A late Pleistocene gastropod fauna from the northern Caspian Sea with implications for Pontocaspian gastropod taxonomy.
The present paper details a very diverse non-marine gastropod fauna retrieved from Caspian Pleistocene deposits along the Volga River north of Astrakhan (Russia). During time of deposition (early Late Pleistocene, late Khazarian regional substage), the area was situated in shallow water of the greatly expanded Caspian Sea. The fauna contains 24 species, of which 16 are endemic to the Pontocaspian region and 15 to the Caspian Sea. The majority of the species (13) belongs to the Pyrgulinae (Hydrobiidae), a group famous for its huge morphological variability in the Pontocaspian region. The phenotypic diversity has led to an inflation of genus and species names in the literature. New concepts are proposed for many of the genera and species found in the present material, with implications for the systematics and taxonomy of the entire Pontocaspian gastropod fauna. Laevicaspia vinarskiisp. n. is described as a new species. This contribution is considered a first step in revising the Pontocaspian gastropod fauna.


Effects of space allocation within a deep-bedded finishing system on pig growth performance, fatty acid composition and pork quality.
The objectives of the current study were to determine the degree to which space allocation in a deep-bedded system influences swine performance and pork quality. The deep-bedded method employed was hoop structures, which are large, tent-like shelters with cornstalks or straw for bedding. One hundred gilts ranging in weight from 59 to 71 kg were randomly assigned to treatments of low (0.70 m2 per pig, n = 50) or high (1.13 m2 per pig, n = 50) space allocation. During the 45-day experimental period, gilts were ad libitum fed a two-phase diet. Six gilts per treatment were used for carcass composition and pork quality evaluation for each replication. Five replications were conducted over a period of 4 months. Pigs finished with greater space allocation had smaller longissimus muscle area and produced pork that appeared to be darker. Variations in fatty acid composition and lipid percentage of subcutaneous adipose and longissimus dorsi muscle were observed when space allocation was changed within hoop structures. Less space resulted in greater proportion of lipid present as polyunsaturated fatty acids. Greater space allocation resulted in lower total lipid in subcutaneous pork adipose tissue. Space allocation did not affect fat firmness. Replications spanned the months of August to November, with temperatures ranging from 32°C to -2°C within the hoop structure. As environmental temperature declined, the proportion of monounsaturated fatty acids increased. Providing more space during finishing in these systems had only a small affect on pig growth and pork quality. Variations observed from replication to replication at fluctuating temperatures provide insight to seasonal differences in growth and adipose tissue composition and firmness. Therefore, finishing pigs in these systems may lead to seasonal variation in lipid composition.


A high-resolution historical sediment record of nutrients, trace elements and organochlorines (DDT and PCB) deposition in a drinking water reservoir (Lake Brêt, Switzerland) points at local and regional pollutant sources.
The (137)Cs and (210)Pb dating of a 61-cm long sediment core retrieved from a drinking water reservoir (Lake Brêt) located in Switzerland revealed a linear and relatively high sedimentation rate (~1 cm year(-1)) over the last decades. The continuous centimeter scale measurement of physical (porewater and granulometry), organic (C(org), P, N, HI and OI indexes) and mineral (C(min) and lithogenic trace elements) parameters therefore enables reconstructing the environmental history of the lake and anthropogenic pollutant input (trace metals, DDT and PCBs) at high resolution. A major change in the physical properties of the lowermost sediments occurred following the artificial rise of the dam in 1922. After ca. 1940, there was a long-term up-core increase in organic matter deposition attributed to enhance primary production and anoxic bottom water conditions due to excessive nutrient input from a watershed predominantly used for agriculture that also received domestic effluents of two wastewater-treatment plants. This pattern contrasts with the terrigenous element input (Eu, Sc, Mg, Ti, Al, and Fe) which doubled after the rising of the dam but continuously decreased during the last 60 years. By comparison, the trace metals (Cu, Pb and Hg) presented a slight enrichment factor (EF) only during the second part of the 20th century. Although maximum EF Pb (>2) occurred synchronously with the use of leaded gasoline in Switzerland (between ca. 1947 and 1985) the Hg and Cu profiles exhibited a relatively similar trend than Pb during the 20th century, therefore excluding the alkyl-lead added to petrol as the dominant (atmospheric) source of lead input to Lake Brêt. Conversely, the Cu profile that did not follow the decrease registered in Pb and Hg during the last 10 years, suggests an additional source of Cu probably linked to the impact of agricultural activities in the area. In absence of heavy industries in the catchment, the atmospheric deposition of DDT and PCBs via surface runoff followed the historical emissions of POPs in Switzerland. Such result highlights the regional contamination of freshwater resources by the large-scale emission of toxic industrial chemicals in the 1960s and 1970s as well as the efficiency of the regulatory measures subsequently taken.


Systematic Review: Genetic Associations for Prognostic Factors of Urinary Bladder Cancer.
Many germline associations have been reported for urinary bladder cancer (UBC) outcomes and prognostic characteristics. It is unclear whether there are overlapping genetic patterns for various prognostic endpoints. We aimed to review contemporary literature on genetic associations with UBC prognostic outcomes and to identify potential overlap in reported genes. EMBASE, MEDLINE, and PubMed databases were queried for relevant articles in English language without date restrictions. The initial search identified 1346 articles. After exclusions, 112 studies have been summarized. Cumulatively, 316 single-nucleotide polymorphisms (SNPs) were reported across prognostic outcomes (recurrence, progression, death) and characteristics (tumor stage, grade, size, age, risk group). There were considerable differences between studied outcomes in the context of genetic associations. The most commonly reported SNPs were located in OGG1, TP53, and MDM2. For outcomes with the highest number of reported associations (ie, recurrence and death), functional enrichment annotation yields different terms, potentially indicating separate biological mechanisms. Our study suggests that all UBC prognostic outcomes may have different biological origins with limited overlap. Further validation of these observations is essential to target a phenotype that could best predict patient outcome and advance current management practices.


Development of a modified head and neck quality assurance phantom for use in stereotactic radiosurgery trials.
An anthropomorphic head phantom, constructed from a water-equivalent plastic shell with only a spherical target, was modified to include a nonspherical target (pituitary) and an adjacent organ at risk (OAR) (optic chiasm), within 2 mm, simulating the anatomy encountered when treating acromegaly. The target and OAR spatial proximity provided a more realistic treatment planning and dose delivery exercise. A separate dosimetry insert contained two TLD for absolute dosimetry and radiochromic film, in the sagittal and coronal planes, for relative dosimetry. The prescription was 25 Gy to 90% of the GTV, with ≤ 10% of the OAR volume receiving ≥ 8 Gy for the phantom trial. The modified phantom was used to test the rigor of the treatment planning process and phantom reproducibility using a Gamma Knife, CyberKnife, and linear accelerator (linac)-based radiosurgery system. Delivery reproducibility was tested by repeating each irradiation three times. TLD results from three irradiations on a CyberKnife and Gamma Knife agreed with the calculated target dose to within ± 4% with a maximum coefficient of variation of ± 2.1%. Gamma analysis in the coronal and sagittal film planes showed an average passing rate of 99.4% and 99.5% using ± 5%/3 mm criteria, respectively. Results from the linac irradiation were within ± 6.2% for TLD with a coefficient of variation of ± 0.1%. Distance to agreement was calculated to be 1.2 mm and 1.3mm along the inferior and superior edges of the target in the sagittal film plane, and 1.2 mm for both superior and inferior edges in the coronal film plane. A modified, anatomically realistic SRS phantom was developed that provided a realistic clinical planning and delivery challenge that can be used to credential institutions wanting to participate in NCI-funded clinical trials.


Computationally effective solution of the inverse problem in time-of-flight spectroscopy.
Photon time-of-flight (PTOF) spectroscopy enables the estimation of absorption and reduced scattering coefficients of turbid media by measuring the propagation time of short light pulses through turbid medium. The present investigation provides a comparison of the assessed absorption and reduced scattering coefficients from PTOF measurements of intralipid 20% and India ink-based optical phantoms covering a wide range of optical properties relevant for biological tissues and dairy products. Three different models are used to obtain the optical properties by fitting to measured temporal profiles: the Liemert-Kienle model (LKM), the diffusion model (DM) and a white Monte-Carlo (WMC) simulation-based algorithm. For the infinite space geometry, a very good agreement is found between the LKM and WMC, while the results obtained by the DM differ, indicating that the LKM can provide accurate estimation of the optical parameters beyond the limits of the diffusion approximation in a computational effective and accurate manner. This result increases the potential range of applications for PTOF spectroscopy within industrial and biomedical applications.


Utilization and Content Validity of the Swedish Version of the Volitional Questionnaire (VQ-S).
The aim of this study was to examine the utility and content validity of the Swedish version of the Volitional Questionnaire (VQ-S). The participants in this study were thirteen occupational therapists selected because they worked with clients for whom the VQ-S is appropriate (in this case, adults with intellectual impairments) and because they had knowledge of the Model of Human Occupation. These participants completed a demographic questionnaire at the beginning of the study. Each therapist then used the VQ-S a total of six times and after each time they completed a questionnaire concerning the utility and content validity of the instrument. After having administered the instrument six times they completed a third questionnaire that assessed their perceptions of the VQ-S based on their total experience. Data from these questionnaires and the six assessment forms with the actual client ratings were analyzed using both quantitative and qualitative procedures. The findings indicate that the VQ-S has clinical relevance and potential for implementation with adults with intellectual impairments. They also support the content validity of the VQ-S.


The limits of agency in walking humans.
An important principle of human ethics is that individuals are not responsible for actions performed when unconscious. Recent research found that the generation of an action and the building of a conscious experience of that action (agency) are distinct processes and crucial mechanisms for self-consciousness. Yet, previous agency studies have focussed on actions of a finger or hand. Here, we investigate how agents consciously monitor actions of the entire body in space during locomotion. This was motivated by previous work revealing that (1) a fundamental aspect of self-consciousness concerns a single and coherent representation of the entire spatially situated body and (2) clinical instances of human behaviour without consciousness occur in rare neurological conditions such as sleepwalking or epileptic nocturnal wandering. Merging techniques from virtual reality, full-body tracking, and cognitive science of conscious action monitoring, we report experimental data about consciousness during locomotion in healthy participants. We find that agents consciously monitor the location of their entire body and its locomotion only with low precision and report that while precision remains low it can be systematically modulated in several experimental conditions. This shows that conscious action monitoring in locomoting agents can be studied in a fine-grained manner. We argue that the study of the mechanisms of agency for a person's full body may help to refine our scientific criteria of self-hood and discuss sleepwalking and related conditions as alterations in neural systems encoding motor awareness in walking humans.


Detecting epigenetic motifs in low coverage and metagenomics settings.
It has recently become possible to rapidly and accurately detect epigenetic signatures in bacterial genomes using third generation sequencing data. Monitoring the speed at which a single polymerase inserts a base in the read strand enables one to infer whether a modification is present at that specific site on the template strand. These sites can be challenging to detect in the absence of high coverage and reliable reference genomes. Here we provide a new method for detecting epigenetic motifs in bacteria on datasets with low-coverage, with incomplete references, and with mixed samples (i.e. metagenomic data). Our approach treats motif inference as a kmer comparison problem. First, genomes (or contigs) are deconstructed into kmers. Then, native genome-wide distributions of interpulse durations (IPDs) for kmers are compared with corresponding whole genome amplified (WGA, modification free) IPD distributions using log likelihood ratios. Finally, kmers are ranked and greedily selected by iteratively correcting for sequences within a particular kmer's neighborhood. Our method can detect multiple types of modifications, even at very low-coverage and in the presence of mixed genomes. Additionally, we are able to predict modified motifs when genomes with "neighbor" modified motifs exist within the sample. Lastly, we show that these motifs can provide an alternative source of information by which to cluster metagenomics contigs and that iterative refinement on these clustered contigs can further improve both sensitivity and specificity of motif detection. https://github.com/alibashir/EMMCKmer.


Mutations in the p53 gene in primary human breast cancers.
Twenty-six primary breast tumors were examined for mutations in the p53 tumor suppressor gene by an RNase protection assay and nucleotide sequence analysis of PCR-amplified p53 complementary DNAs. Each method detected p53 mutations in the same three tumors (12%). One tumor contained two mutations in the same allele. Single strand conformation polymorphism analysis of genomic DNA and complementary DNA proved more sensitive in the detection of mutations. Combining this technique with the other two a total of 12 mutations in the p53 gene were demonstrated in 11 tumors (46%), and a polymorphism at codon 213 was detected in another tumor. Loss of heterozygosity on chromosome 17p was detected by Southern blot analysis in 30% of the tumor DNAs. Not all of the tumors containing a point mutation in p53 also had loss of heterozygosity of the remaining allele, suggesting that loss of heterozygosity may represent a later event.


From transistor to trapped-ion computers for quantum chemistry.
Over the last few decades, quantum chemistry has progressed through the development of computational methods based on modern digital computers. However, these methods can hardly fulfill the exponentially-growing resource requirements when applied to large quantum systems. As pointed out by Feynman, this restriction is intrinsic to all computational models based on classical physics. Recently, the rapid advancement of trapped-ion technologies has opened new possibilities for quantum control and quantum simulations. Here, we present an efficient toolkit that exploits both the internal and motional degrees of freedom of trapped ions for solving problems in quantum chemistry, including molecular electronic structure, molecular dynamics, and vibronic coupling. We focus on applications that go beyond the capacity of classical computers, but may be realizable on state-of-the-art trapped-ion systems. These results allow us to envision a new paradigm of quantum chemistry that shifts from the current transistor to a near-future trapped-ion-based technology.


Spectroscopic characterization of novel polycyclic aromatic polymers.
A series of novel polyphenylenevinylene (PPV) derivative polymers were studied by absorption and photoluminescence spectroscopies. The effect of the sequential introduction of polycyclic aromatic ring substituents into the delocalized backbone was examined with relation to hypsochromatic and bathochromatic shifting. While the replacement of the phenyl units by naphthyl units results in a substantial hypsochromic shift of both the absorption and emission spectra, their subsequent substitution by anthryl units results in a bathochromic shift. The system is modeled according to, and is found to be consistent with, a previous study of donor-acceptor polyenes of varying length. The electronic structure of the backbone is found to be a balance between that of the high electron affinity polycyclic ring system and the contribution to conjugation across the linking vinyl unit. The model is adapted based on electron affinities of the constituent units, and a clear structure-property relationship for the absorption and emission properties of the system is elucidated. The Stokes shift is examined and is seen to be well-correlated with the vinyl contribution to the electron affinity total (EAtotal). The trends observed in the optical properties of the polymeric system are supported by Raman spectroscopy, whereby the spectral signature of the connecting vinyl bond is seen to soften in a fashion which is correlated with the modeled electron affinity parameters.


Genetic-based search for error-correcting graph isomorphism.
Error-correcting graph isomorphism has been found useful in numerous pattern recognition applications. This paper presents a genetic-based search approach that adopts genetic algorithms as the searching criteria to solve the problem of error-correcting graph isomorphism. By applying genetic algorithms, some local search strategies are amalgamated to improve convergence speed. Besides, a selection operator is proposed to prevent premature convergence. The proposed approach has been implemented to verify its validity. Experimental results reveal the superiority of this new technique than several other well-known algorithms.


Piper betle shows antioxidant activities, inhibits MCF-7 cell proliferation and increases activities of catalase and superoxide dismutase.
Breast cancer is the most common form of cancer and the focus on finding chemotherapeutic agents have recently shifted to natural products. Piper betle is a medicinal plant with various biological activities. However, not much data is available on the anti-cancer effects of P. betle on breast cancer. Due to the current interest in the potential effects of antioxidants from natural products in breast cancer treatment, we investigated the antioxidant activities of the leaves of P. betle and its inhibitory effect on the proliferation of the breast cancer cell line, MCF-7. The leaves of P. betle were extracted with solvents of varying polarities (water, methanol, ethyl acetate and hexane) and their phenolic and flavonoid content were determined using colorimetric assays. Phenolic composition was characterized using HPLC. Antioxidant activities were measured using FRAP, DPPH, superoxide anion, nitric oxide and hyroxyl radical scavenging assays. Biological activities of the extracts were analysed using MTT assay and antioxidant enzyme (catalase, superoxide dismutase, glutathione peroxidase) assays in MCF-7 cells. Overall, the ethyl acetate extract showed the highest ferric reducing activity and radical scavenging activities against DPPH, superoxide anion and nitric oxide radicals. This extract also contained the highest phenolic content implying the potential contribution of phenolics towards the antioxidant activities. HPLC analyses revealed the presence of catechin, morin and quercetin in the leaves. The ethyl acetate extract also showed the highest inhibitory effect against the proliferation of MCF-7 cells (IC50=65 μg/ml). Treatment of MCF-7 cells with the plant extract increased activities of catalase and superoxide dismutase. Ethyl acetate is the optimal solvent for the extraction of compounds with antioxidant and anti-proliferative activities. The increased activities of catalase and superoxide dismutase in the treated cells could alter the antioxidant defense system, potentially contributing towards the anti-proliferative effect. There is great potential for the ethyl acetate extract of P. betle leaf as a source of natural antioxidants and to be developed as therapeutics in cancer treatment.


Chlorophyll degradation: the tocopherol biosynthesis-related phytol hydrolase in Arabidopsis seeds is still missing.
Phytyl diphosphate (PDP) is the prenyl precursor for tocopherol biosynthesis. Based on recent genetic evidence, PDP is supplied to the tocopherol biosynthetic pathway primarily by chlorophyll degradation and sequential phytol phosphorylation. Three enzymes of Arabidopsis (Arabidopsis thaliana) are known to be capable of removing the phytol chain from chlorophyll in vitro: chlorophyllase1 (CLH1), CLH2, and pheophytin pheophorbide hydrolase (PPH), which specifically hydrolyzes pheophytin. While PPH, but not chlorophyllases, is required for in vivo chlorophyll breakdown during Arabidopsis leaf senescence, little is known about the involvement of these phytol-releasing enzymes in tocopherol biosynthesis. To explore the origin of PDP for tocopherol synthesis, seed tocopherol concentrations were determined in Arabidopsis lines engineered for seed-specific overexpression of PPH and in single and multiple mutants in the three genes encoding known dephytylating enzymes. Except for modestly increasing tocopherol content observed in the PPH overexpressor, none of the remaining lines exhibited significantly reduced tocopherol concentrations, suggesting that the known chlorophyll-derived phytol-releasing enzymes do not play major roles in tocopherol biosynthesis. Tocopherol content of seeds from double mutants in NONYELLOWING1 (NYE1) and NYE2, regulators of chlorophyll degradation, had modest reduction compared with wild-type seeds, although mature seeds of the double mutant retained significantly higher chlorophyll levels. These findings suggest that NYEs may play limited roles in regulating an unknown tocopherol biosynthesis-related phytol hydrolase. Meanwhile, seeds of wild-type over-expressing NYE1 had lower tocopherol levels, suggesting that phytol derived from NYE1-dependent chlorophyll degradation probably doesn't enter tocopherol biosynthesis. Potential routes of chlorophyll degradation are discussed in relation to tocopherol biosynthesis.


Naphthalene diimide-based non-fullerene acceptors flanked by open-ended and aromatizable acceptor functionalities.
Herein we present the design, synthesis and characterization of two novel, naphthalene diimide (NDI) core-based non-fullerene acceptors, N5 and N6, comprising respectively 2-methoxyethyl-2-cyanoacetate and cyanopyridone acceptor functionalities at the terminals. The influence of terminal units on optoelectronic and photovoltaic properties was studied. The target chromophore bearing cyanopyridone acceptor units (N6) afforded a power conversion efficiency of 6.10% when paired with the conventional donor polymer poly(3-hexylthiophene), a result that is the highest for the NDI core-based non-fullerene acceptors.


Safety pharmacology studies using EFP and impedance.
While extracellular field potential (EFP) recordings using multi-electrode arrays (MEAs) are a well-established technique for monitoring changes in cardiac and neuronal function, impedance is a relatively unexploited technology. The combination of EFP, impedance and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has important implications for safety pharmacology as functional information about contraction and field potentials can be gleaned from human cardiomyocytes in a beating monolayer. The main objectives of this study were to demonstrate, using a range of different compounds, that drug effects on contraction and electrophysiology can be detected using a beating monolayer of hiPSC-CMs on the CardioExcyte 96. hiPSC-CMs were grown as a monolayer on NSP-96 plates for the CardioExcyte 96 (Nanion Technologies) and recordings were made in combined EFP and impedance mode at physiological temperature. The effect of the hERG blockers, E4031 and dofetilide, hERG trafficking inhibitor, pentamidine, β-adrenergic receptor agonist, isoproterenol, and calcium channel blocker, nifedipine, was tested on the EFP and impedance signals. Combined impedance and EFP measurements were made from hiPSC-CMs using the CardioExcyte 96 (Nanion Technologies). E4031 and dofetilide, known to cause arrhythmia and Torsades de Pointes (TdP) in humans, decreased beat rate in impedance and EFP modes. Early afterdepolarization (EAD)-like events, an in vitro marker of TdP, could also be detected using this system. Isoproterenol and nifedipine caused an increase in beat rate. A long-term study (over 30h) of pentamidine, a hERG trafficking inhibitor, showed a concentration and time-dependent effect of pentamidine. In the light of the new Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative to improve guidelines and standardize assays and protocols, the use of EFP and impedance measurements from hiPSCs may become critical in determining the proarrhythmic risk of potential drug candidates. The combination of EFP offering information about cardiac electrophysiology, and impedance, providing information about contractility from the same area of a synchronously beating monolayer of human cardiomyocytes in a 96-well plate format has important implications for future cardiac safety testing.


A novel case of autosomal dominant cutis laxa in a consanguineous family: report and literature review.
Autosomal dominant cutis laxa (ADCL, OMIM #123700) is a rare connective tissue disorder characterized by loose, redundant skin folds that may be apparent form birth or appear later in life. Most severely affected areas are the neck, axillar regions, trunk, and groin. Typically, patients present with characteristic facial features including a premature aged appearance, long philtrum, a high forehead, large ears, and a beaked nose. Cardiovascular and pulmonary complications include bicuspid aortic valves, aortic root dilatation, and emphysema. Sporadically, these complications have been documented to cause premature death. Several rare findings including urogenital anomalies and gastroesophageal problems can be also occur. Most patients harbor a frameshift mutation in one of the five last exons of the ELN gene (ADCL1, OMIM #123700), whereas one patient was described to have a tandem duplication in the FBLN5 gene (ADCL2, OMIM #614434). Here, we present a female ADCL patient, from a consanguineous family, with a novel mutation in ELN and review 39 previously reported ADCL patients. All patients have various skin findings, whereas cardiovascular, pulmonary findings, and multiple hernia were present in 61, 28, and 38% of patients, respectively. Strabismus, urogenital anomalies, gastroesophageal problems, and scoliosis may rarely be present. A clear definition of the ADCL syndrome can enable more accurate genetic counseling.


Toxic trace element assessment for soils/sediments deposited during Hurricanes Katrina and Rita from southern Louisiana, USA: a sequential extraction analysis.
Analysis of soil/sediment samples collected in the southern Louisiana, USA, region three weeks after Hurricanes Katrina and Rita passed was performed using sequential extraction procedures to determine the origin, mode of occurrence, biological availability, mobilization, and transport of trace elements in the environment. Five fractions: exchangeable, bound to carbonates, bound to iron (Fe)-manganese (Mn) oxides, bound to organic matter, and residual, were subsequently extracted. The toxic trace elements Pb, As, V, Cr, Cu, and Cd were analyzed in each fraction, together with Fe in 51 soil/sediment samples. Results indicated that Pb and As were at relatively high concentrations in many of the soil/sediment samples. Because the forms in which Pb and As are present tend to be highly mobile under naturally occurring environmental conditions, these two compounds pose an increased health concern.Vanadium and Cr were mostly associated with the crystal line nonmobile residual fraction. A large portion of the Cu was associated with organic matter and residual fraction. Cadmium concentrations were low in all soil/sediment samples analyzed and most of this element tended to be associated with the mobile fractions. An average of 21% of the Fe was found in the Fe-Mn oxide fraction, indicating that a substantial part of the Fe was in an oxidized form. The significance of the overall finding of the present study indicated that the high concentrations and high availabilities of the potentially toxic trace elements As and Pb may impact the environment and human health in southern Louisiana and, in particular, the New Orleans area.


Parents Are Stressed! Patterns of Parent Stress Across COVID-19.
Background: The Coronavirus Disease 2019 (COVID-19) pandemic has caused numerous unexpected challenges for many families, and these long-lasting demands likely contribute to higher stress for parents. The aim of this study was to describe changes in parent stress longitudinally from before (retrospective) to two timepoints during COVID-19. Stressors that influenced parenting and strategies to manage parenting difficulties at each timepoint during COVID-19 are also described. Methods: Parents (N = 433; 95% female) in the US with >1 child aged 5-18 years completed an online survey in May 2020 (T1; at the peak of stay-at-home mandates) and in September 2020 (T2; children's return to school). Surveys included the 10-item Perceived Stress Scale (PSS) and questions on parenting-specific stress, stressors that influenced parenting, and strategies to manage parenting difficulties during COVID-19. Retrospective report of pre-COVID-19 stress was assessed at T1; current stress was assessed at T1 and T2. Repeated measures analysis of variance examined changes in stress over time. Results: Parent's stress increased from before COVID-19 to T1 (PSS score: 16.3 ± 5.7 to 22.0 ± 6.4, respectively; p < 0.01), and decreased by T2 (19.2 ± 6.0), but remained elevated above pre-COVID-19 values (p < 0.01). Most parents (71.1%) reported an increase parenting-specific stress from before COVID-19 to T1, which continued to increase for 55% of parents at T2. Common stressors that impacted parenting during COVID-19 were changes in children's routines, worry about COVID-19, and online schooling demands. Common strategies parents used to manage parenting difficulties included doing family activities together, keeping in touch with family/friends virtually, and keeping children on daily routines. Conclusions: Parent stress increased substantially during COVID-19 and has not returned to pre-COVID-19 levels, suggesting the need for enhanced mental health resources and supports. Public health interventions should address parenting-specific stressors and effective strategies for managing parenting difficulties to mitigate their deleterious impact.


A rare case of intracerebral hemorrhage due to arteriovenous malformation located at petrous portion of the temporal bone.
Primary intraosseous arteriovenous malformations (AVM) are not infrequently encountered. We report a case of intraosseous arteriovenous malformation arising in the left temporal bone. A 51-year-old male patient presented with loss of conscious. Computerized tomography displayed hematoma measuring 4 cm in diameter in the left temporal lobe. Digital subtraction angiography (DSA) showed that a temporal bone AVM supplied by all the branches of the external carotid artery and vertebral artery. Many treatment modalities can be considered for preoperative steps and/or for definitive treatment. We preferred embolisation for this vascular pathology. To the best of our knowledge this represents the first case of an intraosseous arteriovenous malformation located in the temporal bone.


TRAM1 participates in human cytomegalovirus US2- and US11-mediated dislocation of an endoplasmic reticulum membrane glycoprotein.
The human cytomegalovirus proteins US2 and US11 have co-opted endoplasmic reticulum (ER) quality control to facilitate the destruction of major histocompatibility complex class I heavy chains. The class I heavy chains are dislocated from the ER to the cytosol, where they are deglycosylated and subsequently degraded by the proteasome. We examined the role of TRAM1 (translocating chain-associated membrane protein-1) in the dislocation of class I molecules using US2- and US11-expressing cells. TRAM1 is an ER protein initially characterized for its role in processing nascent polypeptides. Co-immunoprecipitation studies demonstrated that TRAM1 can complex with the wild type US2 and US11 proteins as well as deglycosylated and polyubiquitinated class I degradation intermediates. In studies using US2- and US11-TRAM1 knockdown cells, we observed an increase in levels of class I heavy chains. Strikingly, increased levels of glycosylated heavy chains were observed in TRAM1 knockdown cells when compared with control cells in a pulse-chase experiment. In fact, US11-mediated class I dislocation was more sensitive to the lack of TRAM1 than US2. These results provide further evidence that these viral proteins may utilize distinct complexes to facilitate class I dislocation. For example, US11-mediated class I heavy chain degradation requires Derlin-1 and SEL1L, whereas signal peptide peptidase is critical for US2-induced class I destabilization. In addition, TRAM1 can complex with the dislocation factors Derlin-1 and signal peptide peptidase. Collectively, the data support a model in which TRAM1 functions as a cofactor to promote efficient US2- and US11-dependent dislocation of major histocompatibility complex class I heavy chains.


p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa.
Apoptosis provoked by DNA damage requires the p53 tumor suppressor, but which of the many p53-regulated genes are required has remained unknown. Two genes induced by this transcription factor, noxa and puma (bbc3), stand out, because they encode BH3-only proteins, proapoptotic members of the Bcl-2 family required to initiate apoptosis. In mice with either noxa or puma disrupted, we observed decreased DNA damage-induced apoptosis in fibroblasts, although only loss of Puma protected lymphocytes from cell death. Puma deficiency also protected cells against diverse p53-independent cytotoxic insults, including cytokine deprivation and exposure to glucocorticoids, the kinase inhibitor staurosporine, or phorbol ester. Hence, Puma and Noxa are critical mediators of the apoptotic responses induced by p53 and other agents.


Antioxidant power of phytochemicals from Psidium guajava leaf.
Dried ground leaves of Psidium guajava L. (guava) were extracted by water and aqueous ethyl alcohol 50% (1:10) ratio, and the total phenolic content in the extracts was determined spectrophotometrically according to Folin- Ciocalteu's phenol method and calculated as gallic acid equivalent (GAE). Remarkably high total phenolic content 575.3 +/-15.5 and 511.6+/-6.2 mg of GAE/g of dried weight material (for ethanol guava leaf extracts and water guava leaf extracts, respectively) were obtained. The antioxidant activity of lyophilized extracts was determined at ambient temperature by means of a 2,2-diphenyl-1-picrylhydryzyl (DPPH*) colorimetry with detection scheme at 515 nm. The activity was evaluated by the decrease in absorbance as the result of DPPH* color change from purple to yellow. The higher the sample concentration used, the stronger was the free radical-scavenging effect. The results obtained showed that ascorbic acid was a substantially more powerful antioxidant than the extracts from guava leaf. On the other hand, the commercial guava leaf extracts and ethanol guava leaf extracts showed almost the same antioxidant power whereas water guava leaf extracts showed lower antioxidant activity. The parameter EC(50) and the time needed to reach the steady state to EC(50) concentration (T(EC(50))) affected the antiradical capacity of the sample. The antioxidant efficiency (AE) has been shown to be a more adequate parameter for selecting antioxidants than the widely used EC(50). This study revealed that guava leaf extracts comprise effective potential source of natural antioxidants.


Scattering phase function measurements on single particles and on particle ensembles.
We present measurements of the light-scattering phase function of selected carbon and ash particles in the geometric-optics regime in which the particle diameter is much larger than the wavelength of the light source. Measurements were performed on both single particles and particle ensembles. This was accomplished with two separate methodologies: an electrodynamic levitator for single-particle measurements and a particle feeder for the ensemble measurements. For each methodology, two irradiation sources were utilized: an argon-ion laser (lambda = 496 nm) and a xenon lamp. Results of the normalized phase functions are presented.


The mental health of female sex workers.
There is limited information available about the mental health of female sex workers. Therefore, we aimed to make a comprehensive assessment of the mental status of female sex workers over different outdoors and indoors work settings and nationalities. As the prerequisites of a probability sampling were not given, a quota-sampling strategy was the best possible alternative. Sex workers were contacted at different locations in the city of Zurich. They were interviewed with a computerized version of the World Health Organization Composite International Diagnostic Interview. Additional information was assessed in a structured face-to-face interview. The 193 interviewed female sex workers displayed high rates of mental disorders. These mental disorders were related to violence and the subjectively perceived burden of sex work. Sex work is a major public health problem. It has many faces, but ill mental health of sex workers is primarily related to different forms of violence.


Pathologic manifestations of Immunoglobulin(Ig)G4-related lung disease.
Immunoglobulin(Ig)G4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect virtually any organ and usually presents as tumefactive lesions involving multiple sites. Characteristic histopathology of IgG4-RD consists of dense lymphoplasmacytic infiltrate, fibrosis (often in storiform pattern), and obliterative phlebitis, accompanied by tissue infiltration of IgG4-positive plasma cells with or without elevation of serum IgG4 level. Despite a general similarity in the morphologic manifestations of IgG4-RD, site-specific unique morphologic features have been described in some organs including the lung. Compared with other sites, pulmonary involvement by IgG4-RD has been recognized more recently, and lung biopsy interpretation for this condition is often challenging, as both a relative paucity of pathognomonic features and a plethora of overlapping findings with other fibroinflammatory processes of the lung. This review is focused on the morphologic spectrum of IgG4-related lung disease documented in the current literature and on the pertinent issues in the differential diagnoses with other conditions encountered in the lung.


Durable long-term responses in patients with myelodysplastic syndromes treated with lenalidomide.
Lenalidomide has proven efficacy and safety and has been shown to reduce transfusion requirements and reverse cytogenetic abnormalities in lower-risk myelodysplastic syndromes (MDS). However, long-term follow-up data have not yet been reported. Here, we describe 6 patients with International Prognostic Scoring System low- or intermediate-1-risk MDS who began lenalidomide therapy between April 2002 and June 2003 as part of the MDS-001 study and who have maintained long-term therapy. Five of these patients had an ongoing requirement for red blood cell transfusions despite previous treatment with recombinant erythropoietin. One patient began lenalidomide therapy because of progressive and symptomatic anemia. To date, all patients maintained long-term transfusion independence (over 4.5 years) while receiving oral lenalidomide therapy, including 5 patients who remain on therapy. Sustained erythroid response was reported despite persistence of the deletion 5q [del(5q)] abnormality in 3 of the 4 patients with del(5q) at study entry. Side effects were largely predictable and manageable. The favorable outcomes presented here show that lenalidomide can induce durable erythroid responses with sustained transfusion independence that can exceed 6 years in patients with lower-risk MDS.


Removal of dissolved nitrogen, phosphorus and carbon from stormwater by biofiltration mesocosms.
Biofiltration systems are becoming a popular stormwater treatment device in water sensitive urban design for the removal of fine particulate and dissolved pollutants from stormwater. However, there is limited published data on the effectiveness of these systems for nutrient removal. We constructed biofiltration mesocosms to assess nutrient removal (nitrogen, phosphorus and carbon) under experimental conditions. Different types of media were compared (gravel, sand, and sandy-loam) in vegetated and non-vegetated mesocosms (six treatments in total). Five plant species were used. Vegetated sand and vegetated sandy-loam provided the best overall treatment. Vegetated mesocosms were very effective in removing nitrogen (63-77% removal) and phosphorus (85-94% removal) from synthetic stormwater, and removed substantially more nutrients than the non-vegetated treatments. All treatments removed a substantial portion of the carbon from the stormwater (28-66%). When flushed with tap water, nitrogen and phosphorus were retained by the vegetated mesocosms, but leached from the non-vegetated mesocosms. Plant growth was most vigorous in the sandy-loam media, indicating that this is a good growth media, even without the addition of organic matter.


Why are we vaccinating children against COVID-19?
This article examines issues related to COVID-19 inoculations for children. The bulk of the official COVID-19-attributed deaths per capita occur in the elderly with high comorbidities, and the COVID-19 attributed deaths per capita are negligible in children. The bulk of the normalized post-inoculation deaths also occur in the elderly with high comorbidities, while the normalized post-inoculation deaths are small, but not negligible, in children. Clinical trials for these inoculations were very short-term (a few months), had samples not representative of the total population, and for adolescents/children, had poor predictive power because of their small size. Further, the clinical trials did not address changes in biomarkers that could serve as early warning indicators of elevated predisposition to serious diseases. Most importantly, the clinical trials did not address long-term effects that, if serious, would be borne by children/adolescents for potentially decades. A novel best-case scenario cost-benefit analysis showed very conservatively that there are five times the number of deaths attributable to each inoculation vs those attributable to COVID-19 in the most vulnerable 65+ demographic. The risk of death from COVID-19 decreases drastically as age decreases, and the longer-term effects of the inoculations on lower age groups will increase their risk-benefit ratio, perhaps substantially.


The formation of sunlike stars.
Understanding how stars like the sun formed constitutes one of the principal challenges confronting modern astrophysics. In recent years, advances in observational technology, particularly at infrared and millimeter wavelengths, have produced an avalanche of critical data and unexpected discoveries about the process of star formation, which is blocked from external view at optical and shorter wavelengths by an obscuring blanket of interstellar dust. Fueled by this new knowledge, a comprehensive empirical picture of stellar genesis is beginning to emerge, laying the foundations for a coherent theory of the birth of sunlike stars.


Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B.
Human organic anion-transporting polypeptide B (OATP-B; OATP2B1) is expressed in the human intestinal epithelial cells, and is suggested to be involved in the intestinal absorption of anionic drugs in vivo. Although citrus juices have been shown to inhibit the function of human OATP-A (OATP1A2), the effect of citrus juices on the OATP-B function remains unclear. In this study, we aimed to examine the effects of citrus juices on the function of OATP-B. The effects of citrus juices on the uptake of estrone-3-sulfate, a typical substrate for OATP-B, into human embryonic kidney 293 cells stably expressing OATP-B were evaluated. Juices were diluted with uptake buffer, adjusted to pH 7.4 and approximately 300 mOsm, and used for the experiments. Grapefruit juice (GFJ) and orange juice (OJ) at a concentration of 5% significantly inhibited the OATP-B-mediated uptake of estrone-3-sulfate by 82 and 53%, respectively. Major constituents of GFJ and OJ also significantly inhibited the OATP-B-mediated uptake of estrone-3-sulfate. Glibenclamide, a hypoglycemic drug, was identified for the first time as a substrate for OATP-B with a K(t) value of 6.26 microM. GFJ and OJ inhibited the OATP-B-mediated uptake of glibenclamide. These results suggest that citrus juices may inhibit the intestinal absorption of anionic drugs, such as glibenclamide, via the inhibition of OATP-B.


Mitochondrial-encoded membrane protein transcripts are pyrimidine-rich while soluble protein transcripts and ribosomal RNA are purine-rich.
Eukaryotic organisms contain mitochondria, organelles capable of producing large amounts of ATP by oxidative phosphorylation. Each cell contains many mitochondria with many copies of mitochondrial DNA in each organelle. The mitochondrial DNA encodes a small but functionally critical portion of the oxidative phosphorylation machinery, a few other species-specific proteins, and the rRNA and tRNA used for the translation of these transcripts. Because the microenvironment of the mitochondrion is unique, mitochondrial genes may be subject to different selectional pressures than those affecting nuclear genes. From an analysis of the mitochondrial genomes of a wide range of eukaryotic species we show that there are three simple rules for the pyrimidine and purine abundances in mitochondrial DNA transcripts. Mitochondrial membrane protein transcripts are pyrimidine rich, rRNA transcripts are purine-rich and the soluble protein transcripts are purine-rich. The transitions between pyrimidine and purine-rich regions of the genomes are rapid and are easily visible on a pyrimidine-purine walk graph. These rules are followed, with few exceptions, independent of which strand encodes the gene. Despite the robustness of these rules across a diverse set of species, the magnitude of the differences between the pyrimidine and purine content is fairly small. Typically, the mitochondrial membrane protein transcripts have a pyrimidine richness of 56%, the rRNA transcripts are 55% purine, and the soluble protein transcripts are only 53% purine. The pyrimidine richness of mitochondrial-encoded membrane protein transcripts is partly driven by U nucleotides in the second codon position in all species, which yields hydrophobic amino acids. The purine-richness of soluble protein transcripts is mainly driven by A nucleotides in the first codon position. The purine-richness of rRNA is also due to an abundance of A nucleotides. Possible mechanisms as to how these trends are maintained in mtDNA genomes of such diverse ancestry, size and variability of A-T richness are discussed.


The three CARMA sisters: so different, so similar: a portrait of the three CARMA proteins and their involvement in human disorders.
Initially identified by their ability to modulate the functional activity of BCL10, the three CARMA proteins, CARMA1, -2, and -3, have recently themselves taken a leading role on the stage of molecular medicine. Although considered for some time as simple ancillary proteins, increasingly accumulating recent data evidently indicate a role of primary importance for these three proteins in the pathophysiology of several human tumors and inflammatory disorders. In fact, recent scientific literature clearly establishes that CARMA1 is one of the most mutated genes in a subtype of B-cell lymphoma and, at the same time, responsible for some rare human immunodeficiency conditions. On the other hand, mutations in CARMA2 are responsible for the hereditary transmission of some inflammatory disorders of the skin, including familial psoriasis and ptiriasis; whereas expression of CARMA3 appears to be deregulated in different human tumors. Here we describe and summarize the mutations found in the genes coding for the three CARMA proteins in these different human pathological conditions, and offer an interpretation of the molecular mechanisms from which arise the biological outcomes in which these proteins are involved.


Sorption and release process of polybrominated diphenyl ethers (PBDEs) from different composition microplastics in aqueous medium: Solubility parameter approach.
Microplastics represent a growing environmental concern in the aquatic environment due to its size resemblance to microplankton in addition to its ability to act as concentrators of persistent organic pollutants (POPs). Among them, polybrominated diphenyl ethers (PBDEs) stand out as POPs with dangerous levels in the aquatic environment. In this paper we have developed a methodology for studying the sorption and extraction process of twelve congeners of PBDE from four microplastics: polyethylene terephthalate (PET), polypropylene (PP), low density polyethylene (LDPE) and polystyrene (PS). We have proved that there is a dependence between the polymer composition and the solvent used for the extraction of the analytes. The extraction is function of the ability of the solvent to partially or totally dissolve the plastic that will allow the analyte to have a greater capacity to be released from the polymer structure. The solution of the polymer is achieved by making the free energy (ΔG, or Gibbs potential) of the system negative making the process occurs spontaneously, this will depend on the solubility parameter (∂), specific of both, solvent and polymer. Therefore, this study helps to determine which methodology to be applied for the extraction of pollutants before the start of the analysis. This approach has been applied to microplastic samples collected in different locations in the four oceans and collected from the Barcelona World Race (BWR) 2014-2015 sailing race.


Acute kidney injury: a guide to diagnosis and management.
Acute kidney injury is characterized by abrupt deterioration in kidney function, manifested by an increase in serum creatinine level with or without reduced urine output. The spectrum of injury ranges from mild to advanced, sometimes requiring renal replacement therapy. The diagnostic evaluation can be used to classify acute kidney injury as prerenal, intrinsic renal, or postrenal. The initial workup includes a patient history to identify the use of nephrotoxic medications or systemic illnesses that might cause poor renal perfusion or directly impair renal function. Physical examination should assess intravascular volume status and identify skin rashes indicative of systemic illness. The initial laboratory evaluation should include measurement of serum creatinine level, complete blood count, urinalysis, and fractional excretion of sodium. Ultrasonography of the kidneys should be performed in most patients, particularly in older men, to rule out obstruction. Management of acute kidney injury involves fluid resuscitation, avoidance of nephrotoxic medications and contrast media exposure, and correction of electrolyte imbalances. Renal replacement therapy (dialysis) is indicated for refractory hyperkalemia; volume overload; intractable acidosis; uremic encephalopathy, pericarditis, or pleuritis; and removal of certain toxins. Recognition of risk factors (e.g., older age, sepsis, hypovolemia/shock, cardiac surgery, infusion of contrast agents, diabetes mellitus, preexisting chronic kidney disease, cardiac failure, liver failure) is important. Team-based approaches for prevention, early diagnosis, and aggressive management are critical for improving outcomes.


Type I IFN induced by adenovirus serotypes 28 and 35 has multiple effects on T cell immunogenicity.
Recombinant adenovirus (rAd) vectors are being investigated as vaccine delivery vehicles in preclinical and clinical studies. rAds constructed from different serotypes differ in receptor usage, tropism, and ability to activate cells, aspects of which likely contribute to their different immunogenicity profiles. In this study, we compared the infectivity and cell stimulatory capacity of recombinant adenovirus serotype 5 (rAd5), recombinant adenovirus serotype 28 (rAd28), and recombinant adenovirus serotype 35 (rAd35) in association with their respective immunogenicity profiles. We found that rAd28 and rAd35 infected and led to the in vitro maturation and activation of both human and mouse dendritic cells more efficiently compared with rAd5. In stark contrast to rAd5, rAd28 and rAd35 induced production of IFN-α and stimulated IFN-related intracellular pathways. However, the in vivo immunogenicity of rAd28 and rAd35 was significantly lower than that of rAd5. Deletion of IFN-α signaling during vaccination with rAd28 and rAd35 vectors increased the magnitude of the insert-specific T cell response to levels induced by vaccination with rAd5 vector. The negative impact of IFN-α signaling on the magnitude of the T cell response could be overcome by increasing the vaccine dose, which was also associated with greater polyfunctionality and a more favorable long-term memory phenotype of the CD8 T cell response in the presence of IFN-α signaling. Taken together, our results demonstrate that rAd-induced IFN-α production has multiple effects on T cell immunogenicity, the understanding of which should be considered in the design of rAd vaccine vectors.


Updated unified phylogenetic classification system and revised nomenclature for Newcastle disease virus.
Several Avian paramyxoviruses 1 (synonymous with Newcastle disease virus or NDV, used hereafter) classification systems have been proposed for strain identification and differentiation. These systems pioneered classification efforts; however, they were based on different approaches and lacked objective criteria for the differentiation of isolates. These differences have created discrepancies among systems, rendering discussions and comparisons across studies difficult. Although a system that used objective classification criteria was proposed by Diel and co-workers in 2012, the ample worldwide circulation and constant evolution of NDV, and utilization of only some of the criteria, led to identical naming and/or incorrect assigning of new sub/genotypes. To address these issues, an international consortium of experts was convened to undertake in-depth analyses of NDV genetic diversity. This consortium generated curated, up-to-date, complete fusion gene class I and class II datasets of all known NDV for public use, performed comprehensive phylogenetic neighbor-Joining, maximum-likelihood, Bayesian and nucleotide distance analyses, and compared these inference methods. An updated NDV classification and nomenclature system that incorporates phylogenetic topology, genetic distances, branch support, and epidemiological independence was developed. This new consensus system maintains two NDV classes and existing genotypes, identifies three new class II genotypes, and reduces the number of sub-genotypes. In order to track the ancestry of viruses, a dichotomous naming system for designating sub-genotypes was introduced. In addition, a pilot dataset and sub-trees rooting guidelines for rapid preliminary genotype identification of new isolates are provided. Guidelines for sequence dataset curation and phylogenetic inference, and a detailed comparison between the updated and previous systems are included. To increase the speed of phylogenetic inference and ensure consistency between laboratories, detailed guidelines for the use of a supercomputer are also provided. The proposed unified classification system will facilitate future studies of NDV evolution and epidemiology, and comparison of results obtained across the world.


Cholesterol lowering medication - patients' knowledge, attitudes and experiences.
Despite evidence of the efficacy of cholesterol lowering medication, it is known there is suboptimal patient adherence to this medication. The aim of this study is to investigate patient knowledge, attitudes and experiences of their cholesterol lowering medication, and explore patient views regarding programs to support self management. A semiqualitative exploratory study using semistructured telephone interviews of adult patients with poorly controlled hyperlipidaemia. Twenty-six patients were interviewed. Most patients could name at least one risk factor for their hyperlipidaemia. Approximately one-third of patients reported they did not understand the reasons they were taking their cholesterol medication and over two-thirds did not understand how their medication worked. Most reported that their general practitioner was their main source of information about cholesterol. Many expressed a desire to be better informed about cholesterol, its risk factors and medication and that an information session at their local general practice clinic would be useful. This study provides preliminary evidence that patients on long term statin therapy may have gaps in their knowledge about their condition and treatment options and a desire to be better informed.


MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA).
To identify predictors of radiographic progression in a 2-year randomised, double-blind, clinical study (CIMESTRA) of patients with early rheumatoid arthritis (RA). Patients with early RA (n = 130) were treated with methotrexate, intra-articular betamethasone and ciclosporin/placebo-ciclosporin. Baseline magnetic resonance imaging (MRI) of the wrist (wrist-only group, n = 130) or MRI of wrist and metacarpophalangeal (MCP) joints (wrist+MCP group, n = 89) (OMERACT RAMRIS), x-ray examination of hands, wrists and forefeet (Sharp/van der Heijde Score (TSS)), Disease Activity Score (DAS28), anti-cyclic citrullinated peptide antibodies (anti-CCP), HLA-DRB1-shared epitope (SE) and smoking status were assessed. Multiple regression analysis was performed with delta-TSS (0-2 years) as dependent variable and baseline DAS28, TSS, MRI bone oedema score, MRI synovitis score, MRI erosion score, anti-CCP, smoking, SE, age and gender as explanatory variables. Baseline values: median DAS28 5.6 (range 2.4-8.0); anti-CCP positive 61%; radiographic erosions 56%. At 2 years: DAS28 2.0 (0.5-5.7), in DAS remission: 56%, radiographic progression 26% (wrist+MCP group, similar for wrist-only group). MRI bone oedema score was the only independent predictor of delta-TSS (wrist+MCP group: coefficient = 0.75 (95% CI 0.55 to 0.94), p<0.001; wrist-only group: coefficient = 0.59 (95% CI 0.40 to 0.77), p<0.001). Bone oedema score explained 41% of the variation in the progression of TSS (wrist+MCP group), 25% in wrist-only group (Pearson's r = 0.64 and r = 0.50, respectively). Results were confirmed by sensitivity analyses. In a randomised controlled trial aiming at remission in patients with early RA, baseline RAMRIS MRI bone oedema score of MCP and wrist joints (and of wrist only) was the strongest independent predictor of radiographic progression in hands, wrists and forefeet after 2 years. MRI synovitis score, MRI erosion score, DAS28, anti-CCP, SE, smoking, age and gender were not independent risk factors. NCT00209859.


Calpain Inhibition Is Protective in Machado-Joseph Disease Zebrafish Due to Induction of Autophagy.
The neurodegenerative disease Machado-Joseph disease (MJD), also known as spinocerebellar ataxin-3, affects neurons of the brain and spinal cord, disrupting control of the movement of muscles. We have successfully established the first transgenic zebrafish (Danio rerio) model of MJD by expressing human ataxin-3 protein containing either 23 glutamines (23Q, wild-type) or 84Q (MJD-causing) within neurons. Phenotypic characterization of the zebrafish (male and female) revealed that the ataxin-3-84Q zebrafish have decreased survival compared with ataxin-3-23Q and develop ataxin-3 neuropathology, ataxin-3 cleavage fragments and motor impairment. Ataxin-3-84Q zebrafish swim shorter distances than ataxin-3-23Q zebrafish as early as 6 days old, even if expression of the human ataxin-3 protein is limited to motor neurons. This swimming phenotype provides a valuable readout for drug treatment studies. Treating the EGFP-ataxin-3-84Q zebrafish with the calpain inhibitor compound calpeptin decreased levels of ataxin-3 cleavage fragments, but also removed all human ataxin-3 protein (confirmed by ELISA) and prevented the early MJD zebrafish motor phenotype. We identified that this clearance of ataxin-3 protein by calpeptin treatment resulted from an increase in autophagic flux (indicated by decreased p62 levels and increased LC3II). Cotreatment with the autophagy inhibitor chloroquine blocked the decrease in human ataxin-3 levels and the improved movement produced by calpeptin treatment. This study demonstrates that this first transgenic zebrafish model of MJD is a valuable tool for testing potential treatments for MJD. Calpeptin treatment is protective in this model of MJD and removal of human ataxin-3 through macro-autophagy plays an important role in this beneficial effect.SIGNIFICANCE STATEMENT We have established the first transgenic zebrafish model of the neurodegenerative disease MJD, and identified relevant disease phenotypes, including impaired movement from an early age, which can be used in rapid drug testing studies. We have found that treating the MJD zebrafish with the calpain inhibitor compound calpeptin produces complete removal of human ataxin-3 protein, due to induction of the autophagy quality control pathway. This improves the movement of the MJD zebrafish. Artificially blocking the autophagy pathway prevents the removal of human ataxin-3 and improved movement produced by calpeptin treatment. These findings indicate that induction of autophagy, and removal of ataxin-3 protein, plays an important role in the protective effects of calpain inhibition for the treatment of MJD.


Development and validation of the Cognitive Telephone Screening Instrument (COGTEL) for the assessment of cognitive function across adulthood.
The authors introduce a screening instrument that assesses cognitive-function domains across adulthood over the telephone. The authors administered the Cognitive Telephone Screening Instrument (COGTEL) to 81 younger adults (M = 25.6 years) and 83 older adults (M = 66.9 years). Each participant completed the COGTEL twice, once over the telephone and once in a face-to-face assessment. The authors (a) analyzed the degree of agreement between face-to-face and telephone COGTEL scores, (b) developed a COGTEL Total score that reflects global cognitive functioning, and (c) examined concurrent validity. The method of administration did not largely influence mean levels, rank orders, or factor structure as revealed by confirmatory factor analysis. Moreover, age differences were not modulated by the form of administration. The distribution of COGTEL Total scores followed a Gaussian function, which prevents COGTEL from being limited by ceiling effects. The results provide evidence for the validity and reliability of the COGTEL to assess cognitive functioning in large-scale epidemiological studies, longitudinal studies, and clinical follow-up among healthy adults.


Neurofibrillary tangles in some cases of dementia pugilistica share antigens with amyloid beta-protein of Alzheimer's disease.
Formalin-fixed, paraffin-embedded temporal lobe sections from eight former boxers' brains were examined using an immunohistochemical method with antibodies to amyloid beta protein. In accord with recent observations in Alzheimer's disease, significant numbers of beta-protein immunoreactive neurofibrillary tangles (NFT) were observed in three cases. Most of these immunoreactive NFTs appeared to be tombstone tangles, although not all such tangles were stained. This immunoreaction was completely abolished by preincubation of antibodies with synthetic beta-protein peptides, and the identity of the immunostained NFTs was confirmed by polarization microscopy of sections counterstained with Congo red. However, it is not yet clear if the beta-protein antigens are, in fact, an integral part of paired helical filaments. These observations, together with our recent finding of beta-immunoreactive plaque-like lesions in dementia pugilistica, also emphasize the many similarities in pathology between this condition and Alzheimer's disease.


An overview of innovations and industrial solutions in Protein Microarray Technology.
The complexity involving protein array technology reflects in the fact that instrumentation and data analysis are subject to change depending on the biological question, technical compatibility of instruments and software used in each experiment. Industry has played a pivotal role in establishing standards for future deliberations in sustenance of these technologies in the form of protein array chips, arrayers, scanning devices, and data analysis software. This has enhanced the outreach of protein microarray technology to researchers across the globe. These have encouraged a surge in the adaptation of "nonclassical" approaches such as DNA-based protein arrays, micro-contact printing, label-free protein detection, and algorithms for data analysis. This review provides a unique overview of these industrial solutions available for protein microarray based studies. It aims at assessing the developments in various commercial platforms, thus providing a holistic overview of various modalities, options, and compatibility; summarizing the journey of this powerful high-throughput technology.


The development of the sexually indifferent gonad in the prosimian, Galago crassicaudatus crassicaudatus.
The morphogenesis of the sexually indifferent gonad of the primate Galago crassicaudatus crassicaudatus was studied by high-resolution light microscopy and electron microscopy in 15 embryos aged 26 to 33 days. Onset of gonadal development follows the morphogenesis of the mesonephros by a conspicuous interval and is identified as the time when the first primordial germinal cells arrive in the region ventral to the central third of the mesonephros; this is followed by intense proliferation of the coelomic mesothelial cells lining the area. They become organized into short piles that deepen in the underlying mesenchyme, enclosing the germinal cells in the process. Rapidly, the piles become confluent forming a compact mass, the gonadal blastema, which is soon cleaved into gonadal cords by stroma and vascular lacunae. The mesonephros becomes involved in the morphogenesis of the gonad only in late stages of development when anatomic continuities become established between the capsules of its regressing glomeruli and the elongating gonadal rete cords. These observations show that in the Galago the somatic cells of the gonadal blastema, i.e., the precursors of the definitive testicular and ovarian sustentacular cells, derive from the coelomic mesothelium in contrast to other mammals, e.g., ruminants and rodents, where they are of mesonephric derivation. This important point is discussed in light of the differences that exist among species with regard to the structural complexity, functionality, and stages of differentiation/involution of their mesonephroi on the one hand, and the time of gonadal development on the other.


31P nuclear magnetic resonance studies of bioenergetics and glycolysis in anaerobic Escherichia coli cells.
31P nuclear magnetic resonance spectra of glycolyzing, anaerobic Escherichia coli cells and their perchloric acid extracts were obtained at 145.7 MHz. Time-dependent intracellular concentrations of nucleoside di- and triphosphates, Pi, and sugar phosphates were measured during glycolysis with 2-min resolution, while intracellular and extra-cellular pH values were monitored simultaneously. Upon glucose addition, anaerobic E. coli cells rapidly produce acids and develop a transmembrane pH gradient (delta pH). Glycolysis rates were calculated from the changes in the external pH. It was found that glycolysis rates are strongly dependent on internal pH, sharply decreasing when the pH drops below approximately 7.2. The ATPase inhibitor, dicyclohexylcarbodiimide (DCCD), prevented NTP hydrolysis and inhibited delta pH formation. The uncoupler, carbonyl cyanide p-triflouromethoxyphenyl hydrazone (FCCP), drastically reduced both the delta pH and the NTP level. When the cells were previously treated with DCCD, FCCP collapsed the delta pH while the NTP levels remained high. It is concluded that ATP produced by glycolysis is hydrolyzed by the membrane ATPase to generate a delta pH and that FCCP stimulates ATP hydrolysis by ATPase and collapses the proton gradient.


Global impact of accelerated plant breeding: Evidence from a meta-analysis on rice breeding.
Rice breeders in Asia and elsewhere in the world have long overlooked trying to shorten the time it takes to develop new varieties. Plant breeders have proposed a technique called Rapid Generation Advance (RGA) as a way to accelerate the results of public rice breeding programs. However, little is known about RGA's potential impact. Here, we present the first results of a global impact study of RGA. More specifically, we calculated the multiplicator effects of RGA on the research benefits generated by conventional rice breeding programs and applied them to a meta-analysis of selected impact studies in the literature. These insights are a first crucial step in developing a targeted approach for disseminating RGA technology among rice breeders to accelerate the impact of their public rice breeding programs around the world. We show that the additional benefits due to time savings are considerable and offer some insights into the economics of breeding. Our results confirm that the adoption of accelerated breeding would lead to substantial advantages to rice breeding programs and the earlier variety release leads to significant economic benefits to society. This can be important to policy makers when reshaping their public breeding methods and optimising their return on research investments in breeding.


Periodic patterns in Rodentia: Development and evolution.
Mammalian periodic pigment patterns, such as spots and stripes, have long interested mathematicians and biologists because they arise from non-random developmental processes that are programmed to be spatially constrained, and can therefore be used as a model to understand how organized morphological structures develop. Despite such interest, the developmental and molecular processes underlying their formation remain poorly understood. Here, we argue that Arvicanthines, a clade of African rodents that naturally evolved a remarkable array of coat patterns, represent a tractable model system in which to dissect the mechanistic basis of pigment pattern formation. Indeed, we review recent insights into the process of stripe formation that were obtained using an Arvicanthine species, the African striped mouse (Rhabdomys pumilio), and discuss how these rodents can be used to probe deeply into our understanding of the factors that specify and implement positional information in the skin. By combining naturally evolved pigment pattern variation in rodents with classic and novel experimental approaches, we can substantially advance our understanding of the processes by which spatial patterns of cell differentiation are established during embryogenesis, a fundamental question in developmental biology.


Motor unit discharge rate in dynamic movements of the aging soleus.
Aging is related to a variety of changes at the muscular level. It seems that the age-related changes in motor unit activation are muscle- and intensity dependent. The purpose of this study was to examine the motor unit discharge rate (MUDR) in both isometric and dynamic contractions of the aging soleus muscle. Eight elderly males participated in the study. The subjects performed isometric and dynamic plantar flexions while seated in an ankle dynamometer. The force levels studied were 10, 20, 40, 60, 80 and 100% of the isometric (ISO) maximal voluntary contractions (MVC) in ISO and 10, 20 and 40% in concentric (CON) and eccentric (ECC) contractions. Soleus intramuscular EMG was recorded with bipolar fine-wire electrodes and decomposed to individual trains of motor unit discharges. In ISO the MUDR increased with each force level from 40 to 100% MVC. In dynamic contractions the descriptive analysis showed a higher MUDR in CON compared to ISO or ECC. The difficulties of recording single motor units in dynamic contractions, especially in the elderly is discussed.


Single molecule sensing with solid-state nanopores: novel materials, methods, and applications.
This tutorial review will introduce and explore the fundamental aspects of nanopore (bio)sensing, fabrication, modification, and the emerging technologies and applications that both intrigue and inspire those working in and around the field. Although nanopores can be classified into two categories, solid-state and biological, they are essentially two sides of the same coin. For instance, both garner popularity due to their ability to confine analytes of interest to a nanoscale volume. Due to the vast diversity of nanopore platforms and applications, no single review can cover the entire landscape of published work in the field. Therefore, in this article focus will be placed on recent advancements and developments taking place in the field of solid-state nanopores. It should be stated that the intention of this tutorial review is not to cite all articles relating to solid-state nanopores, but rather to highlight recent, select developments that will hopefully benefit the new and seasoned scientist alike. Initially we begin with the fundamentals of solid-state nanopore sensing. Then the spotlight is shone on the sophisticated fabrication methods that have their origins in the semiconductor industry. One inherent advantage of solid-state nanopores is in the ease of functionalizing the surface with a range of molecules carrying functional groups. Therefore, an entire section is devoted to highlighting various chemical and bio-molecular modifications and explores how these permit the development of novel sensors with specific targets and functions. The review is completed with a discussion on novel detection strategies using nanopores. Although the most popular mode of nanopore sensing is based upon what has come to be known as ionic-current blockade sensing, there is a vast, growing literature based around exploring alternative detection techniques to further expand on the versatility of the sensors. Such techniques include optical, electronic, and force based methods. It is perhaps fair to say that these new frontiers have caused further excitement within the sensing community.


Effects of Body Position and Hypovolemia on the Regional Distribution of Pulmonary Perfusion During One-Lung Ventilation in Endotoxemic Pigs.
Background: The incidence of hypoxemia during one-lung ventilation (OLV) is as high as 10%. It is also partially determined by the distribution of perfusion. During thoracic surgery, different body positions are used, such as the supine, semilateral, lateral, and prone positions, with such positions potentially influencing the distribution of perfusion. Furthermore, hypovolemia can impair hypoxic vasoconstriction. However, the effects of body position and hypovolemia on the distribution of perfusion remain poorly defined. We hypothesized that, during OLV, the relative perfusion of the ventilated lung is higher in the lateral decubitus position and that hypovolemia impairs the redistribution of pulmonary blood flow. Methods: Sixteen juvenile pigs were anesthetized, mechanically ventilated, submitted to a right-sided thoracotomy, and randomly assigned to one of two groups: (1) intravascular normovolemia or (2) intravascular hypovolemia, as achieved by drawing ~25% of the estimated blood volume (n = 8/group). Furthermore, to mimic thoracic surgery inflammatory conditions, Escherichia coli lipopolysaccharide was continuously infused at 0.5 μg kg-1 h-1. Under left-sided OLV conditions, the animals were further randomized to one of the four sequences of supine, left semilateral, left lateral, and prone positioning. Measurements of pulmonary perfusion distribution with fluorescence-marked microspheres, ventilation distribution by electrical impedance tomography, and gas exchange were then performed during two-lung ventilation in a supine position and after 30 min in each position and intravascular volume status during OLV. Results: During one-lung ventilation, the relative perfusion of the ventilated lung was higher in the lateral than the supine position. The relative perfusion of the non-ventilated lung was lower in the lateral than the supine and prone positions and in semilateral compared with the prone position. During OLV, the highest arterial partial pressure of oxygen/inspiratory fraction of oxygen (PaO2/F I O 2) was achieved in the lateral position as compared with all the other positions. The distribution of perfusion, ventilation, and oxygenation did not differ significantly between normovolemia and hypovolemia. Conclusions: During one-lung ventilation in endotoxemic pigs, the relative perfusion of the ventilated lung and oxygenation were higher in the lateral than in the supine position and not impaired by hypovolemia.


Dexamethasone alone and in combination with desipramine, phenytoin, valproic acid or levetiracetam interferes with 5-ALA-mediated PpIX production and cellular retention in glioblastoma cells.
Extent of resection of glioblastoma (GBM) correlates with overall survival. Fluorescence-guided resection (FGR) using 5-aminolevulinic acid (5-ALA) can improve the extent of resection. Unfortunately not all patients given 5-ALA accumulate sufficient quantities of protoporphyrin IX (PpIX) for successful FGR. In this study, we investigated the effects of dexamethasone, desipramine, phenytoin, valproic acid, and levetiracetam on the production and accumulation of PpIX in U87MG cells. All of these drugs, except levetiracetam, reduce the total amount of PpIX produced by GBM cells (p < 0.05). When dexamethasone is mixed with another drug (desipramine, phenytoin, valproic acid or levetiracetam) the amount of PpIX produced is further decreased (p < 0.01). However, when cells are analyzed for PpIX cellular retention, dexamethasone accumulated significantly more PpIX than the vehicle control (p < 0.05). Cellular retention of PpIX was not different from controls in cells treated with dexamethasone plus desipramine, valproic acid or levetiracetam, but was significantly less for dexamethasone plus phenytoin (p < 0.01). These data suggest that medications given before and during surgery may interfere with PpIX accumulation in malignant cells. At this time, levetiracetam appears to be the best medication in its class (anticonvulsants) for patients undergoing 5-ALA-mediated FGR.


Effects of pasteurization of potato slurry by-product fed in corn-or barley-based beef finishing diets.
Pasteurization of vegetable by-products such as potato slurry (PS) before feeding may be necessary to prevent the spread of pathogens and beef carcass blemishes. We hypothesized that pasteurization would increase ruminal fermentability of PS starch. Four ruminally cannulated crossbred beef steers (initial BW = 432) were used in a 4 x 4 Latin square experiment with a 2 x 2 factorial arrangement of treatments to examine the main effects and interactions of pasteurization (54.4 degrees C for 2 h) of PS and grain type (GT; dry-rolled corn and barley) on ruminal and total tract digestion of beef finishing diets. Diets contained 7% alfalfa hay and 14% PS (DM basis) and were fed ad libitum three times daily. Corn-based diets had 71.7% corn, whereas barley-based diets had 60% barley and 11.7% corn. Pasteurization resulted in greater (P = 0.004) soluble, rapidly degradable starch (34.3 vs. 26.7% for pasteurized and nonpasteurized PS, respectively). Ruminal fluid pH was more acidic (P < 0.07) for corn-based diets than for barley-based diets (P = 0.07) at 0200 and 2100 (sample time x GT; P < 0.05). Ruminal fluid pH was more acidic (P = 0.06) at 1400 for corn-based diets containing pasteurized PS compared with other dietary treatments (sample time x pasteurization x GT; P = 0.04). Minimum and maximum ruminal pH were greater (P < 0.10) for barley-based diets than for corn-based diets. Ruminal fluid pH was < 6.0 for a greater (P = 0.04) proportion of the day for corn-based compared with barley-based diets. In vitro incubation measurements revealed that pasteurization of PS resulted in lower (P = 0.06) ruminal fluid ammonia N concentration. Ruminal fluid ammonia N concentration was lower (P = 0.11) for barley-based diets than for corn-based diets. Steers fed barley-based diets had greater (P = 0.02) DMI and lesser (P < 0.05) total tract digestibility of DM and ADF compared with steers fed corn diets. Pasteurization increased (P = 0.10) total tract starch digestibility. Results indicate pasteurization increased rapidly degradable starch, ruminal starch fermentability, and total tract starch digestibility of PS. Grain type interacted with pasteurization such that feeding corn-based diets containing pasteurized PS resulted in periodic reductions in ruminal pH. Feeding management may be more critical when feeding pasteurized PS in beef finishing diets.


Anandamide inhibits breast tumor-induced angiogenesis.
Breast cancer is one of the most frequently diagnosed malignancies and a leading cause of cancer death in women. Great advances in the treatment of primary tumors have led to a significant increment in the overall survival rates, however recurrence and metastatic disease, the underlying cause of death, are still a medical challenge. Breast cancer is highly dependent on neovascularization to progress. In the last years several anti-angiogenic drugs have been developed and administered to patients in combination with chemotherapeutic drugs. Collected preclinical evidence has proposed the endocannabinoid system as a potential target in cancer. The endocannabinoid anandamide has been reported to affect breast cancer growth at multiple levels, by inhibiting proliferation, migration and invasiveness in vitro and in vivo and by directly inhibiting angiogenesis. Aim of the present work is to investigate if anandamide is able to affect the proangiogenic phenotype of the highly invasive and metastatic breast cancer cells MDA-MB-231. We found that following anandamide treatment, MDAMB-231 cells lose their ability to stimulate endothelial cells proliferation in vitro, due to a significant inhibition of all the pro-angiogenic factors produced by these cells. This finding adds another piece of evidence to the anti-tumor efficacy of anandamide in breast cancer.


Intensity Weighted Subtraction Microscopy Approach for Image Contrast and Resolution Enhancement.
We propose and demonstrate a novel subtraction microscopy algorithm, exploiting fluorescence emission difference or switching laser mode and their derivatives for image enhancement. The key novelty of the proposed approach lies in the weighted subtraction coefficient, adjusted pixel-by-pixel with respect to the intensity distributions of initial images. This method produces significant resolution enhancement and minimizes image distortions. Our theoretical and experimental studies demonstrate that this approach can be applied to any optical microscopy techniques, including label free and non-linear methods, where common super-resolution techniques cannot be used.


Firearm possession among arrestees in Trinidad and Tobago.
To describe the sources that active offenders in Trinidad and Tobago use to obtain firearms and report their motivations for obtaining them. To estimate relationships between gang involvement, drug selling, and firearm ownership (or possession). Port of Spain (Republic of Trinidad and Tobago). A cross-sectional research design was used to collect self-report data from 421 recently booked arrestees (within 72 h of their arrest) in the Port of Spain Police District Detention Center. A survey instrument was used to collect data on firearm acquisition, drug use, gang membership and other behaviours. The sample provides insights about guns in the lives of arrestees in Trinidad and Tobago. 15% of respondents reported ever owning (or possessing) a firearm. Among the possessor group, 82% owned a gun primarily for defensive purposes, but approximately half reported using a gun in a crime. Nearly half of gun possessors stored their guns in outside locations. Firearm possession was greater among arrestees involved in gangs and those involved in drug selling. A comprehensive approach of prevention, intervention, and suppression strategies that are intended to prevent gun-related incidents should be focused on gangs, drugs, and guns. Searches for high-risk firearms should focus on public areas where gang members live and socialise. The study shows the value of collecting data from offender-based populations in the region for the purpose of directing violence-prevention strategies.


Public and private hospital services reform using data envelopment analysis to measure technical, scale, allocative, and cost efficiencies.
The aim of this study was to suggest a suitable context to develop efficient hospital systems while maintaining the quality of care at minimum expenditures. This research aimed to present a model of efficiency for selected public and private hospitals of East Azerbaijani Province of Iran by making use of Data Envelopment Analysis approach in order to recognize and suggest the best practice standards. Among the six inefficient hospitals, 2 (33%) had a technical efficiency score of less than 50% (both private), 2 (33%) between 51 and 74% (one private and one public) and the rest (2, 33%) between 75 and 99% (one private and one public). In general, the public hospitals are relatively more efficient than private ones; it is recommended for inefficient hospitals to make use of the followings: transferring, selling, or renting idle/unused beds; transferring excess doctors and nurses to the efficient hospitals or other health centers; pensioning off, early retirement clinic officers, technicians/technologists, and other technical staff. The saving obtained from the above approaches could be used to improve remuneration for remaining staff and quality of health care services of hospitals, rural and urban health centers, support communities to start or sustain systematic risk and resource pooling and cost sharing mechanisms for protecting beneficiaries against unexpected health care costs, compensate the capital depreciation, increasing investments, and improve diseases prevention services and facilities in the provincial level.


Fuzzy Logic-based expert system for evaluating cake quality of freeze-dried formulations.
Freeze-drying of peptide and protein-based pharmaceuticals is an increasingly important field of research. The diverse nature of these compounds, limited understanding of excipient functionality, and difficult-to-analyze quality attributes together with the increasing importance of the biosimilarity concept complicate the development phase of safe and cost-effective drug products. To streamline the development phase and to make high-throughput formulation screening possible, efficient solutions for analyzing critical quality attributes such as cake quality with minimal material consumption are needed. The aim of this study was to develop a fuzzy logic system based on image analysis (IA) for analyzing cake quality. Freeze-dried samples with different visual quality attributes were prepared in well plates. Imaging solutions together with image analytical routines were developed for extracting critical visual features such as the degree of cake collapse, glassiness, and color uniformity. On the basis of the IA outputs, a fuzzy logic system for analysis of these freeze-dried cakes was constructed. After this development phase, the system was tested with a new screening well plate. The developed fuzzy logic-based system was found to give comparable quality scores with visual evaluation, making high-throughput classification of cake quality possible.


How to Estimate Epidemic Risk from Incomplete Contact Diaries Data?
Social interactions shape the patterns of spreading processes in a population. Techniques such as diaries or proximity sensors allow to collect data about encounters and to build networks of contacts between individuals. The contact networks obtained from these different techniques are however quantitatively different. Here, we first show how these discrepancies affect the prediction of the epidemic risk when these data are fed to numerical models of epidemic spread: low participation rate, under-reporting of contacts and overestimation of contact durations in contact diaries with respect to sensor data determine indeed important differences in the outcomes of the corresponding simulations with for instance an enhanced sensitivity to initial conditions. Most importantly, we investigate if and how information gathered from contact diaries can be used in such simulations in order to yield an accurate description of the epidemic risk, assuming that data from sensors represent the ground truth. The contact networks built from contact sensors and diaries present indeed several structural similarities: this suggests the possibility to construct, using only the contact diary network information, a surrogate contact network such that simulations using this surrogate network give the same estimation of the epidemic risk as simulations using the contact sensor network. We present and compare several methods to build such surrogate data, and show that it is indeed possible to obtain a good agreement between the outcomes of simulations using surrogate and sensor data, as long as the contact diary information is complemented by publicly available data describing the heterogeneity of the durations of human contacts.


Activation of an EDS1-mediated R-gene pathway in the snc1 mutant leads to constitutive, NPR1-independent pathogen resistance.
The Arabidopsis NPR1 protein is an essential regulatory component of systemic acquired resistance (SAR). Mutations in the NPR1 gene completely block the induction of SAR by signals such as salicylic acid (SA). An Arabidopsis mutant, snc1 (suppressor of npr1-1, constitutive 1), was isolated in a screen for suppressors of npr1-1. In the npr1-1 background, the snc1 mutation resulted in constitutive resistance to Pseudomonas syringae maculicola ES4326 and Peronospora parasitica Noco2. High levels of SA were detected in the mutant and shown to be required for manifestation of the snc1 phenotype. The snc1 mutation was mapped to the RPP5 resistance (R) gene cluster and the eds1 mutation that blocks RPP5-mediated resistance suppressed snc1. These data suggest that a RPP5-related resistance pathway is activated constitutively in snc1. This pathway does not employ NPR1 but requires the signal molecule SA and the function of EDS1. Moreover, in snc1, constitutive resistance is conferred in the absence of cell death, which is often associated with R-gene mediated resistance.


Appropriate therapy but not inappropriate shocks predict survival in implantable cardioverter defibrillator patients.
Inappropriate implantable cardioverter defibrillator (ICD) shocks have been linked to a worse clinical outcome due to direct myocardial injury. The occurrence of ventricular tachyarrhythmia indicating progression of the underlying heart disease, but not the ICD shock itself, has prognostic impact in clinical routine. In a retrospective study, 1117 recipients of an ICD were analyzed with respect to appropriate and inappropriate therapies and survival. During a mean follow-up of 2.92 years, appropriate therapy occurred in 27.7% and 54.0% of patients who had received an ICD for primary and secondary prevention of sudden cardiac death (SCD), respectively (P<0.0001). Inappropriate shock therapy occurred in 15.0% and 25.4% of patients who had received an ICD for primary and secondary prevention of SCD, respectively (P = 0.122). Appropriate ICD therapy had a strong impact on overall survival (P<0.0001), and this association was found both in primary (P<0.0001) and secondary (P = 0.002) prevention of SCD. Inappropriate ICD shocks had no impact on total mortality, neither in primary nor secondary prevention of SCD. Inappropriate shocks do not affect survival, in strong contrast to appropriate ICD therapy. Our study does not support the hypothesis that shock therapy in itself worsens clinical outcome. However, it confirms that appropriate ICD therapy is a warning sign and should prompt physicians to consider additional treatment strategies.


Implementing online natural gradient learning: problems and solutions.
The online natural gradient learning is an efficient algorithm to resolve the slow learning speed and poor performance of the standard gradient descent method. However, there are several problems to implement this algorithm. In this paper, we proposed a new algorithm to solve these problems and then compared the new algorithm with other known algorithms for online learning, including Almeida-Langlois-Amaral-Plakhov algorithm (ALAP), Vario-eta, local adaptive learning rate and learning with momentum etc., using sample data sets from Proben1 and normalized handwritten digits, automatically scanned from envelopes by the U.S. Postal Services. The strong and weak points of these algorithms were analyzed and tested empirically. We found out that using the online training error as the criterion to determine whether the learning rate should be changed or not is not appropriate and our new algorithm has better performance than other existing online algorithms.


Acquired resistance to imatinib and secondary KIT exon 13 mutation in gastrointestinal stromal tumour.
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. Most of them have an activating mutation of KIT or PDGFRalpha tyrosine-kinase receptors. Imatinib is a selective tyrosine-kinase inhibitor of ABL, KIT and PDGFR, and provides a clinical benefit in about 85% of patients with advanced GIST. Unfortunately, secondary resistance following initial responses occurs in most of the cases, and molecular mechanisms are poorly understood. We sequenced KIT and PGDFRalpha exons from one patient with GIST before and after the development of imatinib resistance. We identified, in addition to a primary mutation in exon 9, a secondary mutation in KIT exon 13 (first kinase domain) in the resistant sample. We demonstrate for the first time the feasibility of sequencing such samples removed by non-surgical biopsies during imatinib therapy. Such a approach, far less invasive than surgery and combined with sequencing, will likely help in better tailoring the treatment of advanced GISTs and understanding the mechanisms of resistance and response to imatinib.


Effect of discontinuation of growth hormone treatment on risk factors for cardiovascular disease in adolescents born small for gestational age.
Hyperlipidemia, diabetes mellitus type 2, and coronary heart disease have been associated with being born small for gestational age (SGA). It has been reported that GH treatment induced higher insulin levels, which has led to concern regarding the long-term effect of GH treatment in predisposed individuals such as children born SGA. In this study, we assessed the effect of discontinuation of long-term GH treatment in 47 adolescents born SGA on oral glucose tolerance tests, blood pressure (BP), and serum lipid levels for two GH dosage groups (3 vs. 6 IU/m2 x d). At 6 months after discontinuation of GH treatment mean (SD) age was 16.0 (2.1) yr. Mean duration of GH treatment had been 6.9 (1.5) yr. Fasting glucose levels and 120-min area under the curve for glucose 6 months after discontinuation of GH treatment showed no difference from pretreatment levels for both GH dosage groups. After discontinuation of GH treatment, fasting insulin levels returned to pretreatment levels (8.4 mU/liter), whereas the 120-min area under the curve for insulin decreased, compared with 6-yr levels (P < 0.01), regardless of GH dosage group. No significant difference was found when levels were compared with a control group. In addition, for both GH dosage groups, no significant changes in systolic and diastolic BP SD score, total cholesterol, and atherogenic index (total cholesterol/high-density lipoprotein cholesterol) were seen from 6 yr of GH until 6 months after discontinuation of GH treatment. In conclusion, in children born SGA, the GH-induced insulin insensitivity disappeared after discontinuation of GH, even after long-term GH treatment. Furthermore, the beneficial effect of GH on BP was not changed after discontinuation of GH, and most children had normal lipid levels.