Identification of a novel dexamethasone responsive enhancer in the human CYP3A5 gene and its activation in human and rat liver cells.
The human liver cytochromes P450 3A (CYP3As), orthologous to the rat glucocorticoid inducible forms, are composed of at least four differentially expressed members. To begin the study of the molecular events in the glucocorticoid regulation of CYP3A5, we fused 5' sequences of CYP3A5 to the chloramphenicol acetyltransferase gene in a vector that contains the herpes simplex virus thymidine kinase promoter. In HepG2 cells, the largest 5' CYP3A5 gene fragment (1.4 kb) suppressed the TK promoter. However, suppression was overcome by addition of 10 microM dexamethasone. A series of unidirectional deletions revealed a unique 219-bp fragment (-891 to -1109 bp upstream from the transcriptional start site) that conferred dexamethasone responsiveness on the TK promoter regardless of either the distance or orientation from the promoter and thus appears to be an enhancer. Nucleotide sequence analysis of this CYP3A5 enhancer revealed no consensus 15-bp glucocorticoid responsive element (GRE) (GGTACANNNTGTTCT); however, two GRE "half-sites" (TGTTCT) were found separated by 160 bp. Although dexamethasone stimulated the CYP3A5 enhancer only 3-4-fold in HepG2 cells, the CYP3A5 enhancer was stimulated 7- and 12-fold in immortalized primary human hepatocytes and primary rat hepatocyte cultures, respectively. The glucocorticoid receptor (GCR) seems to be indispensable to this process because 1) dexamethasone induction can be blocked by the antiglucocorticoid RU-486, 2) dexamethasone-dependent transcriptional activation of the CYP3A5 enhancer in HepG2 cells required cotransfection of an expression vector containing the intact GCR, yet 3) cotransfection with a plasmid that contains a mutation in the ligand binding domain of the GCR does not activate the CYP3A5 enhancer in the presence of dexamethasone. To further localize the dexamethasone responsive region of the 219-bp CYP3A5 enhancer, it was subdivided and fused to the TKCAT expression vector. Transfection analysis in HepG2 cells demonstrated that neither GRE half-site can independently confer dexamethasone responsiveness on the TK promoter. Block mutations of either of the two GRE half-sites or point mutations at specific GCR binding sites eliminates dexamethasone inducibility, demonstrating the half-sites need to interact. Electromobility shift assays indicate that the CYP3A5 5'-GRE half-site 1) specifically binds purified GCR, 2) can displace binding of the GCR to a consensus GRE, and 3) shifts a protein in HepG2 nuclear extracts that is supershifted by GCR antibody, demonstrating that this enhancer is an authentic GRE. This is the first study to demonstrate that a member of the human CYP3A gene family contains an enhancer that binds the GCR and that this binding is critical to transcriptional activation by dexamethasone.


Risk for gastric cancer after cholecystectomy.
It is becoming increasingly evident that chronic inflammation may predispose cancer development. In the stomach, inflammation caused by Helicobacter pylori infection is linked to gastric cancer. Cholecystectomy is regularly followed by duodenogastric bile reflux and reactive gastritis. To test whether a noninfectious long-standing inflammation impels gastric carcinogenesis as well, we assessed the risk of gastric cancer in a large, population-based cohort of cholecystectomized patients. We identified 251,672 individuals, in the Swedish National Inpatient Register, who had undergone cholecystectomy between 1970 and 1997. All incident cases of gastric cancer were identified through linkage to the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for comparisons with cancer rates of the general population in Sweden. We found an 11% greater overall risk of distal gastric cancer (SIR=1.11, 95% CI 1.04-1.19). The risk increase was only observed among men (SIR=1.21, 95% CI 1.10-1.32), whereas no excess risk was evident for women. For men, the risk was elevated for up to 10 yr after surgery, but this elevation disappeared with longer follow-up time. There was no clear association between cholecystectomy and cardia cancer (SIR=0.95, 95% CI 0.76-1.16). Inconsistency over gender strata, implausibly short induction and latency time, and disappearance of the effect over time makes a causal relationship between cholecystectomy and distal gastric cancer less likely. The findings set aside concerns of harmful long-term consequences of cholecystectomy.


Optimal duration of anticoagulation in patients with venous thromboembolism.
The risk of recurrent venous thromboembolism (VTE) approaches 40 per cent of all patients after 10 yr of follow up. This risk is higher in patients with permanent risk factors of thrombosis such as active cancer, prolonged immobilization from medical diseases, and antiphospholipid syndrome; in carriers of several thrombophilic abnormalities, including deficiencies of natural anticoagulants; and in patients with unprovoked presentation. Patients with permanent risk factors of thrombosis should receive indefinite anticoagulation, consisting of subtherapeutic doses of low molecular weight heparin in cancer patients, and oral anticoagulants in all other conditions. Patients whose VTE is triggered by major surgery or trauma should be offered three months of anticoagulation. Patients with unprovoked VTE, including carriers of thrombophilia, and those whose thrombotic event is associated with minor risk factors (such as hormonal treatment, minor injuries, long travel) should receive at least three months of anticoagulation. The decision as to go on or discontinue anticoagulation after this period should be individually tailored and balanced against the haemorrhagic risk. Post-baseline variables, such as the D-dimer determination and the ultrasound assessment of residual thrombosis can help identify those patients in whom anticoagulation can be safely discontinued. As a few emerging anti-Xa and anti-IIa compounds seem to induce fewer haemorrhagic complications than conventional anticoagulation, while preserving at least the same effectiveness, these have the potential to open new scenarios for decisions regarding the duration of anticoagulation in patients with VTE.


Mutual Influence of ROS, pH, and CLIC1 Membrane Protein in the Regulation of G1-S Phase Progression in Human Glioblastoma Stem Cells.
Glioblastoma (GB) is the most lethal, aggressive, and diffuse brain tumor. The main challenge for successful treatment is targeting the cancer stem cell (CSC) subpopulation responsible for tumor origin, progression, and recurrence. Chloride Intracellular Channel 1 (CLIC1), highly expressed in CSCs, is constitutively present in the plasma membrane where it is associated with chloride ion permeability. In vitro, CLIC1 inhibition leads to a significant arrest of GB CSCs in G1 phase of the cell cycle. Furthermore, CLIC1 knockdown impairs tumor growth in vivo Here, we demonstrate that CLIC1 membrane localization and function is specific for GB CSCs. Mesenchymal stem cells (MSC) do not show CLIC1-associated chloride permeability, and inhibition of CLIC1 protein function has no influence on MSC cell-cycle progression. Investigation of the basic functions of GB CSCs reveals a constitutive state of oxidative stress and cytoplasmic alkalinization compared with MSCs. Both intracellular oxidation and cytoplasmic pH changes have been reported to affect CLIC1 membrane functional expression. We now report that in CSCs these three elements are temporally linked during CSC G1-S transition. Impeding CLIC1-mediated chloride current prevents both intracellular ROS accumulation and pH changes. CLIC1 membrane functional impairment results in GB CSCs resetting from an allostatic tumorigenic condition to a homeostatic steady state. In contrast, inhibiting NADPH oxidase and NHE1 proton pump results in cell death of both GB CSCs and MSCs. Our results show that CLIC1 membrane protein is crucial and specific for GB CSC proliferation, and is a promising pharmacologic target for successful brain tumor therapies. Mol Cancer Ther; 17(11); 2451-61. ©2018 AACR.


Next-generation sequencing reveals cryptic mtDNA diversity of Plasmodium relictum in the Hawaiian Islands.
Next-generation 454 sequencing techniques were used to re-examine diversity of mitochondrial cytochrome b lineages of avian malaria (Plasmodium relictum) in Hawaii. We document a minimum of 23 variant lineages of the parasite based on single nucleotide transitional changes, in addition to the previously reported single lineage (GRW4). A new, publicly available portal (Integroomer) was developed for initial parsing of 454 datasets. Mean variant prevalence and frequency was higher in low elevation Hawaii Amakihi (Hemignathus virens) with Avipoxvirus-like lesions (P = 0·001), suggesting that the variants may be biologically distinct. By contrast, variant prevalence and frequency did not differ significantly among mid-elevation Apapane (Himatione sanguinea) with or without lesions (P = 0·691). The low frequency and the lack of detection of variants independent of GRW4 suggest that multiple independent introductions of P. relictum to Hawaii are unlikely. Multiple variants may have been introduced in heteroplasmy with GRW4 or exist within the tandem repeat structure of the mitochondrial genome. The discovery of multiple mitochondrial lineages of P. relictum in Hawaii provides a measure of genetic diversity within a geographically isolated population of this parasite and suggests the origins and evolution of parasite diversity may be more complicated than previously recognized.


Modeling the Human Bone-Tumor Niche: Reducing and Replacing the Need for Animal Data.
Bone is the most common site for cancer metastasis. Understanding the interactions within the complex, heterogeneous bone-tumor microenvironment is essential for the development of new therapeutics. Various animal models of tumor-induced bone disease are routinely used to provide valuable information on the relationship between cancer cells and the skeleton. However, new model systems exist that offer an alternative approach to the use of animals and might more accurately reveal the cellular interactions occurring within the human bone-tumor niche. This review highlights replacement models that mimic the bone microenvironment and where cancer metastases and tumor growth might be assessed alongside bone turnover. Such culture models include the use of calcified regions of animal tissue and scaffolds made from bone mineral hydroxyapatite, synthetic polymers that can be manipulated during manufacture to create structures resembling trabecular bone surfaces, gel composites that can be modified for stiffness and porosity to resemble conditions in the tumor-bone microenvironment. Possibly the most accurate model system involves the use of fresh human bone samples, which can be cultured ex vivo in the presence of human tumor cells and demonstrate similar cancer cell-bone cell interactions as described in vivo. In addition, the use of mathematical modeling and computational biology approaches provide an alternative to preliminary animal testing. The use of such models offers the capacity to mimic significant elements of the human bone-tumor environment, and complement, refine, or replace the use of preclinical models. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.


Topical Desoximetasone 0.25% Spray and Its Vehicle Have Little Potential for Irritation or Sensitization.

BACKGROUND: Topical corticosteroids are the most common dermatologic medications and are available in numerous different vehicles. Adherence is limited by traditional vehicles because they are messy and time consuming to apply. The preferred spray formulations have the advantage of being applied with ease, resulting in improved adherence and subsequently improved psoriasis. One limitation of topical treatments, especially spray vehicles, is the potential for irritation and sensitization.

OBJECTIVE: To evaluate the irritation and sensitization potential of topical desoximetasone spray formulation.

METHODS: A multicenter, double-blinded, randomized, controlled study assessed the irritancy and sensitization of 0.25% and 0.05% topical desoximetasone spray. Controls included vehicle, a positive control (0.1% sodium lauryl sulfate), negative control (0.9% saline), and an active comparator control (clobetasol spray). The primary outcome of the study was to evaluate the difference in mean cumulative irritation and potential sensitization response of desoximetasone 0.25% and 0.05% topical sprays.

RESULTS: Of the 297 enrolled, 269 completed the study per protocol for the irritation phase and 250 completed the protocol for the sensitization phase. At 22 days, desoximetasone 0.25 and 0.5% spray were less irritating than clobetasol 0.05% spray; mean irritation score difference of -0.46 and -0.57, respectively. Median total irritation score over the 22 days was 0 for all products. No subjects demonstrated any sensitization reaction to any of the six products. No serious adverse reactions were reported.

LIMITATIONS: Selection bias, use of a healthy population, limits the external validity. In addition, the duration of the study was short lived, unlike numerous inflammatory skin diseases. Desoximetasone spray has little potential for irritation or sensitization. The availability of another spray option for patients desiring less messy treatment may facilitate better adherence and treatment outcomes.

J Drugs Dermatol. 2017;16(8):755-758.
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Genome sequence of Shimia str. SK013, a representative of the Roseobacter group isolated from marine sediment.
Shimia strain SK013 is an aerobic, Gram-negative, rod shaped alphaproteobacterium affiliated with the Roseobacter group within the family Rhodobacteraceae. The strain was isolated from surface sediment (0-1 cm) of the Skagerrak at 114 m below sea level. The 4,049,808 bp genome of Shimia str. SK013 comprises 3,981 protein-coding genes and 47 RNA genes. It contains one chromosome and no extrachromosomal elements. The genome analysis revealed the presence of genes for a dimethylsulfoniopropionate lyase, demethylase and the trimethylamine methyltransferase (mttB) as well as genes for nitrate, nitrite and dimethyl sulfoxide reduction. This indicates that Shimia str. SK013 is able to switch from aerobic to anaerobic metabolism and thus is capable of aerobic and anaerobic sulfur cycling at the seafloor. Among the ability to convert other sulfur compounds it has the genetic capacity to produce climatically active dimethyl sulfide. Growth on glutamate as a sole carbon source results in formation of cell-connecting filaments, a putative phenotypic adaptation of the surface-associated strain to the environmental conditions at the seafloor. Genome analysis revealed the presence of a flagellum (fla1) and a type IV pilus biogenesis, which is speculated to be a prerequisite for biofilm formation. This is also related to genes responsible for signalling such as N-acyl homoserine lactones, as well as quip-genes responsible for quorum quenching and antibiotic biosynthesis. Pairwise similarities of 16S rRNA genes (98.56 % sequence similarity to the next relative S. haliotis) and the in silico DNA-DNA hybridization (21.20 % sequence similarity to S. haliotis) indicated Shimia str. SK013 to be considered as a new species. The genome analysis of Shimia str. SK013 offered first insights into specific physiological and phenotypic adaptation mechanisms of Roseobacter-affiliated bacteria to the benthic environment.


Stress, depression and fibromyalgia.
There is increasing evidence that stress and depression may play a crucial role in the aetiology and pathophysiology of fibromyalgia (FM). We first review recent studies on the possible role of life stress, including childhood trauma, in FM. Subsequently we focus on clinical and aetio-pathogenetic links between stress, depression and pain. We put forward the hypothesis that chronic stress/depression may contribute to a dysregulation of neuro-endocrine, immune and central pain mechanisms in FM. Finally, we discuss some future directions, including the use of new conceptual models, research topics and strategies, as well as potential implications from recent studies in affective disorders for the treatment of FM.


The Schizosaccharomyces pombe rec16 gene product regulates multiple meiotic events.
Previously isolated meiotic recombination (rec) mutants of Schizosaccharomyces pombe define 16 complementation groups. The rec genes cloned and sequenced to date reveal little amino acid sequence identity to other reported proteins. We examined the rec mutants for alterations in meiotic events other than recombination to gain insight into the rec gene functions and to assess whether they affect recombination directly or indirectly. While mutations in the rec6-12, 14, 15 and 19 genes appeared to affect only meiotic recombination, a mutation in rec16 delayed meiotic DNA synthesis and, in some instances, reduced its amount; mitotic DNA synthesis was not detectably altered, indicating that the rec16 effect is limited to meiosis. In the rec16 mutant some meiotically induced transcripts (e.g., rec7 and 15) were significantly reduced in abundance, whereas others (e.g., rec10 and exo1) were induced and degraded with normal timing and extent during meiosis, indicating that the rec16 mutation leaves the basic meiotic program intact. These results indicate that the rec genes other than rec16 have their primary effect on meiotic recombination. In contrast, the rec16 gene product is essential for normal meiotic replication, recombination, and induction of some transcripts. These meiotic events may be coupled via a dependence of recombination and transcription on replication or via a cascade of gene expression.


Stratified prevention: opportunities and limitations. Report on the 1st interdisciplinary cardiovascular workshop in Augsburg.
Sufficient exercise and sleep, a balanced diet, moderate alcohol consumption and a good approach to handle stress have been known as lifestyles that protect health and longevity since the Middle Age. This traditional prevention quintet, turned into a sextet by smoking cessation, has been the basis of the "preventive personality" that formed in the twentieth century. Recent analyses of big data sets including genomic and physiological measurements have unleashed novel opportunities to estimate individual health risks with unprecedented accuracy, allowing to target preventive interventions to persons at high risk and at the same time to spare those in whom preventive measures may not be needed or even be harmful. To fully grasp these opportunities for modern preventive medicine, the established healthy life styles require supplementation by stratified prevention. The opportunities of these developments for life and health contrast with justified concerns: A "surveillance society", able to predict individual behaviour based on big data, threatens individual freedom and jeopardises equality. Social insurance law and the new German Disease Prevention Act (Präventionsgesetz) rightly stress the need for research to underpin stratified prevention which is accessible to all, ethical, effective, and evidence based. An ethical and acceptable development of stratified prevention needs to start with autonomous individuals who control and understand all information pertaining to their health. This creates a mandate for lifelong health education, enabled in an individualised form by digital technology. Stratified prevention furthermore requires the evidence-based development of a new taxonomy of cardiovascular diseases that reflects disease mechanisms. Such interdisciplinary research needs broad support from society and a better use of biosamples and data sets within an updated research governance framework.


Full-range, complex spatial light modulator for real-time holography.
We demonstrate a full-range complex and transmissive spatial light modulator (SLM) for simultaneous and independent amplitude and phase modulation of an input wave field. Arbitrary scalar complex optical fields are generated by stacking a pixelated liquid crystal display operating in phase-only (2π) modulation with passive polarization-sensitive components. The principle is based on optical combining the light fields of two neighboring phase-only modulating pixels, which were made orthogonally polarized by a structured half-wave plate, then passing through a birefringent plate to laterally shift one of the beams collinear to the other, and finally bringing to interference by a linear polarizer. Complex modulation by the proposed SLM is experimentally verified in monochrome green operation.


Anomalous electroless deposition of less noble metals on Cu in ionic liquids and its application towards battery electrodes.
Electroless deposition can be triggered by the difference in the redox potentials between two metals in an electrolyte. In aqueous electrochemistry, galvanic displacement takes place according to the electrochemical series wherein a more noble metal can displace a less noble metal. Herein we show anomalous behaviour in ionic liquids wherein less noble metals such as Fe and Sb were deposited on Cu at temperatures from 25 to 60 °C. Fe formed spherical structures whereas Cu2Sb/Sb formed nanoplates. A multistep process during the electroless deposition of Sb on Cu took place which was discerned from in situ XPS, and mass spectrometry. In situ AFM was also used to understand the nucleation and growth process of the galvanic displacement reaction. Subsequently, the Cu2Sb/Sb nanoplates were also tested as the anode for both Li-ion and Na-ion batteries. Thus, it is shown that the electrochemistry in ionic liquids significantly differs from aqueous electrolytes and opens up new routes for material synthesis.


A New Approach Using AHP to Generate Landslide Susceptibility Maps in the Chen-Yu-Lan Watershed, Taiwan.
This paper proposes a new approach of using the analytic hierarchy process (AHP), in which the AHP was combined with bivariate analysis and correlation statistics to evaluate the importance of the pairwise comparison. Instead of summarizing expert experience statistics to establish a scale, we then analyze the correlation between the properties of the related factors with the actual landslide data in the study area. In addition, correlation and dependence statistics are also used to analyze correlation coefficients of preparatory factors. The product of this research is a landslide susceptibility map (LSM) generated by five factors (slope, aspect, drainage density, lithology, and land-use) and pre-event landslides (Typhoon Kalmaegi events), and then validated by post-event landslides and new landslides occurring in during the events (Typhoon Kalmaegi and Typhoon Morakot). Validating the results by the binary classification method showed that the model has reasonable accuracy, such as 81.22% accurate interpretation for post-event landslides (Typhoon Kalmaegi), and 70.71% exact predictions for new landslides occurring during Typhoon Kalmaegi.


The first near-complete assembly of the hexaploid bread wheat genome, Triticum aestivum.
Common bread wheat, Triticum aestivum, has one of the most complex genomes known to science, with 6 copies of each chromosome, enormous numbers of near-identical sequences scattered throughout, and an overall haploid size of more than 15 billion bases. Multiple past attempts to assemble the genome have produced assemblies that were well short of the estimated genome size. Here we report the first near-complete assembly of T. aestivum, using deep sequencing coverage from a combination of short Illumina reads and very long Pacific Biosciences reads. The final assembly contains 15 344 693 583 bases and has a weighted average (N50) contig size of 232 659 bases. This represents by far the most complete and contiguous assembly of the wheat genome to date, providing a strong foundation for future genetic studies of this important food crop. We also report how we used the recently published genome of Aegilops tauschii, the diploid ancestor of the wheat D genome, to identify 4 179 762 575 bp of T. aestivum that correspond to its D genome components.


An in vitro study on effect of Delmopinol application on Candida albicans adherence on heat cured denture base acrylic resin: a thorough study.
Denture-related stomatitis is probably the most common form of oral candidiasis and its reported prevalence varies widely ranging up to 65%. In this thorough study, we evaluate the effect of Delmopinol application on Candida albicans adherence on heat cured denture base acrylic resin. A total of 40 specimens of heat-cured acrylic resin were made, 20 specimens were contaminated before Delmopinol treatment and 20 specimens were contaminated after Delmopinol treatment. The each specimen in each tube was individually transferred to a spectrophotometer at 530 nm wavelength in order to measure the turbidity degree, through the transmittance. Aliquots of 10 μL of each tube was then collected and inoculated into agar sabouraud plates containing 500 mMol/L of sucrose, which was incubated for 24 hours at 37°C, in order to check microbial growth. Mean of the turbidity Degree of contamination after Delmopinol application (1440.80, colony-forming unit [CFU] [×10 6 /ml]) was significantly higher than the mean of the turbidity degree of contamination before Delmopinol application (550.85 CFU [×10 6 /ml]). Heat-cured acrylic resin shows greater reduction in adherence of Candida albicans by contamination after Delmopinol application as compared with contamination before Delmopinol application.


A General Statistical Method for Identifying Adaptations by Parameterizing Trait Space.
It is obviously useful to think of evolved individuals in terms of their adaptations, yet the task of empirically classifying traits as adaptations has been claimed by some to be impossible in principle. I reject that claim by construction, introducing a formal method to empirically test whether a trait is an adaptation. The method presented is general, intuitive, and effective at identifying adaptations while remaining agnostic about their adaptive function. The test follows directly from the notion that adaptations arise from variation, heritability, and differential fitness in an evolving population: I operationalize these three concepts at the trait level, formally defining measures of individual traits. To test whether a trait is an adaptation, these measures are evaluated, locating the trait within a three-dimensional parameterized trait space. Within this space, I identify a region containing all adaptations; a trait's position relative to this adaptive region of trait space describes its status as an adaptation. The test can be applied in any evolving system where a few domain-specific statistical measures can be constructed; I demonstrate the construction of these measures, most notably a measure of an individual's hypothetical fitness if it were born with a different trait, in Packard's Bugs ALife model. The test is applied in Bugs, and shown to conform with our intuitive classification of adaptations.


Biomarkers obtained by non-invasive methods in patients with COPD: where do we stand, what do we expect?
Recently, there has been widespread interest in the use of non-invasive methods for the assessment of airway inflammation in a variety of lung diseases including chronic obstructive pulmonary disease (COPD). Sputum induction is a semi-invasive technique the value of which is not restricted to sputum cell counts, as inflammatory mediators can also be measured in the supernatants. However, none of the measurable biomarkers in induced sputum is considered applicable in clinical practice. Despite the predominating sputum neutrophilia, there is increasing evidence that the presence of sputum eosinophilia predicts an objective response to steroid treatment in patients with COPD. The commonly used Exhaled Breath Condensate (EBC) methodologies in COPD patients have considerable variability due to technical issues concerning both sample collection and analysis. Despite the above limitations, biomarkers mainly related to neutrophil derived products and oxidative stress, have been assessed for disease monitoring and response to pharmacological treatment. Endogenous airway acidification, as assessed by EBC pH, represents a measurable marker associated with oxidative stress and sputum neutrophilia. The fraction of exhaled nitric oxide (FeNO) is the most extensively studied exhaled biomarker and increased levels of FeNO have been widely documented in patients with asthma. FeNO measurement in COPD is of limited value due to smoking effect. However, increased values of FeNO have been found in COPD patients with sputum eosinophila. Moreover, measuring FeNO in different exhalation rates may reestablish its value in COPD. Despite the limited use of non-invasive methods, the future direction is a challenge towards new biomarkers or a combination of them that will assist us to move from the research laboratory to daily clinical practice.


Association of human papillomavirus with Fanconi anemia promotes carcinogenesis in Fanconi anemia patients.
Fanconi anemia (FA) is a rare recessive disorder associated with chromosomal fragility. FA patients are at very high risk of cancers, especially head and neck squamous cell carcinomas and squamous cell carcinomas caused by infection of human papillomaviruses (HPVs). By integrating into the host genome, HPV oncogenes E6 and E7 drive the genomic instability to promote DNA damage and gene mutations necessary for carcinogenesis in FA patients. Furthermore, E6 and E7 oncoproteins not only inhibit p53 and retinoblastoma but also impair the FANC/BRCA signaling pathway to prevent DNA damage repair and alter multiple signals including cell-cycle checkpoints, telomere function, cell proliferation, and interference of the host immune system leading to cancer development in FA patients. In this review, we summarize recent advances in unraveling the molecular mechanisms of FA susceptibility to HPV-induced cancers, which facilitate rational preventive and therapeutic strategies.


A neural network model of mathematics anxiety: The role of attention.
Anxiety about performing numerical calculations is becoming an increasingly important issue. Termed mathematics anxiety, this condition negatively impacts performance in numerical tasks which can affect education outcomes and future employment. The disruption account proposes poor performance is due to anxiety disrupting limited attentional and inhibitory resources leaving fewer cognitive resources for the current task. This study provides the first neural network model of math anxiety. The model simulates performance in two commonly-used tasks related to math anxiety: the numerical Stroop and symbolic number comparison. Different model modifications were used to simulate high and low math-anxious conditions by modifying attentional processes and learning; these model modifications address different theories of math anxiety. The model simulations suggest that math anxiety is associated with reduced attention to numerical stimuli. These results are consistent with the disruption account and the attentional control theory where anxiety decreases goal-directed attention and increases stimulus-driven attention.


Posttraumatic stress disorders in civilian orthopaedics.
Posttraumatic stress disorder (PTSD) is a well-characterized anxiety disorder that may occur after exposure to a traumatic event. Research is ongoing to document neuroanatomic, neuroendocrine, and genetic correlates to the behavioral phenotype. PTSD occurs in 20% to 51% of patients with musculoskeletal injury. Orthopaedic outcomes, including return to work, activities of daily living, patient perception of physical recovery, and objective physical parameters, suffer considerably in patients with PTSD. There are several ways by which treating orthopaedic surgeons can recognize at-risk patients and help prevent the development of PTSD. Should prevention prove unsuccessful, effective treatment strategies exist, as well. Research is needed to investigate whether a correlation exists between successful management of the psychiatric manifestations of PTSD and improved physical outcomes.


Occupational lead exposure in Finland. VI. Final report.
Between 1970 and 1973, 2,209 workers representing 30 different types of work were studied in Finland for lead exposure. The indicator of lead exposure was the blood lead concentrations (Pb-B) of the workers. The highest recommended value for Pb-B in Finland, 70 mug/100 ml of blood, was exceeded in the following types of work: PVC plastic manufacturing, storage tank manufacturing and repairing, machine shop work, treating metal surfaces, paint manufacturing, car radiator repairing, spray painting, machine shop work (railway), and storage battery repair. The types of work with the highest average exposure were lead scrap smelting (Pb-B median 79 mug/100 ml, range 35--118), storage battery manufacturing (Pb-B median 66 mug/100 ml, range 19--101), metal founding, (Pb-B median 53 mug/100 ml, range 6--108) shipbreaking (Pb-B median 49 mug/100 ml, range 26--106) crystal glass manufacturing (Pb-B median 41 mug/100 ml, range 12--82), car radiator repairing (Pb-B median 38 mug/100 ml, range 17--83), and PVC plastic manufacturing (Pb-B median 37 mug/100 ml, range 10--126). During the past 5 years cases of clincial lead poisoning have occurred in all of these types of work, and the patients received workmen's compensation. The usefulness of the national poisoning register in predicting the relative hazard of lead exposure in the types of work studied was evaluated with the aid of rank order correlation statistics. The analysis showed that the poisoning register is a useful indicator of lead exposure in the most exposed types of work. However, the present survey also revealed work in which the hazard had escaped recognition in this country: metal founding, car repairing, and car radiator repairing, for example. Although it seems possible to predict the most heavily exposed work types from national poisoning registers only, the detection of workers with less severe manifestations of toxic effects, or somtimes even poisoning, in other types of work first requires a systematic survey of all types of work with possible lead exposure, and then regular monitoring of all exposed workers.


Development of larval Schistosoma japonicum blocked in Oncomelania hupensis by pre-infection with larval Exorchis sp.
Schistosomiasis continues to be a significant public health threat in the world. In the area of parasitic diseases, it is widely considered second only to malaria as a global health problem, with an incalculable drain on the economic resources of countries where it is endemic. Schistosoma japonicum is widespread in eastern and southeastern Asia, where the amphibious snail, Oncomelania hupensis, is the intermediate host. In the present study, we found that infection of O. hupensis with the mature eggs of another trematode, Exorchis sp., inhibited development of S. japonicum mother sporocysts in O. hupensis. Exorchis sp. commonly infects the edible fish Parasilurus asotus in China, but it is harmless to humans. This discovery provides an opportunity for possible biological control of S. japonicum infection and transmission. Additionally, it has the potential to substantially reduce the impact of the global S. japonicum that is independent of antihelminthic use. The mechanisms used by Exorchis sp. to inhibit infection by S. japonicum in the snail require further investigation.


Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb.
Progression of the eukaryotic cell division cycle is regulated by a series of structurally related serine/threonine protein kinases known as cyclin-dependent kinases (CDKs). The D-type cyclin-dependent kinases, CDK4 and CDK6, have been strongly implicated in the control of G1 progression and the phosphorylation of the retinoblastoma protein, pRb. The formation of complexes and enzymatic activity of cyclin D-CDK4 and cyclin D-CDK6 kinases is negatively regulated by p16INK4 (MTS1/CDK4I/CDKN2) via its specific interaction with CDK4 and CDK6 catalytic subunits. Here we report that the p16 mRNA accumulates to a high level in cells lacking pRb function and transcription of p16 is repressed by pRb. Our results provide evidence supporting a feedback regulatory loop involving pRb, p16, and cyclin-dependent kinases.


Distinct transcriptional programs activated by interleukin-10 with or without lipopolysaccharide in dendritic cells: induction of the B cell-activating chemokine, CXC chemokine ligand 13.
To understand the modulation of dendritic cell (DC) function by IL-10, gene expression profiling was performed by using Affymetrix technology (Santa Clara, CA) in human monocyte-derived DC treated with IL-10, alone or in combination with LPS. The modulation of selected genes was validated by real-time PCR, Northern blot, and protein production. IL-10 regulated in DC the expression of a limited number of genes, including IL-7, the receptors for transferrin and vitamin D(3), structural matrix proteins, and signal transduction elements. The combined treatment with LPS plus IL-10 modulated a number of genes comparable to LPS alone, but the expression profiles were distinct. As expected, IL-10 suppressed the expression of several LPS-inducible proinflammatory molecules. Among genes uniquely modulated by the concomitant treatment with LPS plus IL-10, phosphatidylinositol 3-kinase gamma was down-regulated while the suppressor of cytokine signaling 3, signaling lymphocytic activation molecule, regulator of G protein signaling 16, and the chemokine, CXC chemokine ligand (CXCL) 13, were up-regulated. Overall, four distinct transcriptional programs were identified, related to: 1) control of immunity and inflammation; 2) tuning of cytokine receptor and G protein-coupled receptor signaling; 3) remodeling of extracellular matrix; and 4) B cell function and lymphoid tissue neogenesis. Among the latter genes, we further demonstrate that IL-10 synergizes with TLR ligands for the production of functionally active B cell-attracting chemokine, CXCL13, in both myeloid and plasmacytoid DC. This novel finding reveals that IL-10 sustains humoral immunity by inducing the production in APCs of the chemokine, CXCL13, which amplifies B cell recruitment and promotes lymphoid tissue neogenesis.


The role of wild canids and felids in spreading parasites to dogs and cats in Europe. Part I: Protozoa and tick-borne agents.
Over the last few decades, the world has witnessed radical changes in climate, landscape, and ecosystems. These events, together with other factors such as increasing illegal wildlife trade and changing human behaviour towards wildlife, are resulting into thinning boundaries between wild canids and felids and their domestic counterparts. As a consequence, the epidemiology of diseases caused by a number of infectious agents is undergoing profound readjustements, as pathogens adapt to new hosts and environments. Therefore, there is a risk for diseases of wildlife to spread to domestic carnivores and vice versa, and for zoonotic agents to emerge or re-emerge in human populations. Hence, the identification of the hazards arising from the co-habitation of these species is critical in order to plan and develop adequate control strategies against these pathogens. In the first of this two-part article, we review the role that wild canids and felids may play in the transmission of protozoa and arthropod-borne agents to dogs and cats in Europe, and provide an account of how current and future progress in our understanding of the ecology and epidemiology of parasites, as well as of host-parasite interactions, can assist efforts aimed at controlling parasite transmission.


Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr-/- mice.
Aortic calcification is prevalent in type II diabetes (T2DM), enhancing morbidity and tracking metabolic syndrome parameters. Ldlr(-/-) mice fed high-fat "Westernized" diets (HFD) accumulate aortic calcium primarily in the tunica media, mediated via osteogenic morphogens and transcriptional programs that induce aortic alkaline phosphatase (ALP). Because elevated TNF-alpha is characteristic of obesity with T2DM, we examined contributions of this inflammatory cytokine. HFD promoted obesity, hyperglycemia, and hyperlipidemia, and upregulated serum TNF-alpha in Ldlr(-/-) mice. Serum haptoglobin (inflammatory marker) was increased along with aortic expression of BMP2, Msx2, Wnt3a, and Wnt7a. Dosing with the TNF-alpha neutralizing antibody infliximab did not reduce obesity, hypercholesterolemia, or hyperglycemia; however, haptoglobin, aortic BMP2, Msx2, Wnt3a, and Wnt7a and aortic calcium accumulation were downregulated by infliximab. Mice with vascular TNF-alpha augmented by a transgene (SM22-TNFalphaTg) driven from the SM22 promoter upregulated aortic Msx2, Wnt3a, and Wnt7a. Furthermore, SM22-TNFalphaTg;TOPGAL mice exhibited greater aortic beta-galactosidase reporter staining versus TOPGAL sibs, indicating enhanced mural Wnt signaling. In aortic myofibroblast cultures, TNF-alpha upregulated Msx2, Wnt3a, Wnt7a, and ALP. ALP induction was inhibited by Dkk1, an antagonist of paracrine Wnt actions. TNF-alpha promote aortic Msx2-Wnt programs that contribute to aortic calcium accumulation in T2DM.


Neurologic sequelae associated with foscarnet therapy.
To report three cases of possible foscarnet-induced neurologic sequelae. We report two cases of seizures and one case of hand cramping and finger paresthesia after starting foscarnet therapy with no evidence of predisposing risk factors, such as serum laboratory abnormalities, renal dysfunction, or known central nervous system (CNS) involvement. All three patients had stable laboratory values during therapy and when the neurologic adverse effects occurred. All patients were receiving appropriate dosages of foscarnet. The incidence of seizures in AIDS patients was reviewed. A history of CNS lesions, infections, and/or AIDS per se may increase the risk of a neurologic adverse effect while receiving foscarnet therapy. Acute ionized hypocalcemia may cause these neurologic adverse effects. Ionized hypocalcemia is transitory, is related to the rate of foscarnet infusion, and may not be reflected as a change in total serum calcium concentration. Foscarnet probably contributed to the neurologic adverse effects reported here. Foscarnet may need to be administered at a slower rate than is recommended by the manufacturer. Electrolytes must be monitored closely; however, a neurologic adverse effect may not be foreseen.


Cathepsins in the osteoclast.
The mechanism by which bone collagen and other organic components are degraded by the osteoclast during osteoclastic bone resorption was unclear until the 1980s. Studies conducted since the early 1990s have identified lysosomal proteases, mainly cathepsins that are active at low pH, involved in osteoclastic bone resorption. Several cathepsins, such as cathepsins C, D, B, E, G and L, were initially demonstrated to take part in the degradation of organic bone matrix in osteoclasts. Cathepsin K, which has high proteolytic activity and localizes primarily in osteoclasts, was discovered in 1995. This first tissue-specific cathepsin was associated with pycnodysostosis, a genetic disorder observable as an osteopetrotic phenotype in cathepsin K-deficient mice. Cystatin C, an endogenous inhibitor of cysteine proteases, regulates the activity of cathepsin K. However, detailed morphological observations suggest that the organic bone matrix is degraded by not only cathepsin K, but also by matrix metalloproteinases or other cathepsins. The osteoclast possesses a unique endocytotic/exocytotic structure and each cathepsin is specifically localized in the osteoclast, which implies that each cathepsin contributes cooperatively to the process of osteoclastic bone resorption. Further studies may clarify the regulation of cathepsin activities and the roles of cathepsins during bone remodelling.


Serological and molecular survey of hepatitis E virus in cats and dogs in Spain.
Hepatitis E virus (HEV) is an emerging zoonotic pathogen that is currently recognized as one of the major causes of acute human hepatitis worldwide. In Europe, the increasing number of hepatitis E cases is mainly associated with the consumption of animal food products or contact with infected animals. Dogs and cats have been suggested as a zoonotic source of HEV infection. The aim of this study was to assess Orthohepevirus circulation, including HEV-A, HEV-B and HEV-C species, in sympatric urban cats and dogs in southern Spain. Between 2017 and 2020, blood samples were collected from 144 stray cats and 152 dogs, both strays and pets. The presence of antibodies against HEV were tested using a double-antigen sandwich ELISA and seropositive samples were further analysed by western blot. A RT-PCR was performed to detect RNA of Orthohepevirus species (HEV-A, HEV-B and HEV-C). A total of 19 (6.4%; 95%CI: 3.6-9.2) of the 296 animals tested showed anti-HEV antibodies by ELISA. Seropositivity was significantly higher in dogs (9.9%; 15/152; 95%CI: 5.1-14.6) than in cats (2.8%; 4/144; 95%CI: 0.1-5.5). Ten of the 18 ELISA-positive animals that could be further analysed by western blot, reacted against HEV-3 and/or HEV-C1 antigens, which suggest circulation of both genotypes in urban cats and dogs in the study area. However, HEV-A, HEV-B and HEV-C RNA were not detected in any of the tested sera. This is the first study to assess HEV circulation in both stray cats and dogs in Europe. Our results provide evidence of HEV exposure in sympatric urban cat and dog populations in southern Spain. Further studies are needed to determine the role of these species in the epidemiology of HEV.


Familial perisylvian polymicrogyria: a new familial syndrome of cortical maldevelopment.
Two familial X-linked dominant syndromes of cortical maldevelopment have recently been described: double cortex/lissencephaly syndrome and bilateral periventricular nodular heterotopia. We report on 12 kindreds with familial perisylvian polymicrogyria (FPP) presenting at 10 centers, examine the clinical presentation in these familial cases, and propose a possible mode of inheritance. The clinical and radiological pattern was variable among the 42 patients, with clinical differences among the families and even within members of the same family. Pseudobulbar signs, cognitive deficits, epilepsy, and perisylvian abnormalities on imaging studies were not found in all patients. When present, they displayed a spectrum of severity. The only clear correlation in this study was between bilateral imaging findings and abnormal tongue movements and/or pronounced dysarthria. Most of the families provided evidence suggestive of, or compatible with, X-linked transmission. On the other hand, the pedigrees of 2 families ruled out X-linked inheritance. The most likely mode of inheritance for these 2 families was autosomal dominant with decreased penetrance; however, autosomal recessive inheritance with pseudodominance could not be ruled out in 1 family. We conclude that FPP appears to be genetically heterogeneous. However, most of the families probably represent a third previously undescribed X-linked syndrome of cortical maldevelopment.


TNFalpha-stimulated gene product (TSG-6) and its binding protein, IalphaI, in the human intervertebral disc: new molecules for the disc.
Inflammation and irritation of the nerve roots has been indicated as an important factor in the pain associated with symptomatic disc herniations. Tumour necrosis factor alpha (TNFalpha) is now believed to be involved in this pathway. TNFalpha causes connective tissue cells in culture to synthesise a glycoprotein, TNFalpha-stimulated gene-6 (TSG-6). TSG-6 is found in inflammatory diseases of related connective tissues, such as articular cartilage in rheumatoid arthritis, but is not present in unaffected individuals. In order to determine if TSG-6 occurred in intervertebral disc (and cartilage endplate), we have investigated the presence of TSG-6 and its binding protein, inter-alpha-inhibitor (IalphaI), in 58 herniated and 15 non-herniated discs. Immunostaining for the cytokines, IL-1alpha, IL-1beta and TNFalpha, has also been carried out. We have demonstrated that both TSG-6 and IalphaI occur commonly in human intervertebral disc matrix with at least some TSG-6 in 98% of discs studied and IalphaI in all of them. Staining for TSG-6 was greatest in herniated discs, particularly close to blood vessels. IalphaI immunostaining was frequently widespread throughout the disc but there was little in the cartilage endplate. It has been proposed that these molecules have widespread effects, including extracellular matrix stabilisation, down-regulation of the protease network and reduction of inflammation. Hence, the occurrence of TSG-6 and IalphaI in disc tissue could have implications in the aetiopathogenesis and future therapeutics of intervertebral disc disease.


Overexpression of a pH-sensitive nitrate transporter in rice increases crop yields.
Cellular pH homeostasis is fundamental for life, and all cells adapt to maintain this balance. In plants, the chemical form of nitrogen supply, nitrate and ammonium, is one of the cellular pH dominators. We report that the rice nitrate transporter OsNRT2.3 is transcribed into two spliced isoforms with a natural variation in expression ratio. One splice form, OsNRT2.3b is located on the plasma membrane, is expressed mainly in the phloem, and has a regulatory motif on the cytosolic side that acts to switch nitrate transport activity on or off by a pH-sensing mechanism. High OsNRT2.3b expression in rice enhances the pH-buffering capacity of the plant, increasing N, Fe, and P uptake. In field trials, increased expression of OsNRT2.3b improved grain yield and nitrogen use efficiency (NUE) by 40%. These results indicate that pH sensing by the rice nitrate transporter OsNRT2.3b is important for plant adaption to varied N supply forms and can provide a target for improving NUE.


Nitrogen cycling responses to mountain pine beetle disturbance in a high elevation whitebark pine ecosystem.
Ecological disturbances can significantly affect biogeochemical cycles in terrestrial ecosystems, but the biogeochemical consequences of the extensive mountain pine beetle outbreak in high elevation whitebark pine (WbP) (Pinus albicaulis) ecosystems of western North America have not been previously investigated. Mountain pine beetle attack has driven widespread WbP mortality, which could drive shifts in both the pools and fluxes of nitrogen (N) within these ecosystems. Because N availability can limit forest regrowth, understanding how beetle-induced mortality affects N cycling in WbP stands may be critical to understanding the trajectory of ecosystem recovery. Thus, we measured above- and belowground N pools and fluxes for trees representing three different times since beetle attack, including unattacked trees. Litterfall N inputs were more than ten times higher under recently attacked trees compared to unattacked trees. Soil inorganic N concentrations also increased following beetle attack, potentially driven by a more than two-fold increase in ammonium (NH₄⁺) concentrations in the surface soil organic horizon. However, there were no significant differences in mineral soil inorganic N or soil microbial biomass N concentrations between attacked and unattacked trees, implying that short-term changes in N cycling in response to the initial stages of WbP attack were restricted to the organic horizon. Our results suggest that while mountain pine beetle attack drives a pulse of N from the canopy to the forest floor, changes in litterfall quality and quantity do not have profound effects on soil biogeochemical cycling, at least in the short-term. However, continuous observation of these important ecosystems will be crucial to determining the long-term biogeochemical effects of mountain pine beetle outbreaks.


Functional characteristics of NaS2, a placenta-specific Na+-coupled transporter for sulfate and oxyanions of the micronutrients selenium and chromium.
NaS2 is a Na+-coupled transporter for sulfate that belongs to the SLC13 gene family. This transporter was originally cloned from high endothelial venule endothelial cells, but nothing is known about the functional characteristics of this transporter except that it transports sulfate in a Na+-coupled manner. Northern blot analysis indicates that NaS2 is expressed most robustly in placenta. In the present study, we cloned NaS2 from rat placenta and characterized its transport function in detail using the Xenopus laevis oocyte expression system. Rat NaS2 consists of 629 amino acids and is highly similar to human NaS2. In situ hybridization studies with mouse placental sections show that NaS2 transcripts are expressed primarily in trophoblasts of the labyrinth zone. The expression of the transporter is confirmed in primary cultures of trophoblasts isolated from human placenta. When expressed in X. laevis oocytes, rat NaS2 mediates Na+-coupled transport of sulfate. The transport of sulfate is inhibited by oxyanions of selenium, chromium, arsenic, molybdenum, and phosphorous, suggesting that the transporter may mediate the transport of these oxyanions in addition to sulfate. The Kt for sulfate is 153+/-30 microM and the Na+:sulfate stoichiometry is 3:1. The transport process is electrogenic as evidenced from the inhibition of the uptake process by K+-induced depolarization. We conclude that NaS2 is a placenta-specific Na+-coupled, electrogenic, transporter for sulfate expressed in trophoblasts and that it is also responsible for the transport of oxyanions of the micronutrients selenium and chromium.


Field Resistance to Strobilurin (Q(o)I) Fungicides in Pyricularia grisea Caused by Mutations in the Mitochondrial Cytochrome b Gene.
ABSTRACT Gray leaf spot caused by Pyricularia grisea is a highly destructive disease of perennial ryegrass turf. Control of gray leaf spot is dependent on the use of preventative fungicide treatments. Strobilurin-based (Q(o)I) fungicides, which inhibit the cytochrome bc(1) respiratory complex, have proven to be very effective against gray leaf spot. However, in August 2000, disease was diagnosed in Q(o)I-treated perennial ryegrass turf on golf courses in Lexington, KY, Champaign, IL, and Bloomington, IL. To determine if resistance was due to a mutation in the fungicide target, the cytochrome b gene (CYTB) was amplified from baseline and resistant isolates. Nucleotide sequence analysis revealed an intronless coding region of 1,179 bp. Isolates that were resistant to Q(o)I fungicides possessed one of two different mutant alleles, each of which carried a single point mutation. The first mutant allele had a guanine-to-cytosine transition at nucleotide position +428, resulting in a replacement of glycine 143 by alanine (G143A). Mutant allele two exhibited a cytosine-to-adenine transversion at position +387, causing a phenylalanine-to-leucine change (F129L). Cleavable amplified polymorphic sequence analysis revealed that neither mutation was present in a collection of baseline isolates collected before Q(o)I fungicide use and indicated that suspected Q(o)I- resistant isolates found in 2001 in Indiana and Maryland possessed the F129L mutation. The Pyricularia grisea isolates possessing the G143A substitution were significantly more resistant to azoxystrobin and trifloxystrobin, in vitro, than those having F129L. DNA fingerprinting of resistant isolates revealed that the mutations occurred in just five genetic backgrounds, suggesting that field resistance to the Q(o)I fungicides in Pyricularia grisea is due to a small number of ancestral mutations.


Orientations of transfer RNA in the ribosomal A and P sites.
In protein synthesis, peptide bond formation requires that the tRNA carrying the amino acid (A site tRNA) contact the tRNA carrying the growing peptide chain (P site tRNA) at their 3' termini. Two models have been proposed for the orientations of two tRNAs as they would be bound to the mRNA in the ribosome. Viewing the tRNA as an upside down L, anticodon loop pointing down, acceptor stem pointing right, and calling this the front view, the R (Rich) model would have the back of the P site tRNA facing the front of the A site tRNA. In the S (Sundaralingam) model the front of the P site tRNA faces the back of the A site tRNA. Models of two tRNAs bound to mRNA as they would be positioned in the ribosomal A and P sites have been created using MC-SYM, a constraint satisfaction search program designed to build nucleic acid structures. The models incorporate information from fluorescence energy transfer experiments and chemical crosslinks. The models that best answer the constraints are of the S variety, with no R conformations produced consistent with the constraints.


Increased circulating stem cells and better cognitive performance in traumatic brain injury subjects following hyperbaric oxygen therapy.
Traumatic brain injury (TBI) may cause persistent cognitive dysfunction. A pilot clinical study was performed to determine if hyperbaric oxygen (HBO₂) treatment improves cognitive performance. It was hypothesized that stem cells, mobilized by HBO₂ treatment, are recruited to repair damaged neuronal tissue. This hypothesis was tested by measuring the relative abundance of stem cells in peripheral blood and cognitive performance during this clinical trial. The subject population consisted of 28 subjects with persistent cognitive impairment caused by mild to moderate TBI suffered during military deployment to Iraq or Afghanistan. Fluorescence-activated cell sorting (FACS) analysis was performed for stem cell markers in peripheral blood and correlated with variables resulting from standard tests of cognitive performance and post-traumatic stress disorder: ImPACT, BrainCheckers and PCL-M test results. HBO₂ treatment correlated with stem cell mobilization as well as increased cognitive performance. Together these results support the hypothesis that stem cell mobilization may be required for cognitive improvement in this population.


High SARS-CoV-2 Attack Rate Following Exposure at a Choir Practice - Skagit County, Washington, March 2020.
On March 17, 2020, a member of a Skagit County, Washington, choir informed Skagit County Public Health (SCPH) that several members of the 122-member choir had become ill. Three persons, two from Skagit County and one from another area, had test results positive for SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). Another 25 persons had compatible symptoms. SCPH obtained the choir's member list and began an investigation on March 18. Among 61 persons who attended a March 10 choir practice at which one person was known to be symptomatic, 53 cases were identified, including 33 confirmed and 20 probable cases (secondary attack rates of 53.3% among confirmed cases and 86.7% among all cases). Three of the 53 persons who became ill were hospitalized (5.7%), and two died (3.7%). The 2.5-hour singing practice provided several opportunities for droplet and fomite transmission, including members sitting close to one another, sharing snacks, and stacking chairs at the end of the practice. The act of singing, itself, might have contributed to transmission through emission of aerosols, which is affected by loudness of vocalization (1). Certain persons, known as superemitters, who release more aerosol particles during speech than do their peers, might have contributed to this and previously reported COVID-19 superspreading events (2-5). These data demonstrate the high transmissibility of SARS-CoV-2 and the possibility of superemitters contributing to broad transmission in certain unique activities and circumstances. It is recommended that persons avoid face-to-face contact with others, not gather in groups, avoid crowded places, maintain physical distancing of at least 6 feet to reduce transmission, and wear cloth face coverings in public settings where other social distancing measures are difficult to maintain.


Predictive representations can link model-based reinforcement learning to model-free mechanisms.
Humans and animals are capable of evaluating actions by considering their long-run future rewards through a process described using model-based reinforcement learning (RL) algorithms. The mechanisms by which neural circuits perform the computations prescribed by model-based RL remain largely unknown; however, multiple lines of evidence suggest that neural circuits supporting model-based behavior are structurally homologous to and overlapping with those thought to carry out model-free temporal difference (TD) learning. Here, we lay out a family of approaches by which model-based computation may be built upon a core of TD learning. The foundation of this framework is the successor representation, a predictive state representation that, when combined with TD learning of value predictions, can produce a subset of the behaviors associated with model-based learning, while requiring less decision-time computation than dynamic programming. Using simulations, we delineate the precise behavioral capabilities enabled by evaluating actions using this approach, and compare them to those demonstrated by biological organisms. We then introduce two new algorithms that build upon the successor representation while progressively mitigating its limitations. Because this framework can account for the full range of observed putatively model-based behaviors while still utilizing a core TD framework, we suggest that it represents a neurally plausible family of mechanisms for model-based evaluation.


Actin monoubiquitylation is induced in plants in response to pathogens and symbionts.
Most dramatic examples of actin reorganization have been described during host-microbe interactions. Plasticity of actin is, in part, due to posttranslational modifications such as phosphorylation or ubiquitylation. Here, we show for the first time that actins found in root nodules of Phaseolus vulgaris are modified transiently during nodule development by monoubiquitylation. This finding was extended to root nodules of other legumes and to other plants infected with mycorrhiza or plant pathogens such as members of the genera Pseudomonas and Phytophthora. However, neither viral infections nor diverse stressful conditions (heat shock, wounding, or osmotic stress) induced this response. Additionally, this phenomenon was mimicked by the addition of a yeast elicitor or H2O2 to Phaseolus vulgaris suspension culture cells. This modification seems to provide increased stability of the microfilaments to proteolytic degradation and seems to be found in fractions in which the actin cytoskeleton is associated with membranes. All together, these data suggest that actin monoubiquitylation may be considered an effector mechanism of a general plant response against microbes.


DSM-IV pathological gambling in the National Comorbidity Survey Replication.
Little is known about the prevalence or correlates of DSM-IV pathological gambling (PG). Data from the US National Comorbidity Survey Replication (NCS-R), a nationally representative US household survey, were used to assess lifetime gambling symptoms and PG along with other DSM-IV disorders. Age of onset (AOO) of each lifetime disorder was assessed retrospectively. AOO reports were used to study associations between temporally primary disorders and the subsequent risk of secondary disorders. Most respondents (78.4%) reported lifetime gambling. Lifetime problem gambling (at least one Criterion A symptom of PG) (2.3%) and PG (0.6%) were much less common. PG was significantly associated with being young, male, and Non-Hispanic Black. People with PG reported first gambling significantly earlier than non-problem gamblers (mean age 16.7 v. 23.9 years, z=12.7, p<0.001), with gambling problems typically beginning during the mid-20s and persisting for an average of 9.4 years. During this time the largest annual gambling losses averaged US$4800. Onset and persistence of PG were predicted by a variety of prior DSM-IV anxiety, mood, impulse-control and substance use disorders. PG also predicted the subsequent onset of generalized anxiety disorder, post-traumatic stress disorder (PTSD) and substance dependence. Although none of the NCS-R respondents with PG ever received treatment for gambling problems, 49.0% were treated at some time for other mental disorders. DSM-IV PG is a comparatively rare, seriously impairing, and undertreated disorder whose symptoms typically start during early adulthood and is frequently secondary to other mental or substance disorders that are associated with both PG onset and persistence.


Plasma and platelet free catecholamine concentrations in patients with familial hypercholesterolaemia.
1. Plasma and platelet free catecholamine concentrations were measured in 22 normal subjects and in 10 treated and 11 untreated patients with heterozygous familial hypercholesterolaemia. 2. Plasma noradrenaline concentrations were significantly higher in both treated and untreated hypercholesterolaemic patients than in normal subjects. Adrenaline concentrations did not differ. 3. Platelet noradrenaline levels were higher in untreated hypercholesterolaemic patients than in normal subjects. 4. Positive correlations between the plasma noradrenaline concentration and the platelet noradrenaline concentration were observed in both normal subjects and hypercholesterolaemic patients. 5. Combining the data for normal subjects and hypercholesterolaemic patients revealed that the plasma noradrenaline concentration correlated positively with the plasma cholesterol concentration. The platelet noradrenaline concentration was also found to correlate with the plasma cholesterol concentration. 6. Our results suggest that an increased plasma cholesterol concentration may be associated with increased sympathetic nervous system activity as indicated by elevated plasma and platelet noradrenaline levels. Increases in circulating catecholamines may contribute to the platelet hyperaggregability seen in familial hypercholesterolaemia.


Best lung function equations for the very elderly selected by survival analysis.
We evaluated which equations best predicted the lung function of a cohort of nonagenarians based on which best accounted for subsequent survival. In 1998, we measured lung function, grip strength and dementia score (Mini Mental State Examination (MMSE)) in a population-based sample of 2262 Danes born in 1905. Mortality was registered to 2011 when only five (0.2%) subjects were alive. In half the cohort, we recorded forced expiratory volume in 1 s (FEV1). Complete data were available in 592 subjects with results expressed as standardised residuals (SR) using various prediction equations. Cox proportional hazard regression found lower FEV1SR was a predictor of mortality having controlled for MMSE, grip strength and sex. The US National Health and Nutrition Examination Survey (NHANES) III (1999) equations gave a better spread of median survival by FEV1SR quartile: 3.94, 3.65, 3.51 and 2.61 years with a hazard ratio for death of 1, 1.16, 1.32 and 1.60 respectively, compared with equations derived with the inclusion of elderly subjects. We conclude that extrapolating from NHANES III equations to predict lung function in nonagenarians gave better survival predictions from spirometry than when employing equations derived using very elderly subjects with possible selection bias. These findings can help inform how future lung function equations for the elderly are derived.


Smoking cessation treatment in community-based substance abuse rehabilitation programs.
Nicotine dependence is highly prevalent among drug- and alcohol-dependent patients. A multisite clinical trial of smoking cessation (SC) treatment was performed at outpatient community-based substance abuse rehabilitation programs affiliated with the National Drug Abuse Treatment, Clinical Trials Network. Cigarette smokers (N=225) from five methadone maintenance programs and two drug and alcohol dependence treatment programs were randomly assigned in a 2:1 ratio to receive either (1) SC treatment as an adjunct to substance abuse treatment-as-usual (TAU) or (2) substance abuse TAU. Smoking cessation treatment consisted of 1 week of group counseling before the target quit date and 8 weeks of group counseling plus transdermal nicotine patch treatment (21 mg/day for Weeks 1-6 and 14 mg/day for Weeks 7 and 8) after the target quit date. Smoking abstinence rates in SC, 10%-11% during treatment and 5%-6% at the 13- and 26-week follow-up visits, were significantly better than those in TAU during treatment (p< .01). In addition, SC was associated with significantly greater reductions as compared with TAU in cigarettes smoked per day (75% reduction, p< .001), exhaled carbon monoxide levels (p< .001), cigarette craving (p< .05), and nicotine withdrawal (p< .05). Smoking cessation did not differ from TAU on rates of retention in substance abuse treatment, abstinence from primary substance of abuse, and craving for primary substance of abuse. Compliance with SC treatment, moderate at best, was positively associated with smoking abstinence rates. Smoking cessation treatment resulted in significant reductions in daily smoking and modest smoking abstinence rates without having an adverse impact on substance abuse rehabilitation when given concurrently with outpatient substance abuse treatment. Substance abuse treatment programs should not hesitate to implement SC for established patients.


Prophylactic phenobarbitone in young children with severe falciparum malaria: pharmacokinetics and clinical effects.
1. A method is described for the measurement of phenobarbitone (PB) by reversed phase high performance liquid chromatography (h.p.l.c.) from small samples of whole blood dried onto filter paper strips. 2. The disposition of PB given prophylactically to young children with severe malaria on parenteral quinine is contrasted with that in aparasitaemic Kenyan children on no antimalarial drugs. There were no differences in the disposition of PB between the two groups. 3. Peak blood PB concentrations were equal to or greater than 15 mg l-1 in 27% of the patients on quinine and 23% of those not on quinine; a concentration of 10 mg l-1 was achieved or exceeded by 100% and 92% of each group, respectively, and was maintained for 39 +/- 24 h (mean +/- s.d.), and 33 +/- 21 h, respectively. 4. In an open, dose-finding study, the progress of young children with cerebral malaria given prophylactic PB (10 mg kg-1), was contrasted with that of controls given no seizure prophylaxis. 5. The drug had no apparent effect on depth or duration of coma, but neither was the incidence of seizures reduced. 6. A controlled trial of prophylactic PB in young children with cerebral malaria is needed, but a larger dose than 10 mg kg-1 should be studied.


Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects.
Fatty acids that contain a trans double bond are consumed in large amounts as hydrogenated oils, but their effects on serum lipoprotein levels are unknown. We placed 34 women (mean age, 26 years) and 25 men (mean age, 25 years) on three mixed natural diets of identical nutrient composition, except that 10 percent of the daily energy intake was provided as oleic acid (which contains one cis double bond), trans isomers of oleic acid, or saturated fatty acids. The three diets were consumed for three weeks each, in random order. On the oleic acid diet, the mean (+/- SD) serum values for the entire group for total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were 4.46 +/- 0.66. 2.67 +/- 0.54, and 1.42 +/- 0.32 mmol per liter (172 +/- 26, 103 +/- 21, and 55 +/- 12 mg per deciliter), respectively. On the trans-fatty-acid diet, the subjects' mean HDL cholesterol level was 0.17 mmol per liter (7 mg per deciliter) lower than the mean value on the diet high in oleic acid (P less than 0.0001; 95 percent confidence interval, 0.13 to 0.20 mmol per liter). The HDL cholesterol level on the saturated-fat diet was the same as on the oleic acid diet. The LDL cholesterol level was 0.37 mmol per liter (14 mg per deciliter) higher on the trans-fatty-acid diet than on the oleic acid diet (P less than 0.0001; 95 percent confidence interval, 0.28 to 0.45 mmol per liter) and 0.47 mmol per liter (18 mg per deciliter) higher on the saturated-fat diet (P less than 0.001; 95 percent confidence interval, 0.39 to 0.55 mmol per liter) than on the oleic acid diet. The effects on lipoprotein levels did not differ between women and men. The effect of trans fatty acids on the serum lipoprotein profile is at least as unfavorable as that of the cholesterol-raising saturated fatty acids, because they not only raise LDL cholesterol levels but also lower HDL cholesterol levels.


Development of quality indicators for the diagnosis and management of achalasia.
The management of achalasia has improved due to diagnostic and therapeutic innovations. However, variability in care delivery remains and no established measures defining quality of care for this population exist. We aimed to use formal methodology to establish quality indicators for achalasia patients. Quality indicator concepts were identified from the literature, consensus guidelines and clinical experts. Using RAND/University of California, Los Angeles (UCLA) Appropriateness Method, experts in achalasia independently ranked proposed concepts in a two-round modified Delphi process based on 1) importance, 2) scientific acceptability, 3) usability, and 4) feasibility. Highly valid measures required strict agreement (≧ 80% of panelists) in the range of 7-9 for across all four categories. There were 17 experts who rated 26 proposed quality indicator topics. In round one, 2 (8%) quality measures were rated valid. In round two, 19 measures were modified based on panel suggestions, and experts rated 10 (53%) of these measures as valid, resulting in a total of 12 quality indicators. Two measures pertained to patient education and five to diagnosis, including discussing treatment options with risk and benefits and using the most recent version of the Chicago Classification to define achalasia phenotypes, respectively. Other indicators pertained to treatment options, such as the use of botulinum toxin for those not considered surgical candidates and management of reflux following achalasia treatment. Using a robust methodology, achalasia quality indicators were identified, which can form the basis for establishing quality gaps and generating fully specified quality measures.


Anti-angiogenic therapy for high-grade glioma.
This is an updated version of the original Cochrane Review published in September 2014. The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma and carries a median survival in treated patients of about 15 months. Glioblastomas are rich in blood vessels (i.e. highly vascular) and also rich in a protein known as vascular endothelial growth factor (VEGF) that promotes new blood vessel formation (the process of angiogenesis). Anti-angiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several anti-angiogenic agents have been investigated in clinical trials, both in newly diagnosed and recurrent HGG, showing preliminary promising results. This review was undertaken to report on the benefits and harms associated with the use of anti-angiogenic agents in the treatment of HGGs. To evaluate the efficacy and toxicity of anti-angiogenic therapy in people with high-grade glioma (HGG). The intervention can be used in two broad groups: at first diagnosis as part of 'adjuvant' therapy, or in the setting of recurrent disease. We conducted updated searches to identify published and unpublished randomised controlled trials (RCTs), including the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE and Embase to October 2018. We handsearched proceedings of relevant oncology conferences up to 2018. We also searched trial registries for ongoing studies. RCTs evaluating the use of anti-angiogenic therapy to treat HGG versus the same therapy without anti-angiogenic therapy. Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles. After a comprehensive literature search, we identified 11 eligible RCTs (3743 participants), of which 7 were included in the original review (2987 participants). There was significant design heterogeneity in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to glioblastomas and there were no eligible studies evaluating other HGGs. Ten studies were available as fully published peer-reviewed manuscripts, and one study was available in abstract form. The overall risk of bias in included studies was low. This risk was based upon low rates of selection bias, detection bias, attrition bias and reporting bias. The 11 studies included in this review did not show an improvement in overall survival with the addition of anti-angiogenic therapy (pooled hazard ratio (HR) of 0.95, 95% confidence interval (CI) 0.88 to 1.02; P = 0.16; 11 studies, 3743 participants; high-certainty evidence). However, pooled analysis from 10 studies (3595 participants) showed improvement in progression-free survival with the addition of anti-angiogenic therapy (HR 0.73, 95% CI 0.68 to 0.79; P < 0.00001; high-certainty evidence).We carried out additional analyses of overall survival and progression-free survival according to treatment setting and for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone. Pooled analysis of overall survival in either the adjuvant or recurrent setting did not show an improvement (HR 0.93, 95% CI 0.86 to 1.02; P = 0.12; 8 studies, 2833 participants; high-certainty evidence and HR 0.99, 95% CI 0.85 to 1.16; P = 0.90; 3 studies, 910 participants; moderate-certainty evidence, respectively). Pooled analysis of overall survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy also did not clearly show an improvement (HR 0.92, 95% CI 0.85 to 1.00; P = 0.05; 11 studies, 3506 participants; low-certainty evidence). The progression-free survival in the subgroups all showed findings that demonstrated improvements in progression-free survival with the addition of anti-angiogenic therapy. Pooled analysis of progression-free survival in both the adjuvant and recurrent setting showed an improvement (HR 0.75, 95% CI 0.69 to 0.82; P < 0.00001; 8 studies, 2833 participants; high-certainty evidence and HR 0.64, 95% CI 0.54 to 0.76; P < 0.00001; 2 studies, 762 participants; moderate-certainty evidence, respectively). Pooled analysis of progression-free survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone showed an improvement (HR 0.72, 95% CI 0.66 to 0.77; P < 0.00001; 10 studies, 3464 participants). Similar to trials of anti-angiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing, and the potential for thromboembolic events, although generally, the rate of grade 3 and 4 adverse events was low (< 14.1%) and in keeping with the literature. The impact of anti-angiogenic therapy on quality of life varied between studies. The use of anti-angiogenic therapy does not significantly improve overall survival in newly diagnosed people with glioblastoma. Thus, there is insufficient evidence to support the use of anti-angiogenic therapy for people with newly diagnosed glioblastoma at this time. Overall there is a lack of evidence of a survival advantage for anti-angiogenic therapy over chemotherapy in recurrent glioblastoma. When considering the combination anti-angiogenic therapy with chemotherapy compared with the same chemotherapy alone, there may possibly be a small improvement in overall survival. While there is strong evidence that bevacizumab (an anti-angiogenic drug) prolongs progression-free survival in newly diagnosed and recurrent glioblastoma, the impact of this on quality of life and net clinical benefit for patients remains unclear. Not addressed here is whether subsets of people with glioblastoma may benefit from anti-angiogenic therapies, nor their utility in other HGG histologies.


Exploring systematic offsets between aerosol products from the two MODIS sensors.
Long-term measurements of global aerosol loading and optical properties are essential for assessing climate-related questions. Using observations of spectral reflectance and radiance, the dark-target (DT) aerosol retrieval algorithm is applied to Moderate-resolution Imaging Spectroradiometer sensors on both Terra (MODIS-T) and Aqua (MODIS-A) satellites, deriving products (known as MOD04 and MYD04, respectively) of global aerosol optical depth (AOD at 0.55 μm) over both land and ocean, and Angstrom Exponent (AE derived from 0.55 and 0.86 μm) over ocean. Here, we analyse the overlapping time series (since mid-2002) of the Collection 6 (C6) aerosol products. Global monthly mean AOD from MOD04 (Terra with morning overpass) is consistently higher than MYD04 (Aqua with afternoon overpass) by ~13% (~0.02 over land and ~0.015 over ocean), and this offset (MOD04 - MYD04), has seasonal as well as long-term variability. Focusing on 2008, and deriving yearly gridded mean AOD and AE, we find that over ocean, the MOD04 (morning) AOD is higher and the AE is lower. Over land, there is more variability, but only biomass-burning regions tend to have AOD lower for MOD04. Using simulated aerosol fields from the Goddard Earth Observing System (GEOS-5) Earth system model, and sampling separately (in time and space) along each MODIS-observed swath during 2008, the magnitudes of morning versus afternoon offsets of AOD and AE are smaller than those in the C6 products. Since the differences are not easily attributed to either aerosol diurnal cycles or sampling issues, we test additional corrections to the input reflectance data. The first, known as C6+, corrects for long-term changes to each sensors' polarization sensitivity, response-versus-scan angle, and to cross-calibration from MODIS-T to MODIS-A. A second convolves the de-trending and cross-calibration into scaling factors. Each method was applied upstream of the aerosol retrieval, using 2008 data. While both methods reduced the overall AOD offset over land from 0.02 to 0.01, neither significantly reduced the AOD offset over ocean. The overall negative AE offset was reduced. A Collection (C6.1) of all MODIS-atmosphere products was released, but we expect that the C6.1 aerosol products will maintain similar overall AOD and AE offsets. We conclude that: a) users should not interpret global differences between Terra and Aqua aerosol products as representing a true diurnal signal in the aerosol. b) Because the MODIS-A product appears to have overall smaller bias compared to ground-truth, it may be more suitable for some applications, however c) since the AOD offset is only ~0.02 and within noise level for single retrievals, both MODIS products may be adequate for most applications.


Finding the center reliably: robust patterns of developmental gene expression.
We investigate a mechanism for the robust identification of the center of a developing biological system. We assume the existence of two morphogen gradients, an activator emanating from the anterior, and a corepressor from the posterior. The corepressor inhibits the action of the activator in switching on target genes. We apply this system to Drosophila embryos, where we predict the existence of a hitherto undetected posterior corepressor. Using mathematical modeling, we show that a symmetric activator-corepressor model can quantitatively explain the precise midembryo expression boundary of the hunchback gene, and the scaling of this pattern with embryo size.


Impact of Risk Adjustment Using Clinical vs Administrative Data on Hospital Sepsis Mortality Comparisons.
A reliable risk-adjusted sepsis outcome measure could complement current national process metrics by identifying outlier hospitals and catalyzing additional improvements in care. However, it is unclear whether integrating clinical data into risk adjustment models identifies similar high- and low-performing hospitals compared with administrative data alone, which are simpler to acquire and analyze. We ranked 200 US hospitals by their Centers for Disease Control and Prevention Adult Sepsis Event (ASE) mortality rates and assessed how rankings changed after applying (1) an administrative risk adjustment model incorporating demographics, comorbidities, and codes for severe illness and (2) an integrated clinical and administrative model replacing severity-of-illness codes with laboratory results, vasopressors, and mechanical ventilation. We assessed agreement between hospitals' risk-adjusted ASE mortality rates when ranked into quartiles using weighted kappa statistics (к). The cohort included 4 009 631 hospitalizations, of which 245 808 met ASE criteria. Risk-adjustment had a large effect on rankings: 22/50 hospitals (44%) in the worst quartile using crude mortality rates shifted into better quartiles after administrative risk adjustment, and a further 21/50 (42%) of hospitals in the worst quartile using administrative risk adjustment shifted to better quartiles after incorporating clinical data. Conversely, 14/50 (28%) hospitals in the best quartile using administrative risk adjustment shifted to worse quartiles with clinical data. Overall agreement between hospital quartile rankings when risk-adjusted using administrative vs clinical data was moderate (к = 0.55). Incorporating clinical data into risk adjustment substantially changes rankings of hospitals' sepsis mortality rates compared with using administrative data alone. Comprehensive risk adjustment using both administrative and clinical data is necessary before comparing hospitals by sepsis mortality rates.


Inferring single-trial neural population dynamics using sequential auto-encoders.
Neuroscience is experiencing a revolution in which simultaneous recording of thousands of neurons is revealing population dynamics that are not apparent from single-neuron responses. This structure is typically extracted from data averaged across many trials, but deeper understanding requires studying phenomena detected in single trials, which is challenging due to incomplete sampling of the neural population, trial-to-trial variability, and fluctuations in action potential timing. We introduce latent factor analysis via dynamical systems, a deep learning method to infer latent dynamics from single-trial neural spiking data. When applied to a variety of macaque and human motor cortical datasets, latent factor analysis via dynamical systems accurately predicts observed behavioral variables, extracts precise firing rate estimates of neural dynamics on single trials, infers perturbations to those dynamics that correlate with behavioral choices, and combines data from non-overlapping recording sessions spanning months to improve inference of underlying dynamics.


The proteome landscape of the kingdoms of life.
Proteins carry out the vast majority of functions in all biological domains, but for technological reasons their large-scale investigation has lagged behind the study of genomes. Since the first essentially complete eukaryotic proteome was reported1, advances in mass-spectrometry-based proteomics2 have enabled increasingly comprehensive identification and quantification of the human proteome3-6. However, there have been few comparisons across species7,8, in stark contrast with genomics initiatives9. Here we use an advanced proteomics workflow-in which the peptide separation step is performed by a microstructured and extremely reproducible chromatographic system-for the in-depth study of 100 taxonomically diverse organisms. With two million peptide and 340,000 stringent protein identifications obtained in a standardized manner, we double the number of proteins with solid experimental evidence known to the scientific community. The data also provide a large-scale case study for sequence-based machine learning, as we demonstrate by experimentally confirming the predicted properties of peptides from Bacteroides uniformis. Our results offer a comparative view of the functional organization of organisms across the entire evolutionary range. A remarkably high fraction of the total proteome mass in all kingdoms is dedicated to protein homeostasis and folding, highlighting the biological challenge of maintaining protein structure in all branches of life. Likewise, a universally high fraction is involved in supplying energy resources, although these pathways range from photosynthesis through iron sulfur metabolism to carbohydrate metabolism. Generally, however, proteins and proteomes are remarkably diverse between organisms, and they can readily be explored and functionally compared at www.proteomesoflife.org.


A novel anti-lymphoma protein RE26 from Rozites emodensis (Berk.) Moser.
A novel antitumor protein, designated RE26, with anti-lymphoma activity was purified from a Tris-HCl buffer extract of Rozites emodensis (Berk.) Moser by three successive steps of ion exchange chromatography. SDS-PAGE and gel filtration chromatography revealed that RE26 is a monomeric protein of 26 kDa, and isoelectrofocusing assay indicated its isoelectric point of 4.3-4.4. RE26 has high stability over a wide pH range (pH 3-11) but is sensitive to temperature and only stable under 40 °C. Partial amino acid sequences of two RE26 peptide fragments were determined by Edman degradation as GLEEEETLLLLFFPP and GTEQE. The half-maximal inhibitory concentration (IC₅₀) of RE26 against tested lymphoma cell lines was around 4 μg/ml. In vitro experiments showed that RE26 could specifically bind to lymphoma cells; activate the caspases, including caspases 3, 8, and 9 in host cells; and induce apoptosis. Experiments in nude mice indicated local RE26 injection adjacent to tumor site could inhibit lymphoma formation.


In vivo (R)-[(11)C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis.
Evidence is accumulating that immune dysfunction is involved in the pathophysiology of schizophrenia. It has been hypothesized that microglia activation is present in patients with schizophrenia. Various in vivo and post-mortem studies have investigated this hypothesis, but as yet with inconclusive results. Microglia activation is associated with elevations in 18 kDa translocator protein (TSPO) levels, which can be measured with the positron emission tomography (PET) tracer (R)-[(11)C]PK11195. The purpose of the present study was to investigate microglia activation in psychosis in vivo at an early stage of the disease. (R)-[(11)C]PK11195 binding potential (BPND) was measured in 19 patients with recent onset psychosis and 17 age and gender-matched healthy controls. Total gray matter, as well as five gray matter regions of interest (frontal cortex, temporal cortex, parietal cortex, striatum, and thalamus) were defined a priori. PET data were analysed using a reference tissue approach and a supervised cluster analysis algorithm to identify the reference region. No significant difference in (R)-[(11)C]PK11195 BPND between patients and controls was found in total gray matter, nor one of the regions of interest. These findings suggest that microglia activation is not present in recent onset psychosis or that it is a subtle phenomenon that could not be detected using the design of the present study.


Remediation of soil contaminated with organic and inorganic wood impregnation chemicals by soil washing.
The aim of this study was to evaluate the efficiency of a large scale washing/wet sieving technique for a soil contaminated with wood impregnation chemicals by 1) defining the final distribution of trace elements (As, Cu, Cr, Zn) and polycyclic aromatic hydrocarbons (PAH) in separated soil particle size fractions; and 2) defining the leaching behavior of the contaminants in these soil fractions. A soil washing experiment was implemented at waste management facility in Sweden using a full scale soil sorting and washing equipment. Five tons of soil was loaded to the equipment and wet-sieved into the following fractions: >16 mm, 8-16 mm, 2-8 mm, 0.2-2 mm, <0.2 mm and a fraction that floated on top of the slurry before the final separation phase, composed of organic matter (OM). Analysis of total concentrations of contaminants in all soil fractions indicated that wet sieving/soil washing was not efficient to reduce the total volume of soil that needs further treatment. Even the coarsest soil fractions (>8 mm) contained elevated concentrations of total As and PAH. Leaching of As from all washed soil fractions was so high, that none of the particle size fractions could be disposed of without additional treatment.


Evolution and Diversity of the Wild Rice Oryza officinalis Complex, across Continents, Genome Types, and Ploidy Levels.
The Oryza officinalis complex is the largest species group in Oryza, with more than nine species from four continents, and is a tertiary gene pool that can be exploited in breeding programs for the improvement of cultivated rice. Most diploid and tetraploid members of this group have a C genome. Using a new reference C genome for the diploid species O. officinalis, and draft genomes for two other C genome diploid species Oryza eichingeri and Oryza rhizomatis, we examine the influence of transposable elements on genome structure and provide a detailed phylogeny and evolutionary history of the Oryza C genomes. The O. officinalis genome is 1.6 times larger than the A genome of cultivated Oryza sativa, mostly due to proliferation of Gypsy type long-terminal repeat transposable elements, but overall syntenic relationships are maintained with other Oryza genomes (A, B, and F). Draft genome assemblies of the two other C genome diploid species, Oryza eichingeri and Oryza rhizomatis, and short-read resequencing of a series of other C genome species and accessions reveal that after the divergence of the C genome progenitor, there was still a substantial degree of variation within the C genome species through proliferation and loss of both DNA and long-terminal repeat transposable elements. We provide a detailed phylogeny and evolutionary history of the Oryza C genomes and a genomic resource for the exploitation of the Oryza tertiary gene pool.


Hsa-microRNA-1249-3p/Homeobox A13 axis modulates the expression of β-catenin gene in human epithelial cells.
Intercellular adhesion is a key function for epithelial cells. The fundamental mechanisms relying on epithelial cell adhesion have been partially uncovered. Hsa-microRNA-1249-3p (hsa-miR-1249-3p) plays a role in the epithelial mesenchymal transition in carcinoma cells, but its physiological function in epithelial cells is unknown. We aimed to investigate the role and molecular mechanisms of hsa-miR-1249-3p on epithelial cell functions. Hsa-miR-1249-3p was overexpressed in human epithelial cells and uterine cervical tissues, compared to cervical carcinoma cells and precancerous tissues, respectively. Hsa-miR-1249-3p was analyzed to verify its regulatory function on Homeobox A13 (HOXA13) target gene and its downstream cell adhesion gene β-catenin. Functional experiments indicated that hsa-miR-1249-3p inhibition prompted the mRNA and protein overexpression of HOXA13 which, in turn, led to the β-catenin protein expression. Moreover, hsa-miR-1249-3p inhibition induced a strong colony forming ability in epithelial cells, suggesting the miR involvement in cell adhesion machinery. These data indicate that hsa-miR-1249-3p regulates the expression of HOXA13 and its downstream cell adhesion gene β-catenin, possible resulting in cell adhesion modification in epithelial cells. This study will allow the set-up of further investigations aimed at exploring the relationship between the hsa-miR-1249-3p/HOXA13 axis and downstream cell adhesion genes.


Evaluation of 99Tcm nonspecific polyclonal IgG in the detection of rejection in a single lung transplant canine model.
Acute rejection is an important cause of graft failure in single lung transplantation, however, current noninvasive tests are neither sensitive nor specific for this diagnosis. The aim of this study was to determine whether 99Tcm-labelled human nonspecific polyclonal IgG (99Tcm-IgG) may serve as a marker for acute pulmonary rejection following allotransplantation in a dog model. Seventeen mongrel dogs were studied, including four controls and thirteen dogs which underwent surgery [right autotransplant recipient (n = 4), right unmodified allotransplant recipient (n = 5), and right immunosuppressed allotransplant recipient (n = 4)]. At 6 days following surgery, all dogs received 67Ga-citrate and 99Tcm-IgG. Two days later all dogs were sacrificed. Post-mortem examination revealed acute lung rejection in nine animals. No significant difference was found in the percentage uptake of both 99Tcm-IgG and 67Ga-citrate per gram of tissue between rejecting and nonrejecting transplanted lungs. In cases of moderate to severe rejection (n = 5), only 67Ga-citrate showed a significant difference (P = 0.03) in uptake between rejecting and contralateral native lungs, respectively. We conclude that 99Tcm-IgG does not accurately identify acute lung rejection in the early postoperative period.


[Global agenda of the social movements].
The social global movements of health marked the decade of 90. The debate on Global Health is a constituent part of this article aiming at understand the new social struggles in the field of public health. The training of social movements that act as a whole provide a critical review on public health through the articulation and organisation of global causes brought by activists of the field of health. In Brazil, the focus of analysis is the World Social Forum of Health - a movement that was organized from the sum of other global and social struggles that won prominence in South America such moves the profile of public health policy for the State in the last decade and brought questions about the organisation of the new social movements.