigation. There is a significant gap in the evidence base around the effectiveness of GBV risk mitigation across all sectors. Understanding and strengthening measurement approaches in GBV risk mitigation remains a critical task for humanitarian response.


How the health and community development sectors are combining forces to improve health and well-being.
The root causes of poor health experienced by many who live in low-income neighborhoods-such as the lack of access to health care, limited food choices, and exposure to environmental hazards-are well documented, but often go beyond the scope of the health care delivery system. But that is beginning to change. The health sector has begun to collaborate with the community development sector, which for decades has been working in low-income neighborhoods. Encouraging local and national examples of these new partnerships abound. They include an effort in Seattle, Washington, to reduce exposure to allergens and irritants among low-income asthmatic children, and a $500 million federal program to finance the operation of grocery stores in what have previously been urban "food deserts." To nurture such efforts, the Robert Wood Johnson Foundation, the Federal Reserve System, and others have sponsored a series of "healthy community" forums in US cities. In this article we explore the growing partnerships between the health and community development sectors as well as the challenges they face, and we offer policy recommendations that might help them succeed.


Revealing Population Heterogeneity in Vesicle-Based Nanomedicines Using Automated, Single Particle Raman Analysis.
The intrinsic heterogeneity of many nanoformulations is currently challenging to characterize on both the single particle and population level. Therefore, there is great opportunity to develop advanced techniques to describe and understand nanomedicine heterogeneity, which will aid translation to the clinic by informing manufacturing quality control, characterization for regulatory bodies, and connecting nanoformulation properties to clinical outcomes to enable rational design. Here, we present an analytical technique to provide such information, while measuring the nanocarrier and cargo simultaneously with label-free, nondestructive single particle automated Raman trapping analysis (SPARTA). We first synthesized a library of model compounds covering a range of hydrophilicities and providing distinct Raman signals. These compounds were then loaded into model nanovesicles (polymersomes) that can load both hydrophobic and hydrophilic cargo into the membrane or core regions, respectively. Using our analytical framework, we characterized the heterogeneity of the population by correlating the signal per particle from the membrane and cargo. We found that core and membrane loading can be distinguished, and we detected subpopulations of highly loaded particles in certain cases. We then confirmed the suitability of our technique in liposomes, another nanovesicle class, including the commercial formulation Doxil. Our label-free analytical technique precisely determines cargo location alongside loading and release heterogeneity in nanomedicines, which could be instrumental for future quality control, regulatory body protocols, and development of structure-function relationships to bring more nanomedicines to the clinic.


Turbidimetric and HPLC assays for the determination of formulated lysozyme activity.
In several studies lysozyme has been employed as a model protein to investigate the effects of formulation factors upon biological activity. The aim of this work was to develop and validate an HPLC technique to assay lysozyme and to compare the results with biological activity determined from a validated turbidimetric assay. The turbidimetric assay was based upon the lytic action of lysozyme on Micrococcus lysodeikticus cells, whilst the reverse-phase HPLC assay employed an acetonitrile gradient in 0.1% trifluoroacetic acid. The limits of detection and quantification were 3.84 and 6.24 microg mL(-1) for HPLC assay, whilst the corresponding values for turbidimetric assay were 1.94 and 3.86 microg mL(-1). The methods were used to monitor the loss of enzyme activity after heating. Lysozyme concentrations determined from HPLC peak height were found to correlate (r2 = 0.9963) with those obtained from turbidimetric assay.


Field dependence of the ferromagnetic/superconducting proximity effect in a YBCO/STO/LCMO multilayer.
The interaction between superconductivity and magnetism in spatially confined heterostructures of thin film multilayers is investigated in the ferromagnetic manganite La2/3Ca1/3MnO3 (LCMO) and the high-temperature superconductor YBa2Cu3O7-δ (YBCO) mediated by an intermediate insulating SrTiO3 (STO) layer. The STO layer is used to mediate and tune the range of interactions between the ferromagnet and superconductor. A magnetically depleted layer with zero-magnetisation within the LCMO layer is shown by polarised neutron reflectometry measurements. This zero-magnetisation layer is caused by the onset of superconductivity in YBCO despite being separated by an insulating layer with a thickness much larger than the superconducting coherence length. The magnetic field dependence of this interaction is also explored. We show that the magnetism of the depleted layer can be restored by applying a magnetic field that partially destroys the superconductivity in YBCO, restricting the electronic interaction between the materials.


Development, Interlaboratory Evaluations, and Application of a Simple, High-Throughput Shigella Serum Bactericidal Assay.
Shigella is an important cause of diarrhea worldwide, with serotypes Shigella flexneri 2a, S. flexneri 3a, and Shigella sonnei demonstrating epidemiological prevalence. Many development efforts are focused on Shigella lipopolysaccharide (LPS)-based vaccines, as O antigen-specific conjugate vaccines are immunogenic and efficacious. Immunization with Shigella vaccines containing LPS can elicit antibodies capable of killing Shigella in a serotype-specific manner. Thus, to facilitate Shigella vaccine development, we have developed a serum bactericidal assay (SBA) specific for three Shigella serotypes that measures killing of target bacteria at multiple serum dilutions and in the presence of exogenous complement. The SBA has a high analytical throughput and uses simple technologies and readily available reagents. The SBA was characterized with human sera with bactericidal antibodies against S. flexneri 2a, S. flexneri 3a, and S. sonnei Purified LPS of a homologous serotype, but not a heterologous serotype, inhibited bacterial killing. Assessment of precision found median intra-assay precision to be 13.3% and median interassay precision to be 19 to 30% for the three serotypes. The SBA is linear, with slight deviations for samples with low (~40) killing indices. The SBA was sensitive enough to allow about 100-fold predilution of serum samples. Repeat assays yielded results with less than 2-fold deviations, indicating the robustness of the assay. Assay results from four different laboratories were highly comparable when normalized with a reference serum. The Shigella SBA, combined with a reference serum, should facilitate the development of Shigella vaccines across the field.IMPORTANCEShigella is an important cause of diarrhea worldwide, and efforts are ongoing to produce a safe and effective Shigella vaccine. Although a clear immune correlate of protection has not been established, antibodies with bactericidal capacity may provide one means of protecting against shigellosis. Thus, it is important to measure the functional capacity of antibodies, as opposed to only binding activity. This article describes a simple, robust, and high-throughput serum bactericidal assay capable of measuring Shigella-specific functional antibodies in vitro We show for the first time that this assay was successfully performed by multiple laboratories and generated highly comparable results, particularly when SBA titers were normalized using a reference standard. The serum bactericidal assay, along with a reference serum, should greatly facilitate Shigella vaccine development.


Dietary strategies for achieving adequate vitamin D and iron intakes in young children in Ireland.
Inadequate intakes of vitamin D and iron have been reported in young children in Ireland. The present study aimed to identify the main foods determining vitamin D and iron intakes and to model the impact of dietary strategies to improve adequacy of these micronutrients in young children. The present study is based on the Irish National Pre-School Nutrition Survey (NPNS), which estimated food and nutrient intakes in a representative sample (n = 500) of children (aged 1-4 years) using a 4-day weighed food record. Dietary strategies were modelled using DaDiet© software (Dazult Ltd, Co. Kildare, Republic of Ireland) and the usual intake distribution, prevalence of inadequate intakes and risk of excessive intakes were estimated using the National Cancer Institute method. Fortified foods and nutritional supplements were the key foods influencing the intakes of vitamin D and iron. Adding a 5 μg day-1 vitamin D supplement, fortifying cow's milk (CM) with vitamin D or replacing CM with growing-up milk (GUM) would modestly increase intakes of vitamin D. A combined strategy of fortifying CM with vitamin D or replacing CM with GUM plus a 5 μg day-1 vitamin D supplement would increase mean intakes of vitamin D (from 3.5 μg day-1 at baseline to ≥11 μg day-1 ) and substantially reduce the prevalence of inadequate intakes (from >95% to 12-36%). Fortifying CM with iron or replacing CM with GUM would increase mean intakes of iron (from 7.3 mg day-1 to >10 mg day-1 ), achieving adequate intakes across all ages. Based on real food consumption data in a representative sample of Irish children, we have shown that through targeted dietary strategies adequate intakes of iron are achievable and intakes of vitamin D could be greatly improved.


Nonconjugated Polymer Poly(vinylpyrrolidone) as an Efficient Interlayer Promoting Electron Transport for Perovskite Solar Cells.
The interfaces between perovskite layer and electrodes play a crucial role on efficient charge transport and extraction in perovskite solar cells (PSCs). Herein, for the first time we applied a low-cost nonconjugated polymer poly(vinylpyrrolidone) (PVP) as a new interlayer between PCBM electron transport layer (ETL) and Ag cathode for high-performance inverted planar heterojunction perovskite solar cells (iPSCs), leading to a dramatic efficiency enhancement. The CH3NH3PbI3-xClx-based iPSC device incorporating the PVP interlayer exhibited a power conversion efficiency (PCE) of 12.55%, which is enhanced by ∼15.9% relative to that of the control device without PVP interlayer (10.83%). The mechanistic investigations based on morphological, optical, and impedance spectroscopic characterizations reveal that incorporation of PVP interlayer promotes electron transport across the CH3NH3PbI3-xClx perovskite/Ag interface via PCBM ETL. Besides, PVP incorporation induces the formation of a dipole layer, which may enhance the built-in potential across the device, conjunctly promoting electron transport from PCBM to Ag cathode and consequently leading to significantly improved fill factor (FF) from 58.98 to 66.13%.


Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma.
To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors. We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness. With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness. UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.


Evolution and medicine: the long reach of "Dr. Darwin".
In this review we consider the new science of Darwinian medicine. While it has often been said that evolutionary theory is the glue that holds the disparate branches of biological inquiry together and gives them direction and purpose, the links to biomedical inquiry have only recently been articulated in a coherent manner. Our aim in this review is to make clear first of all, how evolutionary theory is relevant to medicine; and secondly, how the biomedical sciences have enriched our understanding of evolutionary processes. We will conclude our review with some observations of the philosophical significance of this interplay between evolutionary theory and the biomedical sciences.


Investigating the need for scholarly communications positions in Association of Academic Health Sciences Libraries member institutions.
The role of health sciences librarians has expanded in the scholarly communications landscape as a result of the increase in federal public access mandates and the continued expansion of publishing avenues. This has created the need to investigate whether academic health sciences libraries should have scholarly communications positions to provide education and services exclusively related to scholarly communication topics. A nine-question online survey was distributed through the Association of Academic Health Sciences Libraries (AAHSL) email discussion list to gather preliminary findings from and opinions of directors of health sciences libraries on the need for scholarly communications positions. The survey received a 38% response rate. The authors found that AAHSL members are currently providing scholarly communications services, and 46% of respondents expressed the need to devote a full-time position to this role. Our survey reveals a juxtaposition occurring in AAHSL member libraries. While administrators acknowledge the need to provide scholarly communications services, they often experience budget challenges in providing a full-time position for these services.


Effect of counterions on the interactions of charged oligothiophenes.
The functionality of conjugated polymer systems often relies on oxidations or reductions, in most cases mediated by the presence of counterions. The effect that the common counterion hexafluorophosphate (PF6-) has on the intermolecular interactions between charged oligothiophenes is investigated here using ab initio quantum chemistry methods. Counterions are explicitly included in the simulations of oxidized oligothiophenes and in the dimerization process. Our calculations provide quantitative and qualitative insight into the intermolecular interactions in oligothiophene-counterion systems and show that the intermolecular pi-stacking of oligothiophenes is not adversely affected by the presence of counterions and that in fact oligothiophene dimerization is further stabilized by their presence.


Role of cilia in the pathogenesis of congenital heart disease.
An essential role for cilia in the pathogenesis of congenital heart disease (CHD) has emerged from findings of a large-scale mouse forward genetic screen. High throughput screening with fetal ultrasound imaging followed by whole exome sequencing analysis recovered a preponderance of cilia related genes and cilia transduced cell signaling genes among mutations identified to cause CHD. The perturbation of left-right patterning in CHD pathogenesis is suggested by the association of CHD with heterotaxy, but also by the finding of the co-occurrence of laterality defects with CHD in birth defect registries. Many of the cilia and cilia cell signaling genes recovered were found to be related to Hedgehog signaling. Studies in mice showed cilia transduced hedgehog signaling coordinates left-right patterning with heart looping and differentiation of the heart tube. Cilia transduced Shh signaling also regulates later events in heart development, including outflow tract septation and formation of the atrioventricular septum. More recent work has shown mutations in cilia related genes may also contribute to valve disease that largely manifest in adult life. Overall, these and other findings show cilia play an important role in CHD and also in more common valve diseases.


The temporal pattern of stimulation determines the extent and duration of MAPK activation in a Caenorhabditis elegans sensory neuron.
The Caenorhabditis elegans ASER sensory neuron is excited when environmental NaCl concentration is decreased. The mitogen-activated protein kinase (MAPK) MPK-1, a homolog of ERK (extracellular signal-regulated kinase), is activated during excitation of ASER sensory neurons. We created and expressed a fluorescence resonance energy transfer (FRET)-based MAPK activity probe in ASER neurons and then exposed the worms to various cyclic patterns of stimulation (changes in NaCl concentration) to monitor the dynamics of MPK-1 activity. We found that the intensity and duration of MPK-1 activity were determined by the temporal pattern of stimulation, namely, a combination of stimulation period length, stimulation duration, and time between stimuli. The complex, nonlinear relationship between stimulation and MPK-1 activation was explained by the properties of intracellular calcium responses upstream of MPK-1. Thus, we visualized the dynamics of MAPK activation in a sensory neuron in living nematodes in response to complex stimuli and present a reporter that can be used in higher eukaryotes to test in silico predictions regarding the MAPK pathway.


Metacognition in human decision-making: confidence and error monitoring.
People are capable of robust evaluations of their decisions: they are often aware of their mistakes even without explicit feedback, and report levels of confidence in their decisions that correlate with objective performance. These metacognitive abilities help people to avoid making the same mistakes twice, and to avoid overcommitting time or resources to decisions that are based on unreliable evidence. In this review, we consider progress in characterizing the neural and mechanistic basis of these related aspects of metacognition-confidence judgements and error monitoring-and identify crucial points of convergence between methods and theories in the two fields. This convergence suggests that common principles govern metacognitive judgements of confidence and accuracy; in particular, a shared reliance on post-decisional processing within the systems responsible for the initial decision. However, research in both fields has focused rather narrowly on simple, discrete decisions-reflecting the correspondingly restricted focus of current models of the decision process itself-raising doubts about the degree to which discovered principles will scale up to explain metacognitive evaluation of real-world decisions and actions that are fluid, temporally extended, and embedded in the broader context of evolving behavioural goals.


Nutrition and physical activity cancer prevention guidelines, cancer risk, and mortality in the women's health initiative.
Healthy lifestyle behaviors are recommended to reduce cancer risk and overall mortality. Adherence to cancer-preventive health behaviors and subsequent cancer risk has not been evaluated in a diverse sample of postmenopausal women. We examined the association between the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines score and risk of incident cancer, cancer-specific mortality, and all-cause mortality in 65,838 postmenopausal women enrolled in the Women's Health Initiative Observational Study. ACS guidelines scores (0-8 points) were determined from a combined measure of diet, physical activity, body mass index (current and at age 18 years), and alcohol consumption. After a mean follow-up of 12.6 years, 8,632 incident cancers and 2,356 cancer deaths were identified. The highest ACS guidelines scores compared with the lowest were associated with a 17% lower risk of any cancer [HR, 0.83; 95% confidence interval (CI), 0.75-0.92], 22% lower risk of breast cancer (HR, 0.78; 95% CI, 0.67-0.92), 52% lower risk of colorectal cancer (HR, 0.48; 95% CI, 0.32-0.73), 27% lower risk of all-cause mortality, and 20% lower risk of cancer-specific mortality (HR, 0.80; 95% CI, 0.71-0.90). Associations with lower cancer incidence and mortality were generally strongest among Asian, black, and Hispanic women and weakest among non-Hispanic whites. Behaviors concordant with Nutrition and Physical Activity Cancer Prevention Guidelines were associated with lower risk of total, breast, and colorectal cancers and lower cancer-specific mortality in postmenopausal women.


Whole-body vibration training compared with resistance training: effect on spasticity, muscle strength and motor performance in adults with cerebral palsy.
The aim of this study was to evaluate the effect on spasticity, muscle strength and motor performance after 8 weeks of whole-body vibration training compared with resistance training in adults with cerebral palsy. Fourteen persons with spastic diplegia (21-41 years) were randomized to intervention with either whole-body vibration training (n=7) or resistance training (n=7). Pre- and post-training measures of spasticity using the modified Ashworth scale, muscle strength using isokinetic dynamometry, walking ability using Six-Minute Walk Test, balance using Timed Up and Go test and gross motor performance using Gross Motor Function Measure were performed. Spasticity decreased in knee extensors in the whole-body vibration group. Muscle strength increased in the resistance training group at the velocity 30 degrees /s and in both groups at 90 degrees /s. Six-Minute Walk Test and Timed Up and Go test did not change significantly. Gross Motor Function Measure increased in the whole-body vibration group. These data suggest that an 8-week intervention of whole-body vibration training or resistance training can increase muscle strength, without negative effect on spasticity, in adults with cerebral palsy.


Increased local concentration of complement C5a contributes to incisional pain in mice.
In our previous study, we demonstrated that local injection of complement C5a and C3a produce mechanical and heat hyperalgesia, and that C5a and C3a activate and sensitize cutaneous nociceptors in normal skin, suggesting a contribution of complement fragments to acute pain. Other studies also have shown that the complement system can be activated by surgical incision, and the systemic blockade of C5a receptor (C5aR) reduces incision-induced pain and inflammation. In this study, we further examined the possible contribution of wound area C5a to incisional pain. Using of a hind paw incisional model, the effects of a selective C5aR antagonist, PMX53, on nociceptive behaviors were measured after incision in vivo. mRNA levels of C5 and C5aR in skin, dorsal root ganglia (DRG) and spinal cord, and C5a protein levels in the skin were quantified after incision. The responses of nociceptors to C5a were also evaluated using the in vitro skin-nerve preparation. Local administration of PMX53 suppressed heat hyperalgesia and mechanical allodynia induced by C5a injection or after hind paw incision in vivo. mRNA levels of C5 and C5aR in the skin, but not DRG and spinal cord, were dramatically increased after incision. C5a protein in the skin was also increased after incision. In vitro C5a did not increase the prevalence of fibers with ongoing activity in afferents from incised versus control, unincised skin. C5a sensitized C-fiber afferent responses to heat; however, this was less evident in afferents adjacent to the incision. PMX53 blocked sensitization of C-fiber afferents to heat by C5a but did not by itself influence ongoing activity or heat sensitivity in afferents innervating control or incised skin. The magnitude of mechanical responses was also not affected by C5a in any nociceptive fibers innervating incised or unincised skin. This study demonstrates that high locally generated C5a levels are present in wounds for at least 72 hours after incision. In skin, C5a contributes to hypersensitivity after incision, but increased responsiveness of cutaneous nociceptors to C5a was not evident in incised skin. Thus, high local concentrations of C5a produced in wounds likely contribute to postoperative pain.


Perceived outcomes of spiritual healing and explanations--a qualitative study on the perspectives of German healers and their clients.
Limited research has been conducted on contemporary spiritual healing in European countries. The aim of this article is to report how German healers and their clients experienced and perceived the outcomes of spiritual healing and which explanations they use to describe the perceived effects. Semistructured interviews and participatory observation was used to collect data from spiritual healers and their clients. Analyses were based on the methodological concept of directed qualitative content analysis. Data was analyzed using MAXQDA software, discussed and reviewed by a multidisciplinary research team consisting of medical anthropologists, medical doctors and a religious studies scholar. In total 15 healers and 16 clients participated in this study, 24 interviews with healers, 20 interviews with clients and 8 participatory observations were analyzed. Healers and clients reported outcomes as positively perceived body sensations, increased well-being, positive emotions and symptomatic relief of medical complaints. Clients often described changes in their self-concepts and adapted life values. Explanations for perceived effects included connecting with transcendent sources, construction of meaning, as a result of the client-healer relationship, and as empowerment to make changes. Because the interviewed clients were recruited by the healers, a selection bias towards positive healing experiences is possible. We hypothesize that concepts of meaning construction, resource activation and the utilization of the clients' expectations help to explain the data. Grounded in the emic perspective, we propose to use the following outcomes for further prospective studies: positive body sensations, changes of self-concepts and values, changes of medical symptoms and complaints. From the etic perspective, physical, emotional, social and spiritual wellbeing, sense of coherence, meaningfulness of life, empowerment, resource activation, change and symptom control should be further explored as potential outcomes.


Validation of neural tube defects in the full featured--general practice research database.
The General Practice Research Database (GPRD) has been used to identify associations between pregnancy medication exposures and birth defects, but experts have argued that databases such as this one cannot provide detailed information for the valid identification of complicated congenital anomalies. Our objective was to determine if the GPRD could be used to identify cases of neural tube defects (NTDs). First, we created algorithms for anencephaly, encephalocele, meningocele, and spina bifida and used them to identify potential cases. We used the algorithms to identify 217 potential NTD cases in either a child's or a mother's record. We validated cases by querying general practitioners (GPs) via questionnaire. Where cases of NTD were identified in the mother's record, in addition to confirming the diagnosis, we asked the GPs if the diagnosis was for the mother or that of her fetus or offspring. Two hundred seventeen cases were identified, and 165 GP questionnaires were returned. We validated an NTD diagnosis for 117 cases, giving our algorithms a positive predictive value (PPV) of 0.71. The PPVs varied by NTD type: 0.81 for anencephaly, 0.83 for cephalocele, 0.64 for meningocele, and 0.47 for spina bifida. Our identification algorithm was useful in identifying three of the four types of NTDs studied. Additional information is necessary to accurately identify cases of spina bifida.


Survey of the diagnosis and management of auditory processing disorder.
A survey of audiologists' diagnosis and intervention protocols for auditory processing disorder (APD) was conducted to determine current protocols and compare results with published recommendations. A survey was distributed by mail to 515 American Speech-Language-Hearing Association audiology members who listed APD as an area of expertise and via e-mail to Educational Audiology Association members. The survey was completed by 195 audiologists. The majority of respondents reported using auditory processing (AP) test batteries selected based on clinical experience, review of the literature, and attendance at professional conferences. The most popular tests were dichotic, monaural low-redundancy speech, and temporal processing tests. Treatment and management recommendations were usually customized for each patient based on deficits found in behavioral AP testing. The majority of respondents indicated that audiologists are responsible for APD diagnosis (97%) and recommendation of treatment/management (81%); in contrast, only 40% of respondents indicated audiologists were responsible for providing treatment/management. Audiologists are selecting AP test batteries based on the age and case history of the patient, which is in accordance with recent national guidelines. Audiologists are primarily responsible for APD diagnosis and recommending treatment/management. APD treatment is provided by speech-language pathologists, educators, and audiologists.


Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1.
The Akt family of serine/threonine-directed kinases promotes cellular survival in part by phosphorylating and inhibiting death-inducing proteins. Here we describe a novel functional interaction between Akt and apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase. Akt decreased ASK1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus Akt site at serine 83 of ASK1. Activation of the phosphoinositide 3-kinase (PI3-K)/Akt pathway also inhibited the serum deprivation-induced activity of endogenous ASK1 in L929 cells. An association between Akt and ASK1 was detected in cells by coimmunoprecipitation. Phosphorylation by Akt inhibited ASK1-mediated c-Jun N-terminal kinase and activating transcription factor 2 activities in intact cells. Finally, activation of the PI3-K/Akt pathway reduced apoptosis induced by ASK1 in a manner dependent on phosphorylation of serine 83 of ASK1. These results provide the first direct link between Akt and the family of stress-activated kinases.


Cyclic AMP mediated arrhythmias induced in the ischaemic pig heart.
Ligation of the anterior descending coronary artery two-thirds from its origin in the pig was found to precipitate ventricular arrhythmias and fibrillation, starting approximately 20 min post-ligation, which were associated with regional accumulation of myocardial cAMP in the ischaemic area. When the arrhythmias stopped, cyclic AMP levels in the ischaemic zone were decreased. Arrhythmias could then be induced by subepicardial infusion (10 microliter/min) close to the visible edge of ischaemia of cAMP analogues [N6-monobutyryl cAMP, N6,O2'-dibutyryl cAMP (5.10(-2) M each)] or agents which increase the myocardial contents of cAMP. These agents were: isoproterenol (10(-6) M), noradrenaline, adrenaline (10(-5) M each), glucagon, histamine (10(-3) M each), theophylline and caffeine (5.10(-2) M each). Also active were dopamine (10(-3) M), ouabain (10(-5) M) and aconitine (10(-6) M). The arrhythmias induced by infusion of catecholamines were dependent on Ca2+ and were abolished by beta-adrenoceptor blocking agents (pindolol, 10(-6) M) and calcium antagonists (isoptin, D 600, 10(-4) M each). Infusion of 150 mM sodium chloride or 100 mM sodium butyrate did not precipitate arrhythmias. It is concluded that myocardial cAMP may play an important role in the genesis of ventricular arrhythmias in the ischaemic heart, probably by augmenting the slow calcium inward current.


Vessel tractography using an intensity based tensor model with branch detection.
In this paper, we present a tubular structure segmentation method that utilizes a second order tensor constructed from directional intensity measurements, which is inspired from diffusion tensor image (DTI) modeling. The constructed anisotropic tensor which is fit inside a vessel drives the segmentation analogously to a tractography approach in DTI. Our model is initialized at a single seed point and is capable of capturing whole vessel trees by an automatic branch detection algorithm developed in the same framework. The centerline of the vessel as well as its thickness is extracted. Performance results within the Rotterdam Coronary Artery Algorithm Evaluation framework are provided for comparison with existing techniques. 96.4% average overlap with ground truth delineated by experts is obtained in addition to other measures reported in the paper. Moreover, we demonstrate further quantitative results over synthetic vascular datasets, and we provide quantitative experiments for branch detection on patient computed tomography angiography (CTA) volumes, as well as qualitative evaluations on the same CTA datasets, from visual scores by a cardiologist expert.


Predictive Factors for Favorable Outcome from Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease.
To investigate predictive factors for a favorable outcome from subthalamic nucleus-deep brain stimulation (STN-DBS) in Parkinson's disease (PD) and whether low serum vitamin B12 (vB12) levels can predict an unfavorable outcome. Thirty-nine patients with PD who underwent bilateral STN-DBS were retrospectively analyzed. A difference of at least 30% between preoperative medication-off and postoperative medication-off stimulation-on Unified PD Rating Scale (UPDRS)-III scores was accepted to be a good outcome. Patients with good and bad outcomes were compared in terms of age, gender, levodopa responsiveness, vB12 levels, UPDRS subscores, presence of diabetes mellitus and hypertension, and presence of lacunes on cranial magnetic resonance imaging (MRI). Twenty-two of 39 patients (56.4%) had a good outcome postoperatively. No significant difference was observed in terms of age, gender, presence of abnormal MRI findings, and comorbid diseases between patients with good and bad outcomes. Mean preoperative bradykinesia score in patients with a good outcome was higher than those with a bad outcome. There was a positive correlation between the benefit of STN-DBS and preoperative levodopa responsiveness. In patients with low vB12 levels, 33.3% had a good outcome, whereas 55.2% of patients with normal vB12 levels had a good outcome (p = 0.589). Our results confirm that patients with better levodopa response have better outcomes. Interestingly, patients with worse bradykinesia had a better surgical outcome. A favorable surgical outcome was less frequent in patients with low vB12 levels and was not statistically significant.


Spook house sporotrichosis. A point-source outbreak of sporotrichosis associated with hay bale props in a Halloween haunted-house.
While isolated cases of sporotrichosis typically occur following contact with contaminated plant materials, outbreaks are distinctly unusual. A temporal increase in the incidence of sporotrichosis in a dermatology practice at a military installation in southwestern Oklahoma prompted an investigation. Patients with sporotrichosis presenting to a single dermatologist in the winter of 1992-1993 were interviewed, epidemiological data were collected, and fungal cultures were obtained from incriminated hay fields. Five patients presented with cutaneous sporotrichosis during a 5-week period beginning in December 1992. Four patients had maintained hay bales in a Halloween haunted house and the fifth patient had visited the house once. As in 3 previous reports, this outbreak was associated with stored hay or hay bales harvested in the US plains states. Contact with hay should be recognized as a risk factor for infection with Sporothrix schenckii. Outbreaks are possible given adequate intensity of exposure and may be difficult to recognize because of the delayed presentation of clinical illness.


Parent-child interactions and objectively measured child physical activity: a cross-sectional study.
Parents influence their children's behaviors directly through specific parenting practices and indirectly through their parenting style. Some practices such as logistical and emotional support have been shown to be positively associated with child physical activity (PA) levels, while for others (e.g. monitoring) the relationship is not clear. The objectives of this study were to determine the relationship between parent's PA-related practices, general parenting style, and children's PA level. During the spring of 2007 a diverse group of 99 parent-child dyads (29% White, 49% Black, 22% Hispanic; 89% mothers) living in low-income rural areas of the US participated in a cross-sectional study. Using validated questionnaires, parents self-reported their parenting style (authoritative, authoritarian, permissive, and uninvolved) and activity-related parenting practices. Height and weight were measured for each dyad and parents reported demographic information. Child PA was measured objectively through accelerometers and expressed as absolute counts and minutes engaged in intensity-specific activity. Seventy-six children had valid accelerometer data. Children engaged in 113.4 ± 37.0 min. of moderate-vigorous physical activity (MVPA) per day. Children of permissive parents accumulated more minutes of MVPA than those of uninvolved parents (127.5 vs. 97.1, p < 0.05), while parents who provided above average levels of support had children who participated in more minutes of MVPA (114.2 vs. 98.3, p = 0.03). While controlling for known covariates, an uninvolved parenting style was the only parenting behavior associated with child physical activity. Parenting style moderated the association between two parenting practices - reinforcement and monitoring - and child physical activity. Specifically, post-hoc analyses revealed that for the permissive parenting style group, higher levels of parental reinforcement or monitoring were associated with higher levels of child physical activity. This work extends the current literature by demonstrating the potential moderating role of parenting style on the relationship between activity-related parenting practices and children's objectively measured physical activity, while controlling for known covariates. Future studies in this area are warranted and, if confirmed, may help to identify the mechanism by which parents influence their child's physical activity behavior.


Structural and functional analysis of the interaction between the nucleoporin Nup98 and the mRNA export factor Rae1.
The export of mRNAs is a multistep process, involving the packaging of mRNAs into messenger ribonucleoprotein particles (mRNPs), their transport through nuclear pore complexes, and mRNP remodeling events prior to translation. Ribonucleic acid export 1 (Rae1) and Nup98 are evolutionarily conserved mRNA export factors that are targeted by the vesicular stomatitis virus matrix protein to inhibit host cell nuclear export. Here, we present the crystal structure of human Rae1 in complex with the Gle2-binding sequence (GLEBS) of Nup98 at 1.65 A resolution. Rae1 forms a seven-bladed beta-propeller with several extensive surface loops. The Nup98 GLEBS motif forms an approximately 50-A-long hairpin that binds with its C-terminal arm to an essentially invariant hydrophobic surface that extends over the entire top face of the Rae1 beta-propeller. The C-terminal arm of the GLEBS hairpin is necessary and sufficient for Rae1 binding, and we identify a tandem glutamate element in this arm as critical for complex formation. The Rae1*Nup98(GLEBS) surface features an additional conserved patch with a positive electrostatic potential, and we demonstrate that the complex possesses single-stranded RNA-binding capability. Together, these data suggest that the Rae1*Nup98 complex directly binds to the mRNP at several stages of the mRNA export pathway.


Relationship maternal subcutaneous adipose tissue thickness and development of gestational diabetes mellitus.
We investigated whether the ultrasonographic measurement of maternal subcutaneous adipose tissue (SAT) thickness in the second trimester played a role in predicting gestational diabetes. This was a prospective cross-sectional study in which 223 women were classified as healthy (n = 177) or as gestational diabetes (n = 46) on the basis of a negative or positive two-step oral Glucose Challenge Test (GCT), respectively. The depth of the abdominal SAT was evaluated by two-dimensional ultrasonography. Body mass index (BMI), waist circumference (WC), and waist/hip ratio were determined. There was a positive strong significant correlation between a 50-g GCT level and BMI, WC, and SAT thickness (p < 0.001). Receiver-operating characteristic curve analysis showed SAT thickness above 16.75 mm predicted gestational diabetes mellitus (GDM) with a sensitivity of 71.7%, a specificity of 57.1%, a positive predictive value of 32.3%, and a negative predictive value of 87.6%. There was a good correlation between SAT, BMI, and WC. Increased SAT, BMI, and WC measurements may be helpful in predicting the risk of the development of GDM in pregnant women.


Discovery of potent and selective inhibitors of the Escherichia coli M1-aminopeptidase via multicomponent solid-phase synthesis of tetrazole-peptidomimetics.
The Escherichia coli neutral M1-aminopeptidase (ePepN) is a novel target identified for the development of antimicrobials. Here we describe a solid-phase multicomponent approach which enabled the discovery of potent ePepN inhibitors. The on-resin protocol, developed in the frame of the Distributed Drug Discovery (D3) program, comprises the implementation of parallel Ugi-azide four-component reactions with resin-bound amino acids, thus leading to the rapid preparation of a focused library of tetrazole-peptidomimetics (TPMs) suitable for biological screening. By dose-response studies, three compounds were identified as potent and selective ePepN inhibitors, as little inhibitory effect was exhibited for the porcine ortholog aminopeptidase. The study allowed for the identification of the key structural features required for a high ePepN inhibitory activity. The most potent and selective inhibitor (TPM 11) showed a non-competitive inhibition profile of ePepN. We predicted that both diastereomers of compound TPM 11 bind to a site distinct from that occupied by the substrate. Theoretical models suggested that TPM 11 has an alternative inhibition mechanism that doesn't involve Zn coordination. On the other hand, the activity landscape analysis provided a rationale for our findings. Of note, compound TMP 2 showed in vitro antibacterial activity against Escherichia coli. Furthermore, none of the three identified inhibitors is a potent haemolytic agent, and only two compounds showed moderate cytotoxic activity toward the murine myeloma P3X63Ag cells. These results point to promising compounds for the future development of rationally designed TPMs as antibacterial agents.


Fos and Jun oncogenes transactivate chimeric or native promoters containing AP1/GCN4 binding sites in plant cells.
The function of mammalian transcription factors of the leucine zipper class was investigated in leaf-derived protoplasts of tobacco. In transient expression experiments, Fos and Jun strongly activated chimeric promoters composed of the TATA box region of the cauliflower mosaic virus 35S transcript preceded by one to five copies of an AP1/GCN4 binding site. Fos and Jun also stimulated a wheat high molecular weight glutenin promoter in which similar binding sites are located more than 500 base pairs from its transcription start site. Both the DNA binding and the transcription activation domains of these proteins were required for proper promoter stimulation by Fos and Jun. Each factor alone was partially active, suggesting that at least the Fos protein can associate with an endogenous plant transcription factor. These observations support the hypothesis that sequences related to AP1/GCN4 binding sites could be cis-acting modules involved in the transcriptional regulation of plant genes.


The effect of a Ta oxygen scavenger layer on HfO2-based resistive switching behavior: thermodynamic stability, electronic structure, and low-bias transport.
Reversible resistive switching between high-resistance and low-resistance states in metal-oxide-metal heterostructures makes them very interesting for applications in random access memories. While recent experimental work has shown that inserting a metallic "oxygen scavenger layer" between the positive electrode and oxide improves device performance, the fundamental understanding of how the scavenger layer modifies the heterostructure properties is lacking. We use density functional theory to calculate thermodynamic properties and conductance of TiN/HfO2/TiN heterostructures with and without a Ta scavenger layer. First, we show that Ta insertion lowers the formation energy of low-resistance states. Second, while the Ta scavenger layer reduces the Schottky barrier height in the high-resistance state by modifying the interface charge at the oxide-electrode interface, the heterostructure maintains a high resistance ratio between high- and low-resistance states. Finally, we show that the low-bias conductance of device on-states becomes much less sensitive to the spatial distribution of oxygen removed from the HfO2 in the presence of the Ta layer. By providing a fundamental understanding of the observed improvements with scavenger layers, we open a path to engineer interfaces with oxygen scavenger layers to control and enhance device performance. In turn, this may enable the realization of a non-volatile low-power memory technology with concomitant reduction in energy consumption by consumer electronics and offering significant benefits to society.


Application of an alternative Aedes species (Diptera: culicidae) surveillance method in Botucatu City, Sao Paulo, Brazil.
One of the main problems with dengue is the control of Aedes aegypti, its major vector. In Brazil, the current control program for Ae. aegypti and Aedes albopictus populations includes larval density surveys. An interesting alternative is the use of a distinct index, the Premise Condition Index (PCI). This tool relates conditions of property, such as houses and yards, and the degree of shade with the occurrence of Aedes sp. oviposition, and is calculated as scores from 3 to 9. The lowest score indicates property in good condition and an unfavorable breeding environment, while the highest score indicates property at high risk for infestation by Aedes sp. The present study is based on the application of the PCI in an urban area of Botucatu, Brazil to confirm its effectiveness.


Mesoscopic study of the ternary phase diagram of the PS-PB-PtBMA triblock copolymer: modification of the phase structure by the composition effect.
We explored in detail the ordered nanostructures and the ternary phase diagram of the polystyrene-polybutadiene-poly(tert-butyl methacrylate) (PS-PB-PtBMA) triblock copolymer via dissipative particle dynamics (DPD) simulations and coarse-grained models. The mesoscopic simulations show that the PS-PB-PtBMA copolymer in the bulk state can generate eight equilibrium phase regions with well-defined morphologies such as core-shell variations of spheres, cylinders, perforated layers, lamellar, gyroid, as well as cylinder-in-lamella, spheres-in-lamella, and cylinders in hexagonal lattice. The ordered phases exhibit high dependence on the chemical nature and volume fraction, thus portraying specific composition regions with high thermodynamic stability over a ternary phase diagram. The ternary phase diagram, including all equilibrium and metastable nanostructures detected, is described, and analysed in this work in detail. Finally, our dynamic simulation outcomes agree with experimental results. Our aim is to contribute to the understanding of the relationship between block volume fractions and bulk morphologies in ternary polymer systems.


Dental cone beam computed tomography: justification for use in planning oral implant placement.
Intra-oral and panoramic radiographs are most frequently used in oral health care. Yet, the inherent nature of jaws and teeth renders three-dimensional diagnosis essential, especially in relation to oral surgery. Nowadays, this can be accomplished by dental cone beam computed tomography, which provides high-quality images at low radiation doses and low costs. Nonetheless, the effective dose ranges of cone beam computed tomography machines may easily vary from 10 to 1000 μSv, this being equivalent to two to 200 panoramic radiographs, even for similar presurgical indications. Moreover, the diagnostic image quality varies massively among available machines and parameter settings. Apart from the radiodiagnostic possibilities, dental cone beam computed tomography may offer a vast therapeutic potential, including opportunities for surgical guidance and further prosthetic rehabilitation via computer-aided design/computer-aided manufacturing solutions. These additional options may definitely explain part of the success of cone beam computed tomography for oral implant placement. In conclusion, dental cone beam computed tomography imaging could be justified for oral implant-related diagnosis, planning and transfer to surgical and further prosthetic treatment, but guidelines for justification and cone beam computed tomography optimization remain mandatory.


Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential.
Sphingolipids belong to a complex class of lipid molecules that are crucially involved in the regulation of important biological processes including proliferation, migration and apoptosis. Given the significant progress made in understanding the sphingolipid pathobiology of several diseases, sphingolipid-related checkpoints emerge as attractive targets. Recent data indicate the multifaceted contribution of the sphingolipid machinery to osteoclast - osteoblast crosstalk, representing one of the pivotal interactions underlying bone homeostasis. Imbalances in the interplay of osteoblasts and osteoclasts might lead to bone-related diseases such as osteoporosis, rheumatoid arthritis, and bone metastases. Areas covered: We summarize and analyze the progress made in bone research in the context of the current knowledge of sphingolipid-related mechanisms regulating bone remodeling. Particular emphasis was given to bioactive sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs). Moreover, the mechanisms of how dysregulations of this machinery cause bone diseases, are covered. Expert opinion: In the context of bone diseases, pharmacological interference with sphingolipid machinery may lead to novel directions in therapeutic strategies. Implementation of knowledge derived from in vivo animal models and in vitro studies using pharmacological agents to manipulate the S1P/S1PRs axes suggests S1PR2 and S1PR3 as potential drug targets, particularly in conjunction with technology for local drug delivery.


Efficacy of salmeterol and formoterol combination treatment in mice with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a severe lung disease characterized by progressive airflow limitation. Salmeterol and formoterol are two commonly used drugs in COPD therapy, which act as β2-receptor agonists. In the current study, a mouse model of COPD induced by airway lipopolysaccharide inhalation was established. The therapeutic efficacy of salmeterol and formoterol co-treatment was investigated in this model over a 56-day-long observation period. It was also identified that functional residual capacity and inspiratory resistance were significantly improved after salmeterol and/or formoterol treatment compared with the control group (all P<0.01). Furthermore, histological staining of lung tissue samples indicated that inflammation, thickening of the smooth muscle, goblet cell hyperplasia and pulmonary small vessel obstruction were reduced in the mice treated with salmeterol and/or formoterol, suggesting that salmeterol and formoterol were beneficial for ongoing airway and blood vessel remodeling in mice with COPD. The most common treatment-associated adverse events were hypertension and proteinuria. In conclusion, combined salmeterol and formoterol treatment was more effective compared with either single agent, suggesting that salmeterol and formoterol combined treatment has therapeutic value for the clinical treatment of patients with COPD.